Prostate Cancer

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Chapter 10. PROSTATE CANCER
Acknowledgments: Hema Samaratunga, Chris Schmidt, Mark Frydenberg, John Yaxley for their guidance and advice in preparation of this document and to the authors of the previous edition Mitchell H Sokoloff, William B Isaacs, and Leland WK Chung.

I. INTRODUCTION
Prostate Cancer is an increasingly common diagnosis in Western societies and in those emulating Western lifestyles and diets. In the year 2001 there were estimated to be 198,100 new cases and almost 31,900 deaths attributable to this condition in the United States (1). Approximately one in seven American men will be diagnosed with prostate cancer during their lifetime, making it the most common solid tissue cancer in the United States. Despite advances in prevention and early detection, reﬁnements in surgical technique and improvements in adjuvant radio-therapy and chemotherapy, the ability to cure many patients with prostate cancer remains elusive. However, mortality rates are changing. Baade et al recently reviewed international trends in prostate cancer mortality and reported signiﬁcant reductions in prostate-cancer mortality in the UK, USA, Austria, Canada, Italy, France, Germany, Australia and Spain with downward trends in the Netherlands, Ireland and Sweden (2). Detection of this disease earlier, as a consequence of introduction of the prostate speciﬁc antigen (PSA) blood test, has been acknowledged by the NCI as one factor contributing to lowering the mortality rate over the past few years (3-6). The use of PSA testing has been estimated to provide a diagnostic lead-time of up to 10 years (7-11). In the mid to late 1980s only one third of prostate cancers were diagnosed at curable stages compared with today when 80% are staged clinically as organ-conﬁned and potentially curable (12-14). Unfortunately, however, even when the tumour is thought to be localized, up to 25% of men have non-localised disease which declares itself subsequently (15). Since curative therapies are directed to localised tumours (3,4,7,16), extending effective but non-invasive treatments to include both primary and secondary lesions remains a major goal and challenge. Once prostate cancer metastasizes, apart from causing loss of life, its toll is often considerable with regard to morbidity from both the disease itself and administered therapies. As a result of increasing numbers of men having their prostate cancers diagnosed earlier, more patients are now eligible for treatment with curative intent. Improved surgical and radiation-based treatments have been developed so that the prognosis of a man diagnosed today with prostate cancer is better than ever before.

II. ANATOMY AND PHYSIOLOGY
The term "prostate", originally derived from the Greek word prohistani which means "to stand in front of," has been attributed to Herophilus of Alexandria who used the term in 355 B.C.E. to describe the small organ located in front of the bladder (17). The prostate gland is a small ﬁrm organ, about the size of a chestnut, located below the bladder and in front of the rectum. The urethra, the channel through which urine is voided, passes from the bladder and through the prostate and penis. The primary function of the prostate gland, which contracts with ejaculation, is to provide enzymes to maintain the ﬂuid nature of seminal ﬂuid and to nourish sperm as they pass through the the prostatic and penile urethra to outside the body.

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Chapter 10. PROSTATE CANCER

III. NATURAL HISTORY OF PROSTATE DISEASE
Traditionally, prostate cancer was considered a disease of "older men." As such, it was generally accepted that "men never died from prostate cancer, they died of other conditions with prostate cancer." Consequently, treatment was conservative and directed toward palliation and prevention of the emergence of debilitating and painful sequelae. In addition, diagnosis was generally made on the basis of palpating a rockhard and nodular prostate on digital rectal exam [DRE] or by symptoms and signs of primary or secondary tumors, such as urinary obstruction, back pain, nerve root or, less commonly, spinal cord compression. Almost invariably, most tumors had already disseminated at the time of diagnosis and, therefore, were incurable. It was in the mid-1980s, with the introduction of the PSA blood test that prostate cancer began to be diagnosed earlier and in younger men. Although methods of diagnosis and treatment of localized disease have become wellestablished, the management of prostate cancer remains controversial due to its variable biologic course, imprecision with clinical staging and limitations in prediction of the clinical outcome of patients with both organ-conﬁned and locally-invasive disease - not to mention the morbidity associated with all currently established treatments. It is sobering to muse that, were the unwanted effects of diagnosis and treatment insigniﬁcant, the dilemma of whether or not to treat would not be an issue.

IV. BASIC SCIENCE OF PROSTATE CANCER
(i) Introduction
As described in the previous section the prostate consists of two major cellular types, the stroma and the epithelium. The stromal component is comprised of smooth muscle cells, ﬁbroblasts and endothelial cells; 5 cell sub-types, basal epithelium, secretory epithelium, transit amplifying cells, neuroendocrine cells and stem cells, constitute the epithelium Prostate cancer is non-regulated proliferation primarily of the epithelium. A number of factors may contribute to dedifferentiation and proliferation of epithelial cells, including aberrations in surrounding stromal cells via cytokines and growth factors secreted by both stromal and epithelial cell types (18,19). To date, the exact triggers for development of prostatic adenocarcinoma have not been elucidated, although epidemiological studies have shown links to both environmental (discussed subsequently) and genetic contributors. A variety of growth factors and cytokines have been shown to inﬂuence the growth rate and development of prostatic cancers, and a number of proteins and genes have been identiﬁed whose regulation and/or function are altered between malignant and benign states. Several of these proteins and genes have been ﬂagged as potential biomarkers and therapeutic targets for prostate cancer. This chapter will provide an overview of the current literature, and will discuss factors that contribute to the development and progression of PCa, as well as the potential of new biomarkers for diagnosing and treating this disorder.

A Genetics of Prostate Cancer
Genetic aberrations, whether inherited or acquired, are universally associated with cancer development, growth, and progression. Several cancer types, such as breast, renal and colorectal, have been shown to have a familial component (20). In an effort to identify important genetic determinants associated with hereditary prostate cancer, a number of research groups have employed different methodologies involving large-scale populations (epidemiology), families (with one or more affected individuals) and twins. 2

Chapter 10. PROSTATE CANCER

(i) Epidemiology:
Major genetic epidemiologic studies published in the last two decades support the notion that prostate cancer may exist as clusters in families. In the 1980s, a Utah Mormon genealogy study found that prostate cancer exhibited the fourth strongest degree of familial clustering after lip, melanoma, and ovarian cancers . Prostate cancer, interestingly, had a higher familial association than either colon or breast carcinoma, which are known to be predisposed by genetic or familial components. A later study, determined cancer pedigrees in 691 men with prostate cancer and 640 spouse controls, and found a positive familial history of prostate cancer . They concluded that men with an affected father or brother were twice as likely to develop prostate cancer as men with no affected relatives. Although these studies strongly suggest that familial clustering of prostate cancer risk does exist, they did not address the underlying aetiological mechanisms. Indeed, familial clustering can reﬂect either shared environmental and lifestyle risk factors, or a genetic mechanism, or indeed both. In order to address the inherent difﬁculties in separating the inheritable and environmental causes of prostate cancer, the International Consortium for Prostate Cancer Genetics (ICPCG) was formed. In early 2005 they published a world-wide study of 1,233 families located in North America, Australia, and Europe. While the study included some families with Asian, Hispanic, Native American and African-American backgrounds, 1,166 of the 1,233 families were Caucasian. The researchers found 5 regions (5q12, 8p21, 15q11, 17q21 and 22q12) in human chromosomes that potentially could harbour cancer susceptibility genes. In addition, the authors ﬂagged chromosomal regions which linked to families with 5 or more affected members (22q12, 1q25, 8q13, 13q14, 16p13 and 17q21) and those which corresponded with early onset of disease (less than 65 years; 3p24, 5q35, 11q22, and Xq12) . While, to date, there are no known cancer susceptibility genes in these loci, work is ongoing to reﬁne the mapping of these regions to the gene level.

(ii) Twin Studies:
Twin studies compare the similarities (concordance rate) of a trait or traits, traced to either monozygotic (MZ) or dizygotic (DZ) twins to dissect the relative genetic and environmental inﬂuences of a disease. Several twin studies (although with limited subject numbers) of prostate cancer reported higher concordance rates in MZ twins compared to DZ twins, implicating a genetic contribution for prostate cancer. Lichtenstein et al (2000) (24) analyzed Swedish, Finnish and Danish twin registries and concluded that the recurrent risk in the twin of an affected man was 21.1% for MZ and 6.4% for DZ. More recent mathematical modeling of genetic risk of a number of cancers, by the same research group (25), found that the contribution of genetic susceptibility to prostate, breast, and colorectal cancers was small to moderate. Although these aforementioned studies clearly demonstrated a potential genetic basis of prostate cancer, albeit low, for a portion of familial prostate cancers, this rate is much lower than coeliac disease where strongly heritable components were found in 75% of the MZ with 11% prevalence in ﬁrst-degree relatives . The signiﬁcant differences in the contribution by the heritable element on the development of prostate cancer, as opposed to coeliac disease, suggest the importance of gene-environment interaction, which may be pivotal in prostate carcinogenesis.

(iii) Gene Association Studies:
In addition to hereditary prostate cancer-associated genes, a number of studies have focused on genetic components that may be associated with prostate cancer development. Association studies are generally case-control studies based on the comparison of frequencies of an allele in unrelated cases and normal controls. A signiﬁcant difference in allele frequency between cases and controls can be expected if a particular allele harbours causal variations or if that allele is closely linked with (or in close proximity to) a disease-causing mutation. These types of association studies are sus3

Chapter 10. PROSTATE CANCER ceptible to aetiological (genetic versus environmental), inheritance (dominant, recessive, or X-linked), and locus heterogeneity, as well as allelic (same gene but different mutations) and founder (same mutation in different genetic background) heterogeneity. Despite these difﬁculties, association studies have identiﬁed genes that may be associated with, or contribute to, prostate cancer development and progression. 1. BRCA1 and BRCA2 BRCA1 and BRCA2 genes, linked to breast cancer development, have also been examined in prostate cancer due to links between these cancers’ aetiology, observed through epidemiologic, biologic, and molecular studies (27, 28). Recent association studies demonstrated an increase in the frequency of BRCA1 and BRCA2 mutations in prostate cancer carriers . The most recent studies have shown that the rate of prostate cancer diagnosis after age 60 in cases with a deleterious mutation in BRCA1 or BRCA2 was 5.2% compared with 1.9% of controls. . In addition, data reported thus far show that mutations of BRCA1 and BRCA2 may increase the risk of prostate cancer, particularly in the case of BRCA2 for early-onset disease. The contribution of germ line mutations in these genes to familial clusters of prostate cancer needs to be more fully assessed.

2. Androgen Receptor Pathway Androgens serve as a most important ligand for prostate cancer, stimulating growth via the androgen receptor action pathway. The androgen receptor action pathway, broadly deﬁned, includes the androgen receptor, the 5-alpha-reductase gene and the various members of the cytochrome p450 family. Mutations within the AR gene are detected in 10 – 20% of prostate cancer specimens, with mutations more common in hormone escape than hormone sensitive specimens . The androgen receptor (AR) is comprised of three important domains: N-terminal transactivation domain, DNA binding domain, and C-terminal steroid binding domain. Mutations in the N-terminal transactivation domain include variations in the number of polymorphic triplet repeats located within this area of the gene . Several studies have suggested that AR genes with shorter repeat lengths may increase the risk of developing more aggressive prostate cancer, as the number of polyglycine repeats is inversely related to the ability of the AR to activate target genes . Mutations at the steroid-binding domain have been associated the promiscuous nature of AR which recognizes non-androgen ligands, such as oestrogen, progesterone, and antiandrogens as agonists that confer AR-induced gene transactivation and growth stimulatory activities (36). Overall, the increase in incidence of mutations and the variety of mutations observed in the AR in metastatic cancers, suggest that these regions of AR heterogeneity may be acquired through gene-environment interactions. Ampliﬁcation or duplication of the AR gene has been associated with the transition from hormone sensitive to hormone refractory tumours. Edwards et al, (2003) (37) found that less than 5% of hormone sensitive prostate cancers contained more than one copy of the AR gene, compared with 20-30% of hormone resistant tumours. In 80% of these cancers there was a corresponding increase in AR protein concentrations. However, it was the presence of the gene duplication and not just higher AR protein levels which signiﬁcantly predicted poorer survival rates for patients in their study . Alterations in the 3-beta-hydroxysteriod dehydrogenase gene (also a member of the AR pathway) have also been strongly associated with hereditary prostate cancer . 3-beta-hydroxysteroid dehydrogenase metabolises dihydrotestosterone to 3-alphaand 3-beta-diol. Recently Guerini et al (2005) have found that 3-beta-diol does not bind androgen receptors but efﬁciently binds the estrogen receptor (ER-beta), and exerts an inhibitory effect on prostate cancer cells through the activation of ER-beta signaling. Subsequently, deletiorous mutations in the 3-beta-hydroxysteriod dehydrogenase gene are thought to confer a growth advantage to cancer cells. 4

Chapter 10. PROSTATE CANCER Although the androgen receptor pathway dominates in hormonal-tumour interactions in prostate cancer, other relationships are also operative. As well as oestrogens having an increasingly recognised role, the growth hormone secretagogue ghrelin and a preproghrelin isoform have been shown to be highly expressed in prostate cancer with activation via the protein kinase pathway (39). Both inhibin and activin subunits are known to be expressed in the normal prostate with the inhibin alpha subunit gene down regulated in prostate cancer with a loss of heterozygosity at the gene locus and methylation of the promoter (40). Overexpression of the activin betaCsubunit has been demonstrated to increase activin AC heterodimer levels, concomitantly reducing activin A levels and decreasing activin signaling in PC3 cells (41).

(iv) Clinical and pathological characterization of hereditary Prostate Cancer
To determine what differences might distinguish hereditary prostate cancer from its sporadic counterparts, a number of clinical features of prostate cancer were examined by Carter, et al. . Clinical stage at presentation, pre-operative PSA, ﬁnal pathologic stage, and prostate weight were examined in a series of approximately 650 patients divided among three categories. Individuals were classiﬁed as having hereditary disease if 3 or more relatives were affected in a single generation, prostate cancer occurred in each of 3 successive generations in either paternal or maternal lineages, or 2 relatives were affected under the age of 65 years. For the other groups, either no other family members were affected (sporadic disease), or other family members were affected but not to the extent found in families classiﬁed as hereditary. In summary, no unique clinical or pathological characteristics distinguished hereditary prostate cancer in this group of patients. This parallel between hereditary and sporadic prostate cancer extends to the incidence of multifocality found in both of these categories.

(v) Other molecular changes in Prostate Cancer
While mutations or gene duplications have been associated with familial prostate cancers, other molecular changes have been documented in the majority of prostate tumours. Although the mechanisms behind these changes have not always been elucidated, it is believed that changes in gene methylation patterns, gene expression proﬁles and expression of non-coding mRNA’s play important roles in cancer development and progression. 1. Silencing of gene expression by CpG methylation One of the mechanisms used by cells to alter gene expression is by conjugation of a methyl group on certain cytosine residues in the gene promoter. In a normal cell this may function to maintain cellular differentiation, but recent reports have described several genes which are abnormally silenced, or activated, in many tumour types including prostate cancer, by promoter methylation. . Lodygin et al, (2005) (43) described many genes, including cell cycle regulating genes, angiogenesis inhibitors, apoptosis inducing genes, growth factor receptors and transcriptional control genes that are “switched off” in prostate cancer. The “switch” could be thrown into reverse by treatment with 5-aza-2’ deoxycytidine, a chemical that removes methyl groups from cytosine residues. A study of 41 primary tumours from prostate cancer patients found that frequencies of CpG methylation detected in the promoter region of a selection of the above genes were as follows, GPX3 (Glutathione peroxidase – detoxiﬁcation), 93%; SRFP1 (Secreted frizzled-related protein 1 – signaling), 83%; COX2 (cyclooxygenase 2 –signaling) 78%; DKK3 (Dickkopf homologue 3 – signaling) 68%; GSTM1(Glutathione S-transferase M1 - detoxiﬁcation), 58% and KIP2/p57 (cell cycle control), 56%.

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Chapter 10. PROSTATE CANCER The authors also found that methylation in some gene promoters did not always equate to reduced transcription rates, and that some genes apparently “switched on” after 5-aza-2’ deoxycytidine treatment did not show detectable CpG methylation. They concluded that silencing of genes by CpG methylation occurs at an early stage of prostate cancer development. This may have implications for the use of certain methylation events as diagnostic markers for prostatic disease (44). Recently, global methylation in the chromosomes of prostate cancer cells has been studied with speciﬁc antibodies that detect all CpG sites, both in gene promoters and elsewhere in the chromosomes (45). Interestingly, the overall amount of methylation in tumour cells was decreased when compared with benign cells from the same individuals. It was also noted that men with recurrent disease and/or positive surgical margins showed overall higher levels of methylation in their tumour cells compared with men with early stage, surgically curable disease (45). Brothman et al, (2005) (45) suggest that genomic hypermethlyation is associated with condensed DNA. Hypomethylation of these regions permits a reduction of DNA condensation and may result in chromosomal rearrangement and genetic instability. In addition they suggest that global DNA hypomethlyation precedes hypermethylation of speciﬁc gene promoters (such as GSTP1) in cancer development, and the balance between the two methylation states may be critical in determination of aggressive vs non-aggressive disease (45). However, whether CpG methylation is a cause or consequence of cancer remains to be shown.

2. Non-coding mRNA’s: With the rise of microarray technologies, analyses of changes in multiple gene transcription rates have been described. Interestingly, some changes in the transcriptional output of the human genome points to the existence of a signiﬁcant number of noncoding RNA transcripts, derived from intronic genomic regions, with some of these being oriented antisense relative to the protein-coding mRNA of the gene. To investigate the expression level of intronic messages in human tissues, a subset of approximately 2,000 totally intronic Expressed Sequence Tags (EST) clusters and 2,000 clusters from exonic segments of known genes, was selected for intronic microarray analysis. Hybridization of these intronic microarrays with 27 prostate tumours and corresponding adjacent normal tissue revealed that in prostate cancer, the fraction of expressed messages arising from exonic or intronic transcripts were similar . Moreover, the expression levels of 23 intronic non-coding transcripts correlated (p value - 0.001) with the degree of prostate tumour differentiation. It has not been determined whether the expression of intronic antisense RNAs in tumours is a true mechanism of cancer disregulation or just reﬂects broad errors in promoter recognition/transcription initiation. However, regulatory elements have been identiﬁed for a number of non-coding RNA’s, including DD3/PCA3 and PCGEM1 – see below.

B. Stromal Epithelial Interaction in Prostate Cancer
While a variety of genetic and environmental determinants may contribute to the cause of malignancy, cancer cells display similar phenotypes and modes of development such as changes in cell adhesion, attachment, migration and invasion. These phenotypes and the genes controlling them are in turn regulated by epigenetic factors, such as soluble proteins, steroids and growth factors released by immune cells and adjacent stromal cells (e.g. ﬁbroblasts, smooth muscle cells, endothelial cells, and neuroendocrine cells) and alterations in the extracellular matrix (ECM) surrounding tumor epithelium . Reciprocal cellular interaction between stroma and epithelium is involved in foetal prostate development, post-natal prostate growth and maturation, maintenance of differentiation status, hormonal responsiveness, and the aging and senescence 6

Chapter 10. PROSTATE CANCER of prostate gland in adulthood ). During neoplastic progression, key phenotypic changes in prostate cancer cells are also modulated by a dynamic, two-way communication between tumour epithelium and various stromal cells, including ﬁbroblasts, smooth muscle cells, vascular endothelium and bone-derived cells including osteoblasts . All of these cell types and the factors they secrete form the cell’s microenvironment that can either enhance or repress cancer development and progression. One of the challenges in understanding carcinogenesis is determining how the tumour microenviroment interacts with genetic changes in the cells themselves.

(i) AR-mediated cell communication
Experimental evidence using co-cultured human benign prostatic hyperplasia (BPH)-derived stromal and epithelial cells indicate that the expression of AR, PSA, and 5 alpha-reductase in epithelial cells relies on the inductive inﬂuence of neighbouring stromal cells . Similarly, in co-cultured rat prostatic epithelial and ﬁbroblast cells, the androgen responsiveness of prostate epithelial cells can be conferred by the presence of ﬁbroblastic cells . Therefore the action of AR in prostate development is mediated by the local stroma. In addition, oestrogens have been shown to have a role in cancer development, yet the oestrogen receptor is predominantly localized in stromal cells. . Animal models have demonstrated prostatic cell proliferation occurs in androgen deﬁcient mice due to exogenous oestrogen. . In addition, elevated androgen levels in oestrogen deﬁcient mice induced prostatic hyperplasia . While neither of these hormones alone induced prostate cancer, combined androgen and oestrogen therapy did evoke prostatic dysplasia and adenocarcinoma. It is proposed, therefore, that both androgens and oestrogens inﬂuence the process of prostate carcinogenesis . The function of androgen ablation therapy (ABT) is to prevent activation of AR regulated genes. Failure of ABT, as in hormonally resistant prostate cancer, was logically linked to genetic modiﬁcation of the AR, as described above. More recently however, there has been recognition of the effect of post-translational modiﬁcations on the AR . In 1998, Blok et al. demonstrated phosphylation of the AR in response to binding by the ligand DHT (dihydrotestosterone). In addition to stabilizing the active AR homodimers, this phosphorylation can inﬂuence AR mediated gene activation . In vivo, phosphorylation of AR by MAPK (serine-threonine kinase) and AKT (protein kinase B) sensitizes AR to low levels of DHT, allowing low levels of androgens, or alternative steroids to induce translocation of the AR to the nucleus, facilitating gene activation . MAPK has been shown to be activated in cell lines derived from hormone-refractory tumours, and is correlated with advanced stage and grade in prostate cancer . While the exact mechanism is not fully known, transfection of cells with c-Ras (cell growth regulator; activated in many cancer types), leads to increased activation of MAPK and development of hormone escape . AKT can be activated via PI3 kinase pathway (involved in cell growth, adhesion and migration in many tumours; (69), and specifically phosphorylates AR at Ser210 and Ser790 (70)– see Figure 1 The control of AR function also involves interaction of the receptor with a number of co-factors or proteins that bind either as part of a complex or directly to AR and increase (co-activators) or inhibit (co-repressors) the transcriptional activity of the AR. Co-activators include CBP (CREB-binding protein), beta-catenin, ARA55 and ARA70 which all act to alter ligand speciﬁcity of the AR . These mechanisms include allowing the antiandrogens such as hydroxyﬂutamide (CBP, ARA70) and bicalutamide (ARA70) to act as agonists and/or by permitting low concentrations of adrenal androgens or oestradial to activate AR (ARA55, beta-catenin, ARA70; . Some co-activators activate AR in the absence of ligands, such as SRC-1, SRC-3, p300, Tip60, and c-Jun. C-Jun binds to the AR, promoting homodimerization and subsequently activating AR dependent transcription initiation of downstream genes (such as PSA) . SRC-1 and SRC-3 are members of the steroid receptor cofactor family, which is commonly overexpressed in hormone-refractory prostate cancer. This 7

Chapter 10. PROSTATE CANCER family of proteins normally facilitates AR transcriptional activity in the presence of androgens, however, phosphorylation of SRC-1 by MAPK (activated as discussed above), may be one mechanism by which SRC-1 activates AR in the absence of androgens. Tip60 is linked to the transcription activation activity of AR by inducing changes to AR acetylation. In cell line models, in the absence of androgens, p300 is required for Il-6 (see below) stimulated growth, and it has been proposed that p300 plays an important role in the development of hormone refractory tumours .

Figure 1. Phosphorylation of the androgen receptor (AR) by MAPK and AKT. Numerous signalling factors (intracellular and extracellular), involved in inducing cell growth and proliferation, stimulate the Ras pathway to activate MAPK. Subsequently, MAPK phosphorylates AR, enabling AR to form dimers, enhancing ARE (androgen response element) dependent gene expression. Similarly, intraand extra-cellular factors inducing cell growth and migration and inhibiting cell adhesion activate the PI3 kinase pathway resulting in AKT dependent phosphorylation, dimerisation and activation of AR. A less well understood mechanism of AR co-activators involves movement of AR to the nucleus. In LNCaP cells, STAT3 binds ligand-free AR and facilitates its translocation to the nucleus, and it is via this mechanism that the STAT3/AR complex activates AR dependent genes (in the absence of androgens) in response to IL-6 stimulation .

(ii) Soluble Factors in Cell signalling
The mediation of stromal-epithelial interactions in the normal and malignant prostatic environment involves a number of soluble factors that can serve paracrine, autocrine or intracrine functions (72). Several soluble factors have been identiﬁed performing a variety of functions from angiogenesis, growth enhancement, and dedifferentiation. These are listed in Table 1 (72). Table 1. Most commonly cited soluble factor signaling pathways regulating prostate growth and differentiation (from Chung et al., 2005 [19]) 8

Chapter 10. PROSTATE CANCER Soluble Growth Factor References Name Source Receptor Receptor Location Function Regulation at Androgen Independent Progression Disease prognosis neg correlation Disease prognosis pos correlation van Moorselaar RJ, 2002) van Moorselaar RJ, 2002) Knudsen BS, 2004; LailTrecker M, 1998

VEGF

Epithelium, stroma

VEGFR-1, Epithe2 lium, stroma

Angiogenic factor

bFGF (FGF-2)

Stroma

FGF-2R

Epithelium, stroma

Angiogenic factor

HGF/SF

Stroma

c-met

Disease Epithelium Stimulates progression pos cell correlation growth Stroma Induces apoptosis, increases angiogenesis stimulates stromal but inhibits epithelial cell growth

TGF-beta

TGF-beta Epithelium I-III receptors

AugBachman, mented 2004 and expres2005; sion at Yingling, androgen 2004 withdrawal

IGF-I

Stroma

IGF-IR

Epithelium, stroma

UpDjavan B, Stimulates regulation 2001; cell at disease Rubin, growth, 2003 blocks Progression apoptosis Promotes differentiation and apoptosis inhibition Increasing IL-6 signaling during disease progression Edwards, 2005a and b; Hideshima., 2005; Royuela M, 2004

IL-6

Epithelium, stroma

IL-6R, sIL-6R

Epithelium, stroma

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Chapter 10. PROSTATE CANCER Soluble Growth Factor References (KGF) (FGF-7) Stroma Gp130 KGF-R StimuEpithelium lates cell Growth Stromal Planz, KGF ex1999 and pression 2004 responded to androgen

1. VEGF Recruitment of neovascular endothelial cells to proliferating cancer cells is thought to be required for the maintenance and stimulation of tumour growth, and is mediated by vascular endothelial growth factor (VEGF) and its receptors. VEGF has been shown to be secreted by both glandular and surrounding stromal cells, and VEGF expression can be modulated by a number of treatments including androgen ablation, ﬁnasteride, and thalidomide .

2. IL-6 High levels of IL-6 secretion from prostate ﬁbroblasts, smooth muscle cells, and tumour cells themselves, are thought to be a mechanism of ligand independent activation of AR activation via the PI3K-Akt, STAT3 and MAPK pathways in PCa . Interference with IL-6 signaling is a potential means of modulating the growth of advanced prostate cancer. Importantly, IL-6 is secreted by bone marrow stromal cells (BMSCs), and this secretion is further augmented by direct interaction between tumour cells and BMSCs . Studies using an anti-IL-6 monoclonal antibody have shown tumoricidal effects in a murine model

3. IGF-1 The insulin-like growth factor-I (IGF-I) pathway is involved with malignant transformation in various tissues. In prostate cancer, it has been proposed that IGF-1 induces ligand-independent activation of the androgen receptor and enhances the expression of matrix metalloproteinase-2 and urokinase plasminogen activator (see next section, insoluble cell signalling). Progression to androgen independence has also been linked to deregulation of the IGF-1-IGF-1-receptor axis (76). Manipulations of the IGF axis have shown therapeutic potential, for example, antisense RNA to IGF-I receptor inhibits prostate cancer proliferation and invasion, while increasing IGF binding protein 3 expression induces cell death .

4. HGS/SF, EGF and bFGF HGS/SF, EGF and bFGF are all members of a large family of heparin bound growth factors. Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the c-met proto-oncogene, were shown to be predominantly expressed by localized and metastatic prostate cancer. Experimental evidence suggests that HGF/SF and c-met downstream signaling may regulate prostate cancer growth and metastasis through enhanced IL-6, androgen receptor, extracellular matrix and integrin interaction . Epidermal growth factor (EGF) its receptor (EGFR), and other family members, erbB2/neu, erbB3 and erbB4, are known to have a role in prostate cancer progression through their interactions with a broad spectrum of soluble factors and their downstream converging signaling pathways (81, 82). 10

Chapter 10. PROSTATE CANCER 5. TGF-beta Transforming growth factor beta type 1 is a ubiquitous cytokine originally named for its ability to transform ﬁbrolasts in culture (83). TGF-beta both inhibits the growth of normal epithelial cells, but paradoxically can induce cancer cell proliferation and promote an Epithelial to Mesenchymal transition (EMT). The mammalian TGF-beta family has 3 subtypes, and can bind to three cell surface receptors (type I, II and III). The type II receptor functions as a tumor repressor gene, and absence of this receptor results in resistance to the growth inhibitory effects of TGF-beta. This growth factor also stimulates angiogenesis, extracellular matrix turnover and host immune surveillance, although the receptors mediating this function have not been well deﬁned (84). TGF-beta speciﬁc inhibitors have been developed and have been proposed to have utility in treatment of progressive prostate cancer .

(ii) Insoluble factors and the Extracellular Matrix in Cell signalling
At the stromal /tumor cell interface of adenocarcinomas, there is a noticeable derangement of Extracellular Matrix (ECM), due mainly to the activity of enzymes derived from the host stroma. (72). However, the mechanisms of this breakdown of ECM are unknown, and whether cancer cell invasion develops before or after interacting with host stroma, or whether stroma response is subject to reciprocal regulation by cancer cells remains undetermined. De Wever, and Mareel (2003)(86) suggest that the maintenance of epithelial homeostasis requires the participation of stroma, and therefore it is likely that stromal changes are subsequent to epithelial aberrations. ECM and its degradative products could signal to cancer cells through their cell surface integrin or non-integrin associated receptors. Subsequently, cell behaviours, such as cell polarity, secretion, adhesion, motility and invasion, and integrated cell functions, such as proliferation, differentiation and survival could be affected. 1 Integrins Integrins are a family of heterodimeric, transmembrane receptors that mediate the attachment of cells to the surrounding ECM and function as sensors of the environment. Alterations in integrin expression and signaling have been implicated in many aspects of tumorigenesis and metastasis including cell survival, migration, and invasion. In prostate cancer, the progression from normal to metastatic cells is accompanied by changes in the repertoire of integrins expressed and up-regulation of key adhesion-dependent signaling pathways . Important mediators of Integrin signaling include the adhesion kinases FAK (focal adhesion kinase) PAK (p21 activated kinase) and MAPK (a serine/threonine kinase) . Potentially, Integrins may have more complex roles by coordinating their actions with metalloproteinases and serine proteases, which together may increase cancer cell invasion and migration into secondary sites of cancer growth (72).

2. FAK Overexpression and increased phosphorylation of FAK has been shown in a variety of tumours and these changes correspond to a malignant and metastatic phenotype . FAK has been shown to promote cell surface expression of metalloproteinases, particularly MT1-MMP. This results in activation of other MMP’s – particularly MMP2 enabling ECM degradation and tumour cell invasion .

3.MMP’s: Matrix metalloproteinases (MMPs) are involved in tumour invasion and metastasis in various malignancies. MMP-2 and MMP-9 are capable of digesting collagen type IV, a signiﬁcant component of basement membranes, and have been implicated in 11

Chapter 10. PROSTATE CANCER prostate cancer progression and metastases ). Preliminary studies show the stimulation of protease induced receptors produced increased levels of MMP-2 and MMP-9 activity in prostate cancer cell lines, indicating their potential role in the metastasis of prostate cancer cells . A crucial role for MMP-9 has been demonstrated in the colonization of bone by prostate cancer cells . Net MMP-9 activity in bone tissues peaked 2 weeks after injection of prostate cancer cells (PC-3), coinciding with a wave of osteoclast recruitment. In vitro, co-culture of PC3 cells with bone tissue led to activation of pro-MMP-9 and increased in secreted MMP-9 activity. Activation of pro-MMP-9 was prevented by metalloprotease inhibitors but not by inhibitors of other classes of proteases. The authors concluded that their data suggested that osteoclast-derived MMP-9 may represent a potential therapeutic target in bone metastasis . MMP-2 has been implicated in initiation of metastases, that is in promoting the movement of tumour cells from the primary lesion into the lymphatic or circulatory systems , but does not appear to have a role in bone metasteses colonisation . Recently inhibition of MMP-2 by genistin, a form of dietary soy, via MAPK and TGF-beta, was demonstrated. This study suggested a physiological role for genestin and conﬁrmed epidemiological studies which demonstrated that dietary intake of genisten was associated with lower rates of metastatic prostate cancer .

4. Urokinase Plasminogen activator The plasminogen plasmin proteolytic cascade is a multi-functional pathway which facilitates a spectrum of biological processes including ECM remodelling during wound healing and tumour invasion, and metastasis. The urokinase-type plasminogen activator (uPA) and its receptor (uPAR), initiate this cascade by converting plasminogen to plasmin. Plasmin subsequently degrades a range of ECM components and activates MMPs (see above) (95-98). Over expression of uPA or uPAR is a feature of a number of malignancies, including prostate, and is correlated with tumour progression and metastasis. In contrast, inhibition of expression of uPA or uPAR or inhibition of uPA and uPAR interaction leads to a reduction in the invasive and metastatic capacity of many tumors (96, 98-100).

5. Kallikreins Kallikreins (KLKs) are highly conserved serine proteases that play key roles in a variety of physiological and pathological processes . Possibly the best known KLK with respect to prostate cancer is KLK3 or PSA. Recently, two other androgen regulated KLK’s have been shown to have altered expression in PCas, KLK2 and KLK4 . The protein product of KLK2, (glandular kallikrein; hGK2) is secreted in ejaculate, and like PSA has been shown to have a number of substrates (105). In particular, KLK2 can proteolyse several IGFB’s (IGFB-2, -3, -4 and -5) more efﬁciently and at lower concentrations than PSA, and potentially may stimulate the IGF axis. KLK4 may also play a role in the IGF axis by activating pro-PSA/KLK3 which induces IGF activity by cleaving IGFB-3. PSA (KLK3) also cleaves latent pro-transforming growth factor-beta (TGF-beta) to active TGF, thereby regulating prostatic cell growth and bone homeostatis. In addition, it has also been suggested that PSA also plays a role in degradation of laminin (the ECM glycoprotein), stimulating cell invasion through the ECM. Both KLK2 and KLK4 can activate pro-uPA to active uPA, initiating the plasminogen plasmin proteolytic cascade (see above). KLK2, can also inactivate plasminogen activator inhibitor-1, repressing regulatory control of the plasminogen plasmin proteolytic cascade. (105) Overexpression studies have shown that KLK4 induces transcriptional repression of E-cadherin, with associated increase in vimentin . Veveris-Lowe et al (2005) (106) concluded that the loss of E-cadherin and associated increase in vimentin are indicative 12

Chapter 10. PROSTATE CANCER of EMT and that KLK4, may have a functional role in the progression of prostate cancer through promotion of tumour cell migration.

C. Molecular Markers of Prostate Cancer.
One of the challenges in diagnosing prostate cancer is the heterogeneity of the disease phenotypically. As described above, alterations occur in cancer cells at many levels, both pre and post transcriptionally (in the genome and transcribed RNA), and post translational protein modiﬁcations (such as phosphorylations). The quest for reliable prostate cancer markers to identify cancer cells in blood, bone marrow, urine, prostatic tissue itself and semen, has embraced a number of candidate biomarkers in addition to PSA. Many methods have been used to identify potential markers for prostate cancer, including analysis of gene expression (microarrays and quantitative PCR) and protein marker (histopathology, Mass-spectrophotometry) changes between disease and non-disease states. Interestingly it has been noted that the genes, their transcription rates and subsequent proteins altered in prostate cancer can be grouped into a number of cellular pathways. These include cell adhesion, cell-cycle regulation, cell signaling, angiogenesis and apoptosis. Some of these proteins and genes have been discussed above, and therefore only their applicability as diagnostic/prognostic or therapeutic targets will be discussed in this section. Table 2. Summary of molecular aberrations in prostate Cancer (Modiﬁed from Quinn et al., European Journal of Cancer 41 (2005) 858–887 [107]) Process Apoptosis Key molecules/markers p53, Bcl-2, Clusterin References Downing SR, 2003 Augustin, 2003; Rubio, 2005; Scaltriti, 2004a; Scaltriti, 2004b Chung, 2005; Williams, 2005; Yang; 2004 Edwards, 2005a and b Quinn, 2005; Epstein 2005; Verambally, 2002 Quinn et al, 2005; Burger, 2002; Haese A, 2005; Kurek R, 2004; Lintula S, 2005; Steuber T, 2005; Stephenson et al, 1999; Ang, 2004 Quinn et al, 2005; Burger, 2002; Chang, 2004 Bussemakers, 1999; Landers, 2005; ; Schalken et al., 2005; Kumar-Sinha, 2004; Jiang, 2004; Srikantan V, 2002; ; Zhigang, 2005; 13

Signal transduction

TGF-beta, KGF, EGF, Caveolins AR c-Myc, p16INK4A, p27KIP1, pRb, apoptotic index, Ki67 p53, EZH2 E-cadherin, alpha-catenin, delta-catenin, metalloproteinases, kallikreins, CD151

Cell cycle regulation

Cell adhesion and cohesion

Angiogenesis Other Molecular Markers

VEGF, VEGF receptors, nitric oxide, PSMA AMACR; DD3/PCA3; pCGEM-1; Hepsin; PSCA

Chapter 10. PROSTATE CANCER 1. Cell Signalling markers As previously discussed, cell-cell signaling is mediated by a number of soluble and insoluble proteins and factors. These include growth factors, such as TGF-beta, EGF and IGF, and cytokines such as Il-6. Several of these factors have utility as biomarkers, such as TGF-beta and, as mentioned above, inhibitors to several of these compounds have been developed (72). Caveolins are major structural proteins of Caveolae, specialized plasma membrane invaginations that are abundant in smooth muscle cells, adipocytes, and endothelium, and act as regulators of signal transduction (108). In a number of tumour models (including prostate) caveolin-1 has been implicated in oncogenic cell transformation and subsequent metastasis. Studies on knock-out mice and in breast cancer models, indicate that caveolin-1 normally functions as a negative regulator of cell transformation and tumorigenesis. However, in prostate cancer caveolin-1 may function as a tumour promoter, potentially via both genetic and post-translational modiﬁcations (108). In addition, a recent study showed that c-Myc and caveolin-1 immunopositivity correlated positively with Gleason score (P = 0.0253) and positive surgical margin (P = 0.0006). Yang (109) found that the combination of positive c-Myc and caveolin-1 in patients with clinically conﬁned prostate carcinoma was a signiﬁcant prognostic marker for disease progression after surgery. As described above, changes in the androgen receptor have been long associated with prostate cancer development. While alterations in the function of this gene appear to be critical for cancer progression, these alterations occur at many levels, both in the genome (such as point mutations) and also post transcriptional and translational (ie at the RNA and protein levels (62, 63). Therefore using detection of any one of these changes as a screening tool for prostate cancer has not yet been shown to be practicable.

2. Cell Adhesion markers Aberrant expression of cell-cell adhesion molecules (C-CAMs) is often associated with the development of tumours. Decreased expression of many C-CAMs including E-cadherin, have been associated with the progression of prostate cancer and several other types of neoplasm (107). While CD44, another cell adhesion molecule, has been associated with prostate cancer, there have been inconsistencies across the few studies as to the prognostic value of this marker . While the loss of these molecules may be useful in immuno-histopathologically- based diagnoses, molecular based proﬁling may depend more on overexpressed molecules. Therefore, the activity of MMP’s 2 and 9, uPA and uPAR, and KLK2, 3 (PSA) and 4 (see above) in interfering with cell adhesion, may prove to be more relevant Both KLK2 mRNA and its protein product, hK2, have been examined for efﬁcacy as stand alone biomarkers or in combinations with other known biomarkers such as PSA . Thus far none of the published studies has found KLK2 to be useful prognostically and it appears to have limited diagnostic value; only one study has found that KLK2 (measured by quantitative PCR) in combination with PSA distinguishes cancers from BPH . A recent study from China found that a functional C748T polymorphism in KLK2 may be associated with increased risk for developing prostate cancer. The frequency of the CC, CT and TT genotypes was 65.7%, 32.7% and 1.6% in patients with prostate cancer and 56.0%, 37.5% and 6.5%, respectively, in controls (p = 0.010). Therefore, C allele carriers (CC and CT genotypes) were at signiﬁcantly higher risk for prostate cancer than TT homozygous subjects (p = 0.002) . As noted previously, KLK4, has also been associated with prostate cancer (114). The KLK4 protein product, hK4, is the ﬁrst member of the KLK family that is intracellularly localized , and KLK4 expression is regulated by androgens, oestrogen and progesterone in prostate cancer cells. In situ hybridization on normal and hyperplastic 14

Chapter 10. PROSTATE CANCER prostate samples indicated that KLK4 is predominantly expressed in the basal cells of the normal prostate gland and overexpressed in prostate cancer . Some cell adhesion associated molecules such as CD151, a member of the tetraspanin family which interacts with integrins (see above), may prove to be relevant prognostically. CD151 plays a role as a link between extracellular matrix and intracellular structures, and increased protein levels of CD151 in well and moderately differentiated prostate cancers correlate with disease relapse subsequent to radical prostatectomy (115)

3. Markers of apoptosis Apoptosis or programmed cell death is part of cell growth and cycling in normal and benign cells. In cancers, key regulators of apoptosis can be pro-apoptotic or antiapoptotic such as p53 and Bcl-2 respectively, show abnormal function and expression. While there are many genes and proteins which fall into this category, many are also cell cycle regulators (such as p21 and p16) and will be discussed below. The pro-apoptotic protein p53 regulates transcription of genes required for G1-phase growth arrest of cells in response to DNA damage. Mutant p53 protein accumulation in malignant cell nuclei has been shown to be a poor prognostic indicator in several human carcinomas including breast, lung and colorectal (107). Mutations in p53 have been shown to be a common event in early stage, organ-conﬁned prostate cancer and the loss of p53 function via expression of viral or cellular oncoproteins also seems common (116). A number of studies have reported that p53 nuclear accumulation in ≥ 20% of tumour cells is adversely prognostic (117). Although using p53 as a diagnostic marker has been debated due to the heterogeneity of expression within tumours, Quinn et al (2000 & 2005) (107, 117), propose that p53 has great potential as a prognostic marker as metastatic, recurrent and androgen resistant cancers show higher number of cells with p53 immunoreactivity compared with primary tumours. Bcl-2 was initially identiﬁed as an apoptosis-inhibiting proto-oncogene in B-cell lymphomas. Its value as a diagnostic marker is unclear with some groups showing that only limited numbers of prostatic tumours express Bcl-2 (118, 119). However, other researchers have shown correlation with Bcl-2 and poor prognostic outcomes, with increased numbers of high-grade and metastatic tumours having Bcl-2 immunoreactivity . Also Bcl-2 overexpression in tumours has been associated with resistance to radiotherapy (123). Subsequently many scientists are looking at Bcl-2 inhibitors (such as transgenes, and antisense RNA oligonucleotides) as a means of sensitizing Bcl-2 expressing tumours to chemo and radiotherapies (125). Another study showed that testosterone-repressed prostate message-2 (TRPM-2), also known as clusterin or sulfated glycoprotein-2, was elevated following androgen withdrawal in both normal and malignant tissues . In prostate adenocarcinoma, TRPM-2/clusterin expression may be useful as both a diagnostic and prognostic marker, with increased TRPM-2/clusterin protein expression evident in prostate cancer (96%) compared with BPH (73%) and normal prostate epithelium (17%) . Pins et al (2004) (129) indicated that TRPM-2/clusterin immunoreactivity in stromal cells surrounding the tumour epithelium predicted PSA relapse but staining within the primary tumour epithelium was not prognostic. The anti-apoptotic function of TRPM-2/clusterin is well documented, both by overexpression studies and through the activities of TRPM-2/clusterin speciﬁc inhibitors (124). However, some studies have shown pro-apoptotic functions of TRPM-2/clusterin in PC-3 androgen-independent prostate cancer cells. Cells overexpressing an intracellular, non secreted form of TRPM-2/clusterin showed signal-independent nuclear localization of the protein - leading to G2-M phase blockade followed by caspase-dependent apoptosis (127, 131). While TRPM-2/clusterin is an attractive target for theraputics, caution is warranted as it seems to have a number of functions 15

Chapter 10. PROSTATE CANCER in cell cycle and apoptosis, with the nuclear form (nClu) being proapoptotic while the secreted form (sClu) has prosurvival effects (131).

4. Cell cycle Regulators as markers Genetic aberrations in the control of progression in the cell cycle are present in most human cancers (107). There are many molecules involved in this process whose expression is altered in prostate cancer, including the cyclin family, RBp (retinoblastoma protein), p16, p21, p27, p53, Smad4, FHIT, and PTEN/MMAC1. Increased expression of p16 and p21 has been associated with poorer prognostic outcomes, and while loss of RBp and p27 may also have some prognostic value, further studies are warranted (107, 110). Strong expression of EZH2, a catalytic subunit of the polycomb repressor complex 2, in clinically localized prostate cancer is related to poor prognosis . EZH2 is also overexpressed in hormone refractory prostate cancers (133). Regulation of EZH2 is controlled by the E2F3 transcription factor and recently Foster (2004) (134) showed that nuclear expression of E2F3 in 20% or more of prostate epithelial cells is also an indicator of an unfavourable clinical outcome.

5. Markers of Angiogenesis As discussed above, angiogenesis or blood vessel growth is an essential factor in cancer growth and progression (135). A key component in angiogenesis, VEGF, is highly expressed in most prostate cancers and has value prognostically (107). A number of VEGF and VEGF-R antibodies and peptide antagonists have been developed with the speciﬁc goal of targeting the neovasculature and growing cancer cells. This targeting pathway may become highly important since hypoxia is a known important factor that induces VEGF production . Another molecule whose expression has been associated with angiogenesis is PSMA (prostate-speciﬁc membrane antigen) which is expressed by both tumor epithelium and tumour associated endothelial cells and neovasculature (137). A number of researchers, (138-140)have made a series of antibodies against the external domain of this protein, which have been used both pre-clinically and clinically for the diagnosis and therapy of prostate cancer. Chromosomal localization of PSMA gene, however, is controversial. It has been mapped to two regions, chromosome 11p11-12 and 11q14 and it has been proposed that a PSMA-like gene may exist in one of the two chromosomal regions through the process of gene duplication. Our research group has shown that a speciﬁc PSMA transcript has applicability as a biomarker for prostate cancer, particularly when used in combination with other gene transcripts (such as DD3/PCA3) (143, 144). PSMA may function as a ligand internalising receptor, an enzyme playing a role in nutrient uptake, and a peptidase involved in signal transduction in prostate epithelial cells (145).

6 Other molecular markers A number of other gene transcripts have been identiﬁed which may have utility as diagnostic and prognostic markers that do not ﬁt into the catergories discussed above. These include Hepsin a transmembrane serine protease, AMACR, (alpha16

Chapter 10. PROSTATE CANCER methylacyl-CoA racemase), PSCA (prostate Stem cell antigen) and the non-coding RNA’s DD3 and PCGEM-1. Hepsin, a type II transmembrane serine protease is differentially expressed in prostate cancer compared with normal and BPH affected prostate tissue (144, 146). Interestingly, in-vitro studies in prostate cell lines found that Hepsin overexpression had growth inhibitory effects . More recently a model for Hepsin and tumour progression was found when the soluble form of Hepsin was found to activate HGF (hepatocyte Growth Factor) . Potentially, antagonists to Hepsin and subsequently HGF activation could be useful therapeutically. Alpha-methylacyl-CoA racemase (AMACR) overexpression in prostate and other cancer tissues has been well characterized at both the mRNA and protein levels (151-153). This enzyme functions in the peroxisomal beta oxidation of branched-chain fatty acid molecules and has been implicated in the link between high meat high fat diets and the increased incidence of prostate cancer observed by many epidemiological studies (154). AMACR immunohistochemistry is being used in conjunction with normal Haemotoxylin and Eosin staining to aid in the diagnosis of prostate cancer histologically (128, 155, 156). As with many of the markers already mentioned clinicians are ﬁnding that using AMACR in conjunction with other prostatic markers gives better diagnostic results than AMACR alone (J153, 157). Molinie (2004)(157) showed that basal cells of normal prostatic glands stained with p63 in 100% of cases, while carcinomas had a p63-/AMACR+ proﬁle, PIN were p63+/AMACR+, and benign lesions were p63+/AMACR-. Recently a number of splice variants of the AMACR transcript have been described which may be relevant for strategies targeting AMACR expression such as RNA antisense oligonucleotides (158). PSCA was identiﬁed as a cell surface antigen expressed by prostate cancer cells and is regulated by the androgen receptor ). It is central to the development of the prostate gland and could provide a new diagnostic and therapeutic target for PCa (161). PSCA overexpression has more recently been shown in pancreatic and urothelial tumor models (162-164) and has been proposed as a target antigen with immuno-based therapeutics (165, 166). DD3/PCA3 was identiﬁed by differential display technology in 1999 as a non-coding RNA highly speciﬁc to prostate cancer . Subsequently a number of researchers have conﬁrmed the over-expression of DD3 (144,168) in a number of different cohorts. More recently the uPM3 (Bostwick) test has utilized this detection of this RNA in a PCR based assay in urines of prostate cancer patients. Two independent studies showed signiﬁcant improvements in detecting cancer compared with the use of PSA alone (169, 170). Tinzl (2004)(169) reported 82% sensitivity, 76% speciﬁcity for the uPM3 assay compared to 98% sensitivity, 5% speciﬁcity, for tPSA (at a cutoff of 2.5 ng/ml). In the tPSA categories <4, 4-10 and >10 ng/ml sensitivity was 73%, 84% and 84% and speciﬁcity was 61%, 80% and 70%, respectively (169). The Canadian-based study (170) sampled 517 patients undergoing biopsy at ﬁve centres, for which 86% had an assessable sample. The overall uPM3 sensitivity and speciﬁcity in this sample group was 66% and 89%, respectively. Once again, in the tPSA categories <4, 4-10 and >10 ng/ml, the sensitivity of the uPM3 assay was 74%, 58% and 79% with speciﬁcity of 91%, 91% and 80% respectively. The positive predictive value of uPM3 was 75% compared with 38% for total PSA. (170). PCGEM1, also a putative non-coding RNA was also identiﬁed by differential display analysis of paired normal and prostate cancer tissues, with subsequent Northern blot analysis of tissues showing that PCGEM1 was expressed exclusively in the human prostate. In-situ analysis showed tumor associated overexpression in 84% of prostate cancer patients while reverse transcription PCR assays revealed tumour-associated overexpression in 56% of patients . Interestingly PCGEM1 over-expression has been shown to be signiﬁcantly higher in prostate cancer cells of African-American men than in Caucasian-American men (P=0.0002). In addition, ‘normal’ prostate epithelial cells from prostate cancer patients with a family history of prostate cancer also displayed increased PCGEM1 expression (P=0.0400). A physiological role for PCGEM1 17

Chapter 10. PROSTATE CANCER in cell growth regulation has been suggested, with cells transfected with PCGEM1 displaying cell proliferation and an increase in colony formation .

D Future Directions
Recently the focus of some studies has changed from identiﬁcation of individual markers to utilising combinations of known prostate cancer-speciﬁc markers as predictors of disease recurrence after treatment with curative intent (172, 173). In our laboratory we have investigated the utility of using combinations of biomarkers in a PCR based diagnostic assay for prostate cancer. We found that using a combination of Hepsin, DD3 and PSMA allowed us to distinguish 100% of prostate tumour from BPH tissues (144). As with diagnosis, it has been proposed that a number of genes can be used to build a “ﬁngerprint” of an aggressive tumour . The challenge remaining is how to apply this information in biologically relevant samples such as serum, ejaculate and urine sediments. With the development of methods that allow large scale gene expression proﬁling, such as microarrays and quantitative RT-PCR, the list of genetic alterations in prostate cancer cells has increased dramatically. Now the same technology is being applied to proteins (proteomics). These advances in technology should allow the scientist to determine that genetic changes translate into the proteome and identify post-translational modiﬁcations which are biologically signiﬁcant in cancers. Although this chapter has attempted to summarise the current literature, this area of science is ever-expanding and subsequently there are many other biomarkers for prostate canceer, and other cancers which may be relevant in PCa, that were not discussed. Over the past decade there has been an explosion of research into the basic science of prostate cancer. Consequently, we are developing new paradigms for understanding the natural history of the disease as well as creating novel approaches to therapy. Later in this chapter, some of these advances will be discussed in further detail. Currently, surgery and radiation therapy are the conventionally accepted primary treatment modalities for localized prostate cancer. However, with the advent of new molecular-based therapies, combination therapy using surgery and/or radiation with these novel agents has been proposed as a method of improving therapeutic outcomes. More importantly, molecular-based therapies are being studied in phase I, II, and II trials in men with advanced and hormone-refractory prostate cancer, for which no curative therapies currently exist.

V. PREVENTION OF PROSTATE CANCER
Introduction
Predisposition to any cancer can be considered in terms of environmental and extrinsic factors, such as foods and interventions, and intrinsic or inherent susceptibility related to the person’s genes apportioned at conception. For prostate cancer in particular, many people hold strong opinions regarding various strategies to avoid contracting it and for treatment of the condition, very often without any clear evidence of beneﬁcial effect. It should be borne in mind that many advocated supplements and unconventional therapies are expensive and, although some ultimately may be proven to be of beneﬁt, many will not and some may be harmful.

18

Chapter 10. PROSTATE CANCER

Dietary & Natural Therapies
(i) Dietary fat and animal meat
A body of epidemiological data links high meat consumption and a diet rich in saturated fats with an increased risk of prostate cancer. (175-177). As stated in the previous section, alpha-methylacyl-CoA racemase (AMCR), an enzyme involved in oxidation of fatty acid molecules, has been implicated in the link between high fat diets and prostate cancer (154). Fatty acids in dietary fats can be divided into essential and non-essential with the former consisting of omega-6 (linoleic acid derived) and omega-3 fatty acids (which are linolenic acid in origin). Current evidence suggests that omega-3 fatty acids offer a protective role. (178, 179). Mutagens in cooked meats and fat, which include heterocyclic amines and polycyclic aromatic hydrocarbons, are known to be activated by cytochrome p450 and N-acetyl transferase enzymes in the prostate to produce an increase in markers of dietary stress. (180). These, in turn, generate reactive oxygen species (ROS) leading to mutation of DNA base pairs and oncogene expression. Another mode of action invoked is degradation of omega-6 fatty acids via the arachidonic acid pathway production of prostaglandin and lipoxygenase products which, in addition to resulting in inﬂammation, are known to decrease apoptosis, stimulate proliferation and induce angiogenesis. (181-184).

(ii) Lycopene
The relevance of the anti-oxidant lycopene, an isomer of β -carotene, has been reported in relation to various cancers, including prostate, in a number of epidemiological studies. Lycopene, which is the carotenoid responsible for the red colour in tomatoes is thought to have a protective effect as an inverse relationship has been observed between tomato intake or blood lycopene level and the risk of cancer. (180, 185, 186)

(iii) Selenium & vitamin E
The essential micronutrient selenium is present in water and food, especially seafood, meats and Brazil nuts. In countries with selenium-poor soils such as New Zealand, locally produced foodstuffs may be low in selenium content. A number of epidemiological studies have reported an increased risk of prostate and other cancers with selenium deﬁciency and, conversely, a reduced incidence of prostate cancer with selenium supplementation. (187, 188). Selenium is a component of many proteins, such as glutathione peroxidase which is a key enzyme in surveillance against oxidative stress, involved in maintenance of genomic stability. (189). In addition to an effect in reducing tumour initiation, selenium is considered to have an inhibitory effect in relation to progression by blocking cellcycle arrest through down-regulation of CDK1, CDK2 and cyclin A and activation of p19/INK4d and p21/WAF1. (190). Gianduzzo et al (2003) (191) demonstrated in a randomised, controlled trial that oral selenium supplementation resulted in signiﬁcantly higher levels of this compound in prostatic tissue removed at transurethral resection of the prostate (TURP). Importantly, these investigators also found that blood and prostate levels correlated poorly, suggesting that peripheral blood measurements are a poor indicator of prostatic selenium content (191). Vitamin E is present in a wide range of foods which include vegetables, vegetable oils, nuts and egg yolks. Through its most active form, α-tocopherol, vitamin E causes G1 cell-cycle arrest via cell regulatory proteins D1, D3 and E and cdk2 and cdk4. (190) In the Alpha-Tocopherol, Beta-Carotene study in the United States, a one-third reduction in prostate cancer incidence and a 40% reduction in prostate cancer deaths 19

Chapter 10. PROSTATE CANCER were reported in men taking vitamin E (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994) Currently, 2 large prevention studies are in progress to evaluate selenium and vitamin E supplementation. SELECT (Selenium and Vitamin E Cancer Prevention Trial) is American based and APPOSE (Australian Prostate cancer Prevention Trial Using Selenium) are expected to produce results in the next few years (180, 192).

(iv) Soy products/isoﬂavones/green tea
Dietary differences between people living in Asian countries and those in the West correlate with marked differences in prostate cancer incidence. However, with adoption of western dietary patterns, there is an increase incidence of diseases of afﬂuence, such as diabetes mellitus, breast, colorectal and prostate cancer (193). These traditional differences have been attributed to the high content of soy, tofu and isoﬂavinoids in many traditional asian diets. (194, 195). The major isoﬂavone components of soy, including genistein, daidzein and their metabolites, have been shown to inhibit benign and malignant prostatic epithelial cell growth, down-regulate androgen-related genes and reduce tumour growth in some animal models (190). Huang et al (2005) (94) reported inhibition of MMP-2 by genistein via MAPK and TGF-beta. This study suggested a physiological role for genestin and conﬁrming epidemiological studies which demonstrated that dietary intake of genisten was associated with lower rates of metastatic prostate cancer . deVere-White et al (2005)(196) very recently presented their experience with GCP, a proprietary nutritional supplement, the major constituents of which are genestine and diadzin. The preparation functions as a tyrosine kinase inhibitor and facilitates entry of prostate cancer cells into apoptosis. For13 men on active surveillance for their prostate cancer, six months of GCP resulted in a lowering of PSA; the trial is ongoing (196). Dalais et al (2004)(197) studied 29 men diagnosed with prostate cancer and scheduled to undergo RRP who were randomized to one of three groups; soy (high phytoestrogen), soy and linseed (high phytoestrogen), or wheat (low phytoestrogen) in the form of specially prepared breads. Their ﬁndings indicated that a daily diet containing four slices of a bread rich in soy grits favourably inﬂuenced the PSA level and the free/total PSA ratio in patients with prostate cancer, providing supportive evidence for epidemiological studies claiming that men who consume high phytoestrogen diets have a reduced risk of prostate cancer development and progression (197). Schröder et al (2005) (198) reported on 49 patients with rising serum PSA levels after radical prostatectomy (n = 34) or radiotherapy (n = 15) who participated in a randomised, double-blind, placebo-controlled crossover study of a dietary supplement of soy, isoﬂavones, lycopene, silymarin and antioxidants as main ingredients. The soy-based dietary supplement delayed PSA progression in a signiﬁcant fashion with a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods (198). An integral part of most asian diets, green tea has had many beneﬁts accorded to it, often through association with other dietary components. In terms of its affect on inhibiting prostate cancer development, it is thought to provide a beneﬁt through the presence of polyphenols (also present in red wine) which induce apoptosis and inhibit proliferation via WAF1/p21 cell- cycle effects (190)

Pharmacological
(i) COX-2 Inhibition
Continuous use of Nonsteroidal anti-inﬂammatory drugs (NSAIDs), in particular as20

Chapter 10. PROSTATE CANCER pirin, has been reported to reduce the likelihood of development of several malignancies, including prostate cancer (199). Indeed, aspirin and other NSAIDs have been considered to decrease the risk of developing prostate cancer by 24-66% (200-2002) Non-selective NSAIDS such as aspirin inhibit both cyclooxygenase (COX-1 & COX-2) enzymes with the COX-2 isoform believed to be the relevant one in terms of prostate cancer development. COX-2 converts arachidonic acid to prostaglandin so both nonspeciﬁc and speciﬁc COX-2 inhibitors act at this site, although some speciﬁc COX-2 inhibitors may have other actions as well. Speciﬁc COX-2 inhibition by celecoxib and nimesulide has been reported to reduce expression of several androgen-inducible genes, repress androgen-receptor mediated activation of PSA and hK2 promoter activity and repress androgen receptor protein expression. (203). Cost implications aside, the recent reporting of previously unappreciated serious side-effects with two prominent COX-2 inhibitors, rofecoxib and celecoxib, have resulted in some reluctance to change from using NSAIDS to selective COX-2 inhibitors for prostate cancer prophylaxis.

(ii) Finasteride
Based on the observations that androgens are necessary for the development of prostate cancer and that men with a congenital deﬁciency of the 5-α-reductase type 2 enzyme do not develop prostate cancer, a 7-year randomised, controlled trial with the drug ﬁnasteride was undertaken with 18 882 men who were >55 years, had a normal prostate on digital rectal examination and a PSA of <3 ng/ml. The study was ended 15 months prematurely because the end-point had been reached and continuing the trial would not have changed the outcome. Men who received ﬁnasteride, which inhibits conversion of testosterone to dihydrotestosterone (DHT) by targeting the 5-α-reductase type 2 enzyme, had a prostate cancer prevalence reduction of 24.8% (24.4% to 18.4%. However, the prevalence of Gleason 7-10 tumours was higher in the ﬁnasteride arm (6.4% versus 5.1%) although 98% of the tumours were clinically localised. (204). Klein et al (2005) (205) have questioned the validity of the conclusion in relation to the rate of clinically-signiﬁcant prostate cancer detection in this trial. They present a model of risk and beneﬁt that estimates the potential inﬂuence of histological artefact (due to ﬁnasteride-induced effect on prostatic epithelial appearances) in the assignment of excess risk for high-grade disease and possible overdetection bias introduced by ﬁnasteride-induced volume reduction in prostates for the treated patients (205). A further industry-sponsored study, the REDUCE (Reduction by DUtasteride in prostate cancer Events) trial is in progress. In this randomised, controlled study involving 8 000 men with PSA values between 2 and 10 ng/ml dutasteride, which inhibits both isoforms of the 5-α-reductase enzyme, is being used in the treatment arm. All patients in this trial are being biopsied at least twice during the study unlike the ﬁnasteride study in which prostatic biopsies were recommended if the annual PSA (adjusted for the effect of ﬁnasteride) exceeded 4 ng/ml or if the digital rectal examination was abnormal. Recent research suggests that inhibition of the irreversible action of 5α-reductase to convert testosterone to the more transcriptionally active dihydrotestosterone may have untoward effects in relation to prostate cancer. Dihydrotestosterone in turn is hydroxylated to 3α-diol and 3β -Adiol which do not bind to the androgen receptor but have a strong afﬁnity for oestrogen receptors, the result of which is thought to have a direct effect on prostate development and homeostasis (206). The binding of 3β -Adiol to oestrogen receptor beta (ERβ ) induces expression of the cell adhesion molecule E-cadherin, loss of which is associated with a more aggressive phenotype in prostate cancer cells (38).

21

Chapter 10. PROSTATE CANCER

Conclusion
The genesis of prostate cancer is multifactorial, with changes arising over a considerable period of time. Consequently, with respect to preventative or ameliorating measures, it is axiomatic that these should be implemented early and sustained for longer rather than shorter duration if their beneﬁcial effects are to be maximised.

VI. DIAGNOSING PROSTATE CANCER
A. Introduction
Indisputably, early detection and treatment of prostate cancer are more effective than ever before with a consistent decline in mortality rates in many Western countries (2). However, this statement does not accomodate the fact that many men continue to die with prostate cancer and that the consequences of this tumour and its treatments may contribute signiﬁcantly to the demise of many of these men, both directly and indirectly. Albertsen et al (207, 208) estimated that, for conservative treatment, men with moderately and poorly differentiated tumours lost approximately 4-5 years and 6-8 years of life, respectively, compared with those with well-differentiated tumours whose life-expectancies were little different to age-matched controls (207, 208). This problem of identifying patients with the more aggressive cancers is relevant to men of all ages, consistent with the ﬁndings of Parker et al (2001) (209) who concluded in their meta-analysis that age is not a signiﬁcant prognostic factor in contemporary clinical practice (209). Using the SEER database, Lu-Yao and Yao (1997) (210) found that the disease-speciﬁc 5 year survival for poorly differentiated tumours was 63-69% (210). Albertsen et al (2005) (211), reporting on 767 men diagnosed between 1971 and 1984 and treated without curative intent, found that, for low-grade prostate cancers (Gleason 2-4), men have a minimal risk of dying from prostate cancer during 20 years of follow-up. Those with Gleason scores of 5 or 6 have an intermediate risk of prostate cancer being the cause for their demise but patients with high-grade prostate cancers (Gleason 8-10) have a high probability of dying from prostate cancer within 10 years of diagnosis (211). The zeal to diagnose and treat must be tempered by realisation that neither detection nor therapeutic intervention may be in the best interests of many men. Establishing the right balance between the beneﬁts and disadvantages of diagnosis and treatment is problematical and, consistent with the variation in the natural history of prostate cancer, it is not difﬁcult for the unwanted effects of intervention to be worse than the disease being treated. Of necessity, it is important to recognise that the risks of competing mortalities are very different for men of different ages. Based on Queensland data, Baade et al (2005) estimated that about 60% of men diagnosed in their 50s could be expected to die a premature death (ie, before reaching 80 years of age) from prostate cancer compared with corresponding rates of 50% and 38% for men diagnosed at 60 and 70 years. Thus, for a 50 year-old man, a diagnosis of prostate cancer is more likely to result in a premature death from prostate cancer than for men diagnosed in their 70s (212). Hence, whether or not to diagnose the condition should be a carefully considered decision.

B. Making Decisions about whether or not to diagnose Prostate cancer
While prostate cancer is the most common male malignancy in the developed world and the second most common cause of cancer deaths, uncertainties remain about management practices at several points in the illness continuum. For example, owing to a lack of deﬁnitive data conﬁrming that widespread screening for prostate cancer will reduce the death rate from this disease, population-based screening for 22

Chapter 10. PROSTATE CANCER prostate cancer in asymptomatic men is not currently recommended in most countries . Rather, it is suggested that men should be able to access PSA testing as long as they are fully informed of the pros and cons of testing. For those diagnosed with localised prostate cancer, further decisions present with three possible treatment options at a minimum: watchful waiting, radiation therapy, or RRP - extending more recently to include in some settings brachytherapy and laparoscopic and robotic surgery . Men who are diagnosed with advanced disease will also face difﬁcult treatment decisions such as when to commence treatment and what method of hormonal ablation to select, each with various quality of life ‘tradeoffs’, to accept . In the setting in which no one treatment approach is clearly superior with regards to cancer cure and where quality of life outcomes differ markedly, the quality of patients’ decision making about medical treatments is critical. As a result, strategies to assist in meaningfully considering prostate cancer treatment options, and the risks and beneﬁts of these options in order to achieve high quality patient decisions, are essential . The approach that is considered to be optimal for achieving high quality patient decisions is shared decision making . Shared decision making is deﬁned as a process carried out between a patient and his health care professional where both parties share information and the patient understands the risks and beneﬁts of each treatment option, participates in the decision to the extent that he desires and makes a decision consistent with his preferences and values, or defers the decision to another time. Shared decision making may not be easy to achieve for all patients . For example, although many patients with cancer indicate a preference for sharing decision making with their clinicians, some, in the case of prostate cancer between 8% to 58% of men, prefer a passive decision making role where clinicians make treatment decisions on their behalf . However, clinicians still need to understand patients’ preferences to ensure that they are making quality decisions on behalf of their patients. As well, there is often a gap between the clinical ideal of shared decision making and actual clinical practice where decision complexity and time constraints may make this approach difﬁcult for both parties to achieve . There are, however, deﬁned strategies and decision aids that can facilitate this process .

Supporting Patient Choice about Testing for Prostate cancer
Many groups advocate an informed decision-making process as an evidence-based approach and necessary precursor to screening for early prostate cancer . Others have suggested that informed decision-making on this health topic is also necessary as a medico-legal risk management strategy . While some researchers have suggested a set of information that needs to be communicated to men about this health decision , there are few explicit guidelines on this subject . Problematically, patients and clinicians do not agree on core content . It has been advised that, for any screening test, patients need to understand the purpose of the test, the likelihood of false-negatives and false-positives, the uncertainties and risks associated with testing, signiﬁcant medical, social or ﬁnancial implications of testing and any possible sequelae and follow up care plans (www.ipdas.ohri.ca). Such information needs to be communicated to patients in a logical and balanced sequence in order to promote better understanding and increased decisional control by men. One approach that has been widely tested in primary care in Australia is the use of six decision steps (see Table 1). Each decision step logically follows to prompt the clinician to overview important health information, with tailoring suggested in Step 1 to ensure the discussion is consistent with the patient’s concerns. For example, for a man with a signiﬁcant family history of prostate cancer, this factor is likely to be central to the patient discussion . Men who experience uncomplicated lower urinary tract symptoms (LUTS) often worry about prostate cancer, so addressing this concern ﬁrst may be priority . In this regard, resources for patients that explain about male reproductive health problems such as urinary symptoms and sexual dysfunction are available at www.andrologyaustralia.org1. As well, National Health and 23

Chapter 10. PROSTATE CANCER Medical Research Council guidelines are available about the management of LUTS (http://www.health.gov.au/nhmrc/publications/synopses/cp42syn.htm). Table. Box 1: Six Decision Steps Six Decision Steps for Informed Choice about PSA Testing in Asymptomatic Men 1. Identify the patient’s main concern 2. Explain where the prostate is and tests available to detect prostate cancer 3. Discuss prostate cancer risk and risk factors 4. Explain the pros and cons of early detection of prostate cancer 5. Identify patient’s personal preferences 6. Support the patient’s choice, and if requested implement a prostate cancer risk management plan

Source: Steginga S, Pinnock C, Baade P. "The early detection of prostate cancer in general practice: supporting patient choice ", practice resource in “Supporting patients’ choice about PSA testing in general practice” A collaborative project of the Queensland Cancer Fund. Brisbane, 2005 From this point, checking to ensure the patient has a basic understanding of both the prostate and possible tests is needed and, given many men may be unaware of the location and function of the prostate gland, an anatomical diagram may be a useful teaching tool here. Next, a consideration of individual risk with regard to both the incidence and mortality of prostate cancer is needed. Communicating health risks effectively is a challenge in the provision of effective decision support. In general people ﬁnd probabilities hard to understand, often estimate their level of risk incorrectly, and tend not to weigh up pros and cons in a systematic way when deciding about treatments . As well, population based statistics provide data about populations, not individuals, so risk communication needs to acknowledge this as a limitation and, where possible, refer to age-based risk estimates and relevant individual factors such as family history ). There are a number of communication strategies that have been suggested to help patients understand risk. These include 1. using numbers as well as words to explain risk 2. where possible providing the absolute risk or beneﬁt 3. using frequencies rather than single event probabilities 4. using consistent denominators 5. putting the risk into context by comparing it to other life events 6. offering both the possible negative and positive outcomes to balance the message frame . However, a quality health decision goes beyond the simple transfer of information and includes consideration and incorporation of each patient’s values and personal preferences . Thus, Step 5 in Box 1 prompts the clinician to discuss each man’s individual preferences. A number of strategies can be used to do this, most commonly the use of a pros and cons exercise in which patients are encouraged to explicitly consider the factors that matter most to them personally in this decision, and the 24

Chapter 10. PROSTATE CANCER direction and leaning of their preferences either for or against each possible option. One approach to support this process for this health topic is the inclusion of a values table within a decision card (see Table 1). A decision aid that incorporates both the six decision steps and this values clariﬁcation exercise can be found on http://www.ncci.org.au/services/PSA_decision_card.pdf . Table 3. What is most important to you? FOR: Is this like you? AGAINST: Is this like you?

I’m concerned that I might get prostate cancer I want the best chance of ﬁnding it early, if I do get it I’m not interested in waiting for all the proof to be in

I think my chance of getting prostate cancer is low I am not convinced about the effectiveness of testing I am more concerned about avoiding treatment side effects, if there’s no guarantee I’d be reducing my risk of dying from prostate cancer

I want to do everything possible to reduce my risk of dying from prostate cancer Decision aids are also effective in supporting patients to make informed choices. With regards to PSA testing, patient focussed decision aids have been found to be effective in increasing men’s knowledge about PSA testing and decreasing decision-related distress , with a variable effect on actual testing behaviour. A range of aids is freely available from the web ( www.prostatehealth.org.au2; www.cdc.gov/cancer/prostate3; www.cancerbacup.org.uk4). Cancer helplines also often provide such information, for example, The Cancer Council Australia Cancer Helpline on 13 11 20; the UK helpline on 0808 800 1234; the USA Cancer Helpline on 1800 227 2345.

C. Digital Rectal Examination
Traditionally, palpation of the prostate by digital rectal examination (DRE) was the manner by which a diagnosis of prostate cancer was suspected. In historical series, up to 50% of palpable masses were attributable to prostate cancer (243, 244). Although DRE by itself is a poor method for diagnosing this malignancy (245, 246), it does still have an important diagnostic role as 25% of tumours are detected in men with normal PSA levels (247). Unfortunately, when a prostate cancer is diagnosed based on a palpable tumour, the risk of the patient already harbouring metastatic or locally advanced malignancy is considerable (248-250). However, a PSA-based prostate cancer detection strategy which omits DRE runs the low risk of missing some curable cancers (251).

D. Prostate-speciﬁc Antigen (PSA)
PSA testing has revolutionized the detection of prostate cancer and monitoring of its treatment. However, its application in early detection is contentious with attitudes to population-based screening for prostate cancer in asymptomatic men varying considerably. (252, 253) In the US, PSA screening is currently recommended for all men older than 50 years and advocated to begin at 45 years in those with ﬁrst-degree relatives with prostate 25

Chapter 10. PROSTATE CANCER cancer and African-American men because of their higher risk of contracting this tumour.( 247, 254) Population screening is not currently recommended in most Western countries (213) although case selection is widely practised with peer organisations endorsing the importance of informed patient participation in decision-making for diagnostic testing, as outlined above.

Background to PSA as a screening test
The FDA initially approved PSA testing in 1986 for monitoring the disease status of prostate cancer patients and, subsequently in 1994, it was endorsed as a screening method for prostate cancer (255). However, the beneﬁts for screening in improving survival are yet to be proven (256). Fitzpatrick (255) summarised the state of the evidence for screening recently. Although the results from the Quebec trial published in 1999 (16) and the experience in the Tyrol compared with the rest of Austria (3) are encouraging, the results of two large randomised trials are awaited with considerable interest. The Prostate, Lung, Colorectal and Ovarian Cancer Study (PLCO) (n = 74 000) in the US and the European Randomised Study for Screening for Prostate Cancer (ERSPCC) ( n = 239 000) from Europe are both on-going with results from the PLCO study due in 2006 and those from the ERSPC trial in 2008. Whether these 2 studies demonstrate a beneﬁt for screening in reducing mortality, and from prostate cancer in particular, it is unlikely that early detection will disappear which, currently, remains PSA-based. The topic is reviewed in BJU Int, volume 95 supplement 3, 2005.

Strengths, limitations and adaptations of PSA
Although emergence of an abnormal PSA due to prostate cancer can precede the appearance of a palpable mass by as many as ten years (8, 10, 11), tumour-induced symptoms by 5-10 years and, on average, death by prostate cancer by 17 years (257), it must be remembered that PSA is not a test for prostate cancer (258, 259). An abnormal serum PSA merely indicates that something is likely to be awry in the prostate that includes cancer as one possibility. Contemporarily, the large majority of patients diagnosed with prostate cancer present with elevated serum PSA levels, mostly between 4-10 ng/ml, (260) in the absence of any other discernable abnormality. Although the prevalence of prostate cancer depends on the population examined, most men undergoing prostatic biopsies – usually the next step in elucidating the cause of an elevated PSA - have negative histology for cancer, even when >8 transrectal ultrasound (TRUS)-guided biopsies are taken,(261-263) with biopsies repeated if suspicion of an undetected malignancy is high.(260). In order to increase the likelihood of detecting prostate cancer earlier, a serum PSA ‘cut-off’ of 3 ng/ml has been advocated. However, Lodding et al (1998) (251) reported that approximately 15% of prostate cancers detected by investigating a serum PSA level between 3 and 4 ng/ml had extraprostatic growth (251). Furthermore, for a PSA threshold of 3 ng/ml, the negative biopsy rate is increased which Hessels et al (2004) (264) considered to be 70-80% (264). Thompson et al (2005) (265) for the Prostate Cancer Prevention Trial, reported on a randomised, prostpective study of 18, 882 healthy men >55 years, PSA levels <3.0 ng/ml and normal DREs followed for 7 years with annual DREs and serum PSA measurements conducted from 1993 to 2003 at 221 US centres. Biopsies were recommended for either a PSA >4.0 ng/ml or an abnormal DRE and for all participants at the end of 7 years. They concluded from their ﬁndings that there is no cutpoint of PSA with simultaneous high sensitivity and high speciﬁcity for monitoring healthy men for prostate cancer but rather a continuum of prostate cancer risk at all values of PSA (265). In their analysis of 3,446 consecutive volunteers with a PSA level of 2.0-10.0 ng/ml (free PSA 18% or less) screened in the Tyrol project who underwent 10 systematic prostate biopsies and an additional ﬁve Doppler-enhanced targeted biopsies on the 26

Chapter 10. PROSTATE CANCER basis of age-speciﬁc PSA reference ranges, Pelzer et al (2005) (266) focused on ﬁndings of those patients with PSA levels <4 ng/ml. They found that more than one third of prostate cancers were detected in 313 men with a PSA value of 2-3.9 ng/mL. Of these 313 patients, 24% had a Gleason score of 7 or greater compared with 33% of 560 patients with a PSA value of 4.0-10.0 ng/mL (P = 0.004). In addition, the prostate cancer cases with a low PSA level occurred in younger patients and at lower stages with smaller prostate volumes (266).Aus et al (2005) (267) also found similarly in their study of 5,855 men, 539 cases of whom had prostate cancer detected after a median follow-up of 7.6 years. However, based on their ﬁnding that there was not a single case of prostate cancer detected within 3 years in 2950 men (50.4% of the screened population) with an initial PSA level <1 ng/ml, they concluded that retesting intervals should be individualized on the basis of the PSA level, and that the large group of men with PSA levels of <1 ng/ml can be safely scheduled for a 3-year testing interval (267). On the basis of an evaluation of their data from the Rotterdam section of the ERSPC, Roobol et al concur that patients with a PSA of <1 ng/ml are at low risk of developing prostate cancer. They concluded that a strategy of PSA screening every 8 years for men with a PSA level of <1.0 ng/ml would result in a minimal risk of missing an aggressive cancer at a curable stage (268). Table 4a. Age-based Ranges for PSA Age range 40-49 50-59 60-69 70-79 50th percentile median 0.65 0.85 1.39 1.64 95th percentile upper limit of normal 2.0 3.0 4.0 5.0

Between 50th & 95th percentile, higher long-term risk of cancer PSA increases at ~3.3% pa – if rate of increase is greater, the risk of cancer is greater References: 11, 269-271

Table 4b. Non-prostate cancer contributors to increases in PSA

1. Benign prostatic hyperplasia (BPH) 2. Ejaculation (both free & total) up to 48 hours 3. Bacterial infection of prostate 4. Prostatic massage 5. Instrumentation (including catheterisation) of prostatic urethra 6. Prostatic biopsy #Finasteride lowers PSA levels by ~50% http://ncci.org.au/services/prostate_GPresources.htm

As indicated in table 4(b), non-malignant causes can produce an elevated PSA (>4.0 27

Chapter 10. PROSTATE CANCER ng/ml): these include infection, benign prostatic hyperplasia [BPH] and ageing (endorsing age-based reference ranges) (272). Instrumentation of the prostate and urinary tract can also raise PSA levels (273). Certain drugs, such as ﬁnasteride can lower PSA values by approximately 50% (274, 275). Physical examination and symptomatology can help differentiate BPH and prostatitis from cancer. The combination of a serum PSA test and digital rectal exam remains the most sensitive combination for diagnosing a prostatic malignancy (245, 247). Because of these limitations, adaptations to enhance the diagnostic utility of PSA for diagnosing prostate cancer have been advocated. It is important to recognise that these serve only as a guide in helping to decide whether or not to proceed to biopsies, with limited utility for extrapolation to individual patients. 1. Free/total PSA This test measures the percentage of free (or unbound) PSA in the blood, and compares it with the percentage bound to proteins (α1 antichymotrypsin and α2 macroglobulin) with its application most useful in younger men, as alluded to, above. In prostate cancer, most of the PSA in blood is bound so the lower the ratio of free to total PSA or the percentage of free PSA, the higher the likelihood that the patient has prostate cancer. The proportion of free PSA in seminal ﬂuid is much higher than in serum, consistent with its physiological role in liquefaction (276). Levels of free-PSA but not complex-PSA in blood signiﬁcantly correlate with PSA in semen in young men, with blood levels of complex-PSA, but not free-PSA, increasing with age (277). The free/total PSA test can help to discriminate between patients with indeterminate PSA levels (4-10.0 ng/ml) who are at the greatest risk of having prostate cancer, in particular aggressive disease (257, 278).

2. PSA velocity PSA velocity measures the speed at which a series of PSA values increases in value over a period of time (279). Any change in PSA >0.75 ng/ml in a year, is concerning for cancer although bacterial prostatic infection may be responsible for this degree of change.

3. PSA density PSA density is a measure of the concentration of PSA in a man’s prostate. It compares the value of his PSA and the size of his prostate (280). Most neoplastic prostate glands produce higher serum PSA levels than do non-malignant glands. Consequently, a serum PSA of 5.0 ng/ml in a patient with a 20 gram prostate is more worrisome for cancer than that a PSA of 5.0 ng/ml in a man with a 60 gram prostate, especially if there is a predominance of transitional zone tissue (BPH) in the latter. To determine the PSA density, a PSA level is obtained and is divided by the volume of the prostate, as estimated by TRUS. A value >0.15 ng/ml per gram of prostate tissue is considered worrisome for prostate cancer. PSA density has been extended to include transition zone measurements in relation to the overall size of the prostate as the transition zone is the site in which BPH develops with ~25% of prostate cancers also arising in this zone. The larger the transition zone in relation to the overall size of the gland, the lower the likelihood of prostate cancer, other things being equal.

E. Prostatic Fluid
Deﬁciencies in the use of PSA in the diagnosis of prostate cancer have led to research into examining the cellular contents of the prostate more directly. 28

Chapter 10. PROSTATE CANCER Bostwick Laboratories provide a test that assays for PCA3/DD3 RNA ( http://www.bostwicklaboratories.com/) from prostatic cells in urine immediately following DRE (168, 169). Tinzl et al (2004) (169) reported that detection of the non-coding PCA/DD3 RNA, which is highly overexpressed in most prostate cancers (167), provided sensitivities of 73%, 84% and 84% with speciﬁcities of 61%, 80% and 70% for serum PSA values of <4 ng/ml, 4-10 ng/ml and >10 ng/ml, respectively, in the detection of prostate cancer (169). Fradet et al (2004) (170) reported on a multi-centre evaluation of this marker in a paper titled ‘uPM3, a new molecular urine test for the detection of prostate cancer’. 443 of 517 (86%) samples provided by patients undergoing prostatic biopsies at 5 centres were assessable by this molecular assay. The overall uPM3 sensitivity and speciﬁcity were 66% and 89%, respectively. In men with a PSA level <4 ng/ml, the sensitivity was 74% and speciﬁcity 91%; for PSA levels 4-10 ng/ml, the sensitivity was 58% and speciﬁcity 91%; for PSA levels >10 ng/ml, the sensitivity and speciﬁcity was 79% and 80%, respectively. The overall accuracy was 81% compared with 43% and 47% for total PSA at a cutoff of 2.5 and 4.0 ng/ml, respectively.

F. Prostate Needle Biopsies
Once the possibility of a prostatic cancer is raised, whether by rectal examination, PSA parameters, or a combination of both, the second part of the contemporary two-step early-diagnostic approach, TRUS-guided prostate biopsies, is usually performed. TRUS imaging permits spatial positioning of spring-loaded biopsy needles to provide a methodical approach for obtaining tissue cores for standard histopathology. With few exceptions, TRUS imaging by itself is non-diagnostic as only gross changes register as an abnormal appearance on the monitor. The number of biopsy cores taken is important with the chance of missing a cancer by standard sextant biopsy estimated to be approximately 25% (281) so that, more recently, the numbers of cores recommended are at least 8 and preferably a minimum of 10. In addition, it is advocated that biopsies should be directed laterally and that they should include the anterior horns of the peripheral zone (263, 282-287). Many urologists routinely take 12 biopsy cores now to minimise the likelihood of missing cancer. Guidelines established by the American Urologic Association recommend prostate needle biopsies for any man with a PSA value greater than 4.0 ng/ml, or an abnormal prostate on digital rectal examination (247). The issue of repeat biopsies was addressed by Djavan et al (2001) particularly in relation to when it is reasonable to stop repeating the biopsies. Cancer-detection rates in 1051 men biopsied were 22%, 10%, 5% and 4% with 1-4 TRUS biopsy sessions with 58%, 60.9%, 86.3% and 100%, respectively, having organ-conﬁned disease. Recently, Yanke et al (2005) extended experience with the Kattan Nomogram to predict the likelihood of a positive ﬁnding at a subsequent biopsy session. Predictor variables studied in the nomogram were patient age, family history of prostate cancer, prostate speciﬁc antigen slope, months from initial negative biopsy session, months from previous negative biopsy session, cumulative number of negative cores previously taken and previously detected high grade PIN or atypical small acinar proliferation. The authors evaluated a total of 356 repeat biopsy procedures for 230 patients. The mean number of total cores per patient was 17.9 with 78 men having biopsies positive for cancer. The area under the ROC curve was 0.71, which was greater than any single risk factor (288). Routine practice involves peri-operative antibiotic prophylaxis with a pre-procedural enema and not proceeding if any faeces at all is present in the rectum, as determined by DRE. Since TRUS biopsies are unpleasant and uncomfortable, many urologists use anaesthesia (local or general) as a routine. Minor morbidity is common with this procedure with well over 50% of patients experiencing at least one complication. Fortunately the dreaded complication of life-threatening sepsis is uncommon, generally <1%, even though rates of bacteraemia vary greatly; blood in the urine, ejaculate and 29

Chapter 10. PROSTATE CANCER faeces are not infrequent sequelae with some men having difﬁculty voiding immediately following the procedure. (289-291).

G. Histologic Analysis
The Gleason Grading System
The biopsy result provides important information for the patient and clinician on which to base management decisions (292, 293). In addition to the pre-biopsy PSA level, important prognostic factors include tumour volume (percentage of the core involved and the number of positive cores) and the histological grade of the tumour. Increasing tumour burden and poor histologic differentiation are associated with a higher risk of metastatic disease, an increased chance of post-treatment failure, and a worse overall prognosis (275, 294, 295). Histological analysis is based on the Gleason grading system that is regarded as the ‘gold standard’ for classifying prostatic adenocarcinoma (296). Based on architectural patterns, tumour is assigned a rating between 1 and 5, with higher numbers representing less differentiated, more aggressive tumours (see Table 1 and Figure 1). A single prostate can harbour multiple foci of different histologic patterns of adenocarcinoma, and it is possible to have Gleason grade 3, 4 and 5 patterns in the same specimen: 85% of prostate tumours are multifocal. The Gleason score (or Gleason sum) is generated by combining the values of the ﬁrst and second most common (dominant and subdominant). grades (i.e.: in a tumour with mostly Gleason grade 3 and some Gleason grade 4 disease, the Gleason score will be 3+4 = 7), assessed by the uropathologist using low-power light microscopy. The Gleason score provides important prognostic information. Table 5. Gleason grading system Grade 1&2 3 Histology closely-packed glands forming a nodule small inﬁltrating glands, completelumen formation fused glands, incomplete lumen formation solid sheet or single cells, no lumen formation Biologic Behaviour Indolent disease, rarely progressive most common pattern; less aggressive than pattern 4 indicates tumour progression Very aggressive, late stage

4 5

30

Chapter 10. PROSTATE CANCER

Figure 2a. The presence of Gleason grade 4 or greater histology carries a signiﬁcantly poorer prognosis (297, 298). Stamey demonstrated that Gleason score 7 tumours can be stratiﬁed, based on the amount of grade 4 disease (299). Those with <50% grade 4 behave similarly to Gleason score 6 (more favourable), while those with >50% grade 4 act like Gleason score 8 (unfavourable) cancers. The transition from Gleason 3 to Gleason 4 appears to be a common event and represents a critical juncture in which the tumor acquires a signiﬁcantly more aggressive phenotype.

31

Chapter 10. PROSTATE CANCER

Prostatic Intra-epithelial Neoplasia

Figure 2b. Prostatic Intra-epithelial Neoplasia Prostatic intraepithelial neoplasia [PIN] is believed to be a precursor of prostate cancer, given the strong association between high grade PIN and prostatic adenocarcinoma (300-303). The presence of high grade PIN is often indicative of the presence of prostate cancer. It has been shown that more than 80 percent of prostates with adenocarcinoma also contain high-grade PIN (PIN-11 & III). High-grade PIN has cytologic features resembling cancer and carries many of the genetic alterations of prostate cancer. The ﬁnding of high-grade PIN alone in a biopsy has been cited as an indication to proceed with repeat biopsies given the high co-frequency between high-grade PIN and carcinoma. However, in current practice, the predictive value of PIN in ﬁnding cancer on subsequent biopsies has declined, probably due to the extended biopsy techniques yielding higher rates of initial cancer detection (304). A diagnosis of PIN by itself is certainly insufﬁcient for a patient to undergo either radical prostatectomy or radiotherapy.

Atypical prostatic glandular proliferations
Foci of atypical glands, also labeled atypical small acinar proliferation of uncertain signiﬁcance, have features suspicious for but not diagnostic of cancer. These encompass a variety of lesions including benign mimickers of cancer, high-grade prostatic intraepithelial neoplasia (PIN), and small foci of carcinoma which, for a variety of reasons, cannot be accurately diagnosed. The reported incidence of these lesions on prostate needle biopsies is 1.5% to 5.3% (304). Patients with atypical glands on needle biopsy have a high risk of harbouring cancer. The reported incidence of prostate cancer from repeat biopsies has ranged from 34 to 60%. (304-306). Following an atypical diagnosis, biopsies need to be repeated (307).

H Staging system
Once a diagnosis of prostate cancer is made, it must be determined whether the pa32

Chapter 10. PROSTATE CANCER tient is a candidate for potentially curative treatment (surgery or radiation). This depends upon several factors, including general health and projected longevity in conjunction with the likelihood that the cancer is still localized within the prostate and has not yet metastasized. The most important factor, however, is the patient’s decision after he has considered the ‘pros and cons’ of the various choices as they relate to him (see below). Currently, the TNM system is used for staging, and prostate cancers can be assigned both a clinical stage and, should the prostate be removed surgically, a pathologic stage. This differentiation is important with the clinical and pathological stage designated by the letters ‘c’ and ‘p’, respectively, preceding the stage denotation (e.g. cT2a = clinically, tumour is palpably involving one lobe of the prostate or less). Table 6. TNM staging classiﬁcations Primary Tumour Tx T0 T1 T1a T1b T1c T2 T2a T2b T2c T3 T3a T3b T4 Lymph Nodes Nx N0 N1 Distant Metastases Mx M0 M1 M1a M1b Regional nodes not assessed No Metastases No distant Non-regional lymph nodes Bone(s) 33 Regional nodes were not assessed No regional nodes Regional node metastases Primary tumour cannot be assessed No evidence of primary tumour Clinically inapparent tumour not palpable not visible by imaging Incidental tumour in < 5% of TUR tissue Incidental tumour in > 5% of TUR tissue Needle biopsy prompted by elevated PSA Organ conﬁned Tumour involves one half of one lobe or less Tumour involves more than half of one lobe but not both lobes Tumour involves both lobes Tumour extends beyond the prostatic capsule Extracapsular, unilateral and bilateral Tumour invades seminal vesicles (s) Tumour invades bladder neck, sphincter, rectum, pelvic side wall

Chapter 10. PROSTATE CANCER Primary Tumour M1c Other site(s) with or without bone disease

VII. PROSTATE CANCER TREATMENT OPTIONS
A. Introduction
Traditionally, for a man with clinically-localized prostate cancer, there have been three treatment options: watchful waiting, radical RRP, and radiotherapy. For patients with advanced prostate cancer or for those men with sufﬁciently serious comorbidities such that surgery and radiotherapy are contraindicated, treatment options have generally been limited to hormonal ablation or watchful waiting (308, 309). Over the past few years, chemotherapy and other experimental approaches also have been championed for those with advanced disease (310). A recent paper by Bill-Axelson et al (2005) (311) is timely in relation to whether treatment with curative intent, in particular by RRP, makes a difference to survival. From October 1989 to February 1999, these authors recruited 695 men who were randomised to RRP or watchful waiting. The updated data from this Scandinavian study demonstrates a signiﬁcant difference in the overall (and not just cancer deemed) death rates in favour of RRP with a median of 8.2 years of follow-up; 83/347 men in the surgery group and 106/348 men assigned to watchful-waiting died (P=0.04). (For 30/347 men randomised to surgery (8.6%) and 50/348 men assigned to watchful waiting (14.4%), death was attributed to prostate cancer). In their interim report, Holmberg et al (2002) (312) revealed the difference between their patients and those presenting contemporarily. For those men randomised to watchful waiting and RRP, respectively 1. only 10.9% (38/348) and 12.4% (43/347) had their prostate cancers diagnosed through investigations of an abnormal PSA level 2. 45.4% (158/348) and 50.7% (176/347) of men had serum PSA levels >10.1 ng/ml at baseline 3. 29.6% (103/348) and 26.2% (91/347) had Gleason scores of >7 4. for 9.5% (33/348) and 13.3% (46/347) the diagnosis was made cytologically or the biopsy specimen could not be retrieved. Nevertheless, the updated 2005 results of this randomised, controlled trial are notable in that RRP reduced disease-speciﬁc mortality, overall mortality, and the risks of metastases and local progression. Although the absolute reduction in the risk of death after 10 years was small, the reductions in the risks of metastasis and local tumour progression were substantial (311). Both RRP and radiotherapy (including brachytherapy) have undergone substantial modiﬁcations during the past 1-2 decades. Unfortunately, however, both these forms of potentially curative treatment continue to have risks of signiﬁcant unwanted effects in subgroups of men (see below). As a result, patients have to choose and, in so doing, ‘trade off’ the risks of side-effect risks from one form of treatment with those from others. Other options, such as cryotherapy and High-Intensity Focused Ultrasound (HIFU) do not have sufﬁciently-established track records at this time to be recommended as routine options for localised prostate cancer, except in research settings. Unwanted consequences of HIFU vary considerably with impotence rates 44%61%, grade 2-3 incontinence 0%-14%, and rectal ﬁstulae 0.7%-3.2% (313). Although there have been a signiﬁcant advancements in understanding the mechanisms of can34

Chapter 10. PROSTATE CANCER cer cryotherapy for tumour destruction with improved delivery methods resulting in more effective local prostate cancer control, its most appropriate application is for patients with bulky local disease and local recurrence after radiation therapy. These topics have been reviewed recently in an excellent supplement of Urology (314, 315). http://www.nhmrc.gov.au/publications/_ﬁles/cp88.pdf http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm http://www.uroweb.nl/ﬁles/uploaded_ﬁles/2005ProstateCancer.pdf http://www.cancer.gov/cancertopics/understanding-prostate-cancertreatment/page5

B. Pre-treatment decision-making
Making decisions about prostate cancer treatments
Men who are diagnosed with prostate cancer often ﬁnd themselves in a situation of choosing between unfamiliar and often complex treatment choices, while facing the psychological distress of a cancer diagnosis. In this context decision-related distress is common and persistent . Population-based studies suggest that the medical treatments received by men with localised prostate cancer are inﬂuenced by age and by socio-economic factors that affect access to medical services. For example, assessed 3,073 North American men six months after treatment for localised prostate cancer. Conservative management was predicted by later stage disease, physical comorbidity, older age, and being unmarried. As well, radical prostatectomy was received more frequently by Hispanics compared with non-Hispanic Caucasians and less frequently by men with lower education and income levels. utilised cancer registry data about 2,941 patients diagnosed with prostate cancer in the Netherlands and found that the presence of co-morbidities such as cardiovascular disease or diabetes had little effect on what medical treatments men received. Rather, men were more likely to receive radical prostatectomy if they were younger, had a small clinically localised tumour that was moderately differentiated and when they had been diagnosed in a hospital with a high clinical case load. These researchers concluded that treatment was mostly determined by the patient’s age and the extent of the urologist’s surgical experience. assessed clinical and socio-demographic factors to identify predictors of treatment choices amongst 1,809 North American men, predominantly white middle class and afﬂuent, who were diagnosed with prostate cancer as a result of a screening program. Younger age, a higher cancer stage and PSA level and being of non African-American race predicted receiving curative treatments. Men with normal sexual function were more likely to receive watchful waiting whereas men with normal urinary function were more likely to receive radical prostatectomy. Several studies have found that the clinician’s recommendation strongly inﬂuences men’s treatment choice . As well, lay health beliefs, such as the view that surgery is the best way to cure a cancer are a strong inﬂuence, with the use of such beliefs acting as a short cut to more effortful systematic processing . As one example, found only 13% of men made their decision about treatment for localised prostate cancer by weighing up the risks and beneﬁts of each different medical treatment. Thus, there is a need for care to be taken in supporting informed and patient oriented choice. In order to support men’s decision making, as a minimum men should be provided with evidence-based patient decision support materials to provide them with an opportunity to become well informed about their treatment options. A recent Cochrane review provides guidance on acceptable attributes of evidence based decision aids and some of these can be web accessed ( www.prostatehealth.org.au10; www.ohri.ca/decisionaid11). As well, a generic decision aid, the Ottawa Personal Decision Guide is available that can be adapted for use for most patient populations (www.ohri.ca/decisionaid). Two of the present authors (SKS and RAG) are currently 35

Chapter 10. PROSTATE CANCER validating a revised version of the Ottawa Personal Decision Guide within a randomised control trial of a multi-component intervention targeted to the speciﬁc challenges men experience in the early diagnostic and treatment phase of prostate cancer. This approach integrates psychoeducation and decision support in a novel approach . The psycho-educational component is informed by the stress and coping model and problem solving therapy . Structured counselling protocols and patient education materials underpin a telephone based nurse delivered support intervention that commences at diagnosis and extends 6 to 8 weeks after treatment. Peer support may also be helpful to men at the time of deciding about treatments. Peers can provide support from the perspective of shared personal experience . In this regard, men who have been previously diagnosed with prostate cancer can provide ﬁrst hand advice about what it is like to live with the effects of treatments, practical advice about ways to cope, and ongoing social support. A range of peer support programs are available world wide, with research suggesting they are positively received by men . Peer support programs work well when they are integrated into a broader support framework and are linked to clinicians, and many are available that do this (table 7). Table 7. Examples of prostate cancer Speciﬁc Peer support programmes Group Example Group Example Canadian prostate cancer Network (CAN) Us Too (US) Website Website http://www.cpcn.org/

http://www.ustoo.com/

PSA: Prostate cancer Support Association (UK)

http://www.prostatecancersupport.info/

Prostate cancer Foundation of Australia (AUST)

http://www.prostate.org.au/support.htm

Prostate Awareness and Support Society (NZ) The Scottish Association of prostate cancer Support Groups Irish Cancer Society: Men against cancer

http://www.prostate.org.nz/index.html http://www.prostatescot.co.uk/

http://www.cancer.ie/support/mac.php

C. Clinical staging
(i) Clinically insigniﬁcant tumours
Because there was a pronounced increase in the number of men diagnosed with 36

Chapter 10. PROSTATE CANCER prostate cancer following the introduction and widespread use of the PSA blood test, concern arose that a proportion of these patients had insigniﬁcant disease which did not warrant treatment. As a result, Epstein et al (1994) (334) developed criteria to identify insigniﬁcant prostate cancer. These included a PSA density <0.15, a biopsy Gleason score <6, the presence of disease in fewer than 3/6 biopsy cores and <50% prostate cancer involvement in each of these cores. Bastian et al (2004) (335) reported on the analysis of these criteria in relation to 237 patients who had RRPs between December 2002 and August 2003. The large majority (67%) had only one TRUS biopsy core positive and most (89.9% had Gleason 6 in the RRP specimen. However, 9.7% had Gleason 7 or 8 tumours and 8.4% had non-organ conﬁned disease, illustrating the problem of ‘undercalling’ when relying on biopsy information for stratifying patients into a good prognostic group.

(ii) Determining whether the tumour is localised
The presence of any cancer cells outside the prostate locally or at distant sites following treatment with curative intent, is regarded as a portent for ultimate treatment failure. The likelihood of cancer becoming evident after prostatectomy and radiotherapy increases with pathologic stage (336, 337), both these therapies being potentially curative for men with localized (T1 and T2; N0; M0) prostate cancer (336-338). Because these treatments are considerable undertakings and may cause problems in terms of their unwanted effects, it is imperative that, as far as possible, pre-treatment staging excludes any evidence of locally-advanced or metastatic disease. However, the clinical staging of prostate cancer is inexact and this imprecision continues to be a serious limitation in the overall management of patients with this malignancy. PSA serology is a poor predictor of pathologic stage and needle biopsies can misrepresent - usually understate - the volume, histology, and thus the expected behaviour of a patient’s tumour (339, 340). In addition, the presence of extraprostatic extension is easily underappreciated by digital palpation, and conventional imaging studies can fail to detect metastatic spread (341). Approximately 25% of men with clinically localised disease experience an early relapse despite successful treatment of the primary lesion, and up to 50 percent of men with clinically organ-conﬁned lesions are discovered to be understaged at time of surgery (15, 342-346). Cancer cells, particularly in the case of higher grade tumours, are apt to change phenotype and be motile. Facilitated by enzymic breakdown of the extracellular matrix, inﬁltration of motile cancer cells proceeds into extracellular tissues with intravasation into vascular and lymphatic channels, occurring much earlier than was appreciated previously. However, the rate-limiting steps in terms of metastasising are extravasation from the circulation into tissues remote from the primary lesion and the ability to grow and thrive in these new environments which, for prostate cancer, are particularly the bone of the axial skeleton and pelvic and retroperitoneal lymp nodes. A very recent report indicates that bone marrow-derived haemopoietic progenitor cells expressing vascular endothelial growth factor 1 (VEGFR1) home to tumour-speciﬁc pre-metastatic sites and form clusters, preceding the arrival of tumour cells. These VEGFR1+ cells also express VLA-4 which binds to ﬁbronectin, upregulated in resident ﬁbroblasts by tumour-speciﬁc growth factors, to provide a permissive niche for incoming tumour cells. Thus a favourable environment for secondary tumour cells to become established is pre-arranged even before arrival or the tumour cells themselves (347). One important though easily neglected role of clinicians is to inform patients of the potential that RRP or radiotherapy, including brachytherapy, may not result in cure. To help with this task, the Partin Tables may be used (248, 260). Initially published in 1993, these were subsequently updated to accommodate an earlier stage of presentation at diagnosis for the majority of patients (348). The Partin Tables have been validated by others in multicentre studies ( 349 ) although not all reports have conﬁrmed an improvement from earlier versions ( 350 ). In addition, Steuber at al ( 2005 ) found that the Partin Tables were less predictive for predominantly transition zone 37

Chapter 10. PROSTATE CANCER tumours. They attributed this variance to the different biological tumour characteristics of transitional zone lesions ( 351 ). First published in 1993, subsequently modiﬁed (352) and validated in a number of centres (353), nomograms have been created to summarize a multivariate logistic regression analysis for the prediction of pathologic stage using the combination of DRE, serum PSA and Gleason score. While these estimations do not predict whether or not a given patient will be cured with surgery, they do provide an indication of likelihood of disease-free recurrence at 5 years. Stratifying patients is often a helpful exercise in this regard. The use of nomograms based on age have been extended recently to include the use of percentage free PSA for determining the presence of prostate cancer ( 354 ). Problems with the application of tables and nomogram ﬁndings to individual patients are that PSA is a labile enzyme with serum levels affected by factors other than prostate cancer, TRUS biopsies tend to understate cancer both in terms of the extent of tumour and its Gleason score and clinical staging is subjective and relatively insensitive. Nevertheless, tables and nomograms based on pre-operative ﬁndings are useful to a degree. Post-operatively, however, incorporation of more deﬁnitive and comprehensive parameters obtained from pathology of the RRP specimen itself, enable formulation of more predictive nomograms (355). A number of studies have stratiﬁed patients with respect to likelihood of tumour progression with recurrent disease, if it does become evident, likely to do so for the ﬁrst time within 5 years after RRP. Partin et al were the ﬁrst to develop a simple biostatistical model equation which allowed categorisation of cases after RRP into 3 risk groups reﬂecting a low, intermediate and high likelihood of PSA recurrence (356). After an extensive multifactorial regression analysis, they identiﬁed only 3 variables viz. a sigmoidal transformation of PSA, Gleason sum of the RRP specimen and margin status or tumour conﬁnement within the prostate. Other studies have conﬁrmed the importance of these parameters and the prognostic value of the 3-group categorisation approach (357, 358). Table. Box 2. Stratifying patients: Factors indicating a high likelihood of recurrence following treatment with curative intent PSA >10 ng/ml Gleason grade 4 or 5 pattern on biopsy Stage 2b (and higher stage) tumour

(iii) Methods for Clinical Staging of Prostate cancer
A combination of the following parameters is used routinely to estimate whether a prostate cancer is localized: 1. clinical stage of the primary tumour (based on digital rectal examination) 2. PSA serology 3. the histologic grade of the prostate biopsy/ies (Uropathology expertise is essential in this interpretation) 4. The number of positive cores and percentage involvement by tumour 5. Imaging studies to identify the presence of metastases

38

Chapter 10. PROSTATE CANCER 1. Digital rectal examination (DRE) Digital rectal examination understages organ-conﬁned disease (245, 342-346). In a published series of 601 men undergoing RRP, of the 565 men with cT2 disease, only 52% had organ-conﬁned tumours (248). By comparison, of 36 men with cT3 disease, 19% had organ-conﬁned lesions. Although there are reports of cure by RRP for cT3 disease, the presence of a bulky extra-prostatic tumour generally indicates a poor outcome, given the high associated risk of metastatic disease (359, 360). Of particular importance is palpable disease at the prostatic apex. The presence of a nodule on digital rectal examination at the apex is often indicative of extraprostatic extension at that location and tends to foreshadows a positive surgical margin or poorer result post-radiotherapy (361-363).

2. PSA Serology As PSA levels increase, the chance of non-localised disease increases accordingly (247). Partin reported that, for men with PSA <10 ng/ml, 70-80% will have organconﬁned disease. This decreases to approximately 50% for men with PSA >10 ng/ml, and to approximately 25% for men with PSA >50 ng/ml (248). Sanwick et al (1998) (295) showed that 37.5% of patients with PSA values between 10-15 ng/ml and all patients with PSA values >15 ng/ml had evidence of extracapsular extension (295). Because PSA values vary widely within a given stage and overlap between different stages, the predictive value of PSA in determining pathologic stage is weak (340). Even with the combined use of DRE, serum PSA, and TRUS, it is not feasible to reliably estimate the stage of an individual tumour prior to treatment. However, after studying the PSA velocity of 1095 men with localized prostate cancer during the year before diagnosis, D’Amico et al (2004) (364) concluded that patients whose PSA levels increase >2.0 ng per ml are particularly at risk of dying from prostate cancer despite undergoing RRP. Despite initial enthusiasm for RT-PCR molecular staging assays, at this time there is no indication for their routine use in preoperative staging (365-367).

3. Histology Oesterling et al. demonstrated the importance of Gleason grade on prostate needle biopsies as a predictor of ﬁnal pathology (368). Gleason score 6 tumours were associated with a 24% risk of capsular penetration and a 29% probability of positive surgical margins. This increased to a 62% risk of capsular penetration and a 48% probability of positive surgical margins for Gleason score 7 cancers, and 85% and 59%, respectively, for Gleason score 8-10. Of 72 men with Gleason sore 8-10 tumors, Partin et al. noted extraprostatic disease in 92% (248). Furthermore, some circumspection should be exercised in using biopsy histology for prognosticating since there is a tendency to under-represent the Gleason score and tumour volume relative to pathology ﬁndings in the whole gland.

4. Tumour Volume from TRUS-guided biopsies McNeal and associates have demonstrated that tumour volume on prostatectomy specimens correlates with extracapsular extension (369). However, they found that an accurate measurement of tumour volume based on biopsy ﬁndings is very difﬁcult technically. McNeal and Stamey have further proposed that the biological aggressiveness of prostate cancer is a direct function of the tumour volume (370). Hence, it can be implied that the larger the volume with biopsies, the greater the likelihood of extracapsular disease. This relationship has been conﬁrmed in several studies which suggest that the tumour extent with prostate biopsies can predict T3 disease. Using multivariate analysis models, Goto et al., determined that the length of cancer in needle biopsies could predict extraprostatic disease, and Sebo et al. demonstrated that the percent of needle biopsy cores and the surface area positive for cancer were strong 39

Chapter 10. PROSTATE CANCER predictors of pathologic stage and tumour volume of the pathologic specimen (294, 371).

5. Imaging Clinical staging is performed routinely with technetium labelled phosphate radioisotope bone scanning. Sites of increased radio-tracer uptake are those with greater metabolic activity, so called ‘hot-spots’, and a malignant cause has to be differentiated from non-malignant diagnoses such as arthritis and Pagets Disease. The predilection for prostate cancer metastases to strongly favour the axial skeleton with limb involvement (apart from upper femora) much less common, helps in differentiating malignant prostatic from other causes of increased radio-isotope activity. Routine bone scanning is usual prior to treatment, irrespective of the likelihood or lack of likelihood of metastases being demonstrable, as a bone scan at this time serves as a baseline reference for subsequent monitoring. CT scanning is not always performed at baseline in men with a prostate cancer diagnosis. For detecting soft-tissue metastases, CT is the usual ﬁrst-line investigation. However lymph node deposits need to be >1cm before they are usually regarded as pathological with the enlargement presumed to be due to prostate cancer until proven otherwise, especially if sited in pelvic and para-aortic regions. Magnetic Resonance Imaging (MRI) involving the use of an endorectal coil has been promoted to provide an improvement in detection of extracapsular disease but, in the overall context of patient assessment, this investigation adds little to clinical staging; however, MRI can be helpful in evaluating spinal secondaries, especially in relation to possible neural compression. The roles of positron emission tomography (PET) and ProstaScint scanning are not well established. A 70-80% sensitivity has been cited for ProstaScint in detecting lymph node metastases (372).

D. Management Options
Although routine PSA-based detection has increased the percentage of newly-diagnosed cases potentially curable by surgery or radiotherapy, a considerable proportion of patients are not candidates for such intervention (1). Common exclusionary factors include unresectable (locally-advanced) disease, ‘poor tumour pathology’, the presence of demonstrable metastases and advancing age in association with a limited life-expectancy, this last factor begging the question why a diagnosis of prostate cancer was sought in the ﬁrst place. In addition, there are some men who refuse therapy altogether for fear of anaesthesia or concerns over risks of incontinence and impotence. Because prostate cancer is relatively slowly growing, only those men with at least a 10-year life expectancy are usually considered for aggressive, potentially-curative treatment. Although RRP is not offered to men with cT3 or cT4 disease, radiotherapy, in combination with androgen ablation therapy, does have a more recognised role in locally advanced disease, especially with neo-adjunctive or adjunctive androgen suppressive treatment (373-377). Justiﬁcation may be based on a need to achieve local control of the cancer, however, a proportion of patients with cT1 or cT2 tumors that are upstaged to pT3 at time of surgery have been reported to have durable cancer remissions (336, 378). For clinically localised disease, there are 3 management options viz. RRP, radiotherapy in the form of either external beam radiotherapy or brachytherapy and watchful waiting. The last of these is not synonymous with patient disregard as, apart from a need for ongoing support and counselling, these men need to be monitored for disease progression and for potential future therapeutic intervention, which may include treatment with curative intent. 40

Chapter 10. PROSTATE CANCER

E. Sexuality and prostate cancer
While most men appear to adjust well psychologically to the experience of prostate cancer, sexual difﬁculties are frequently described as a bothersome problem experienced by men following both surgery and radiation therapy for prostate cancer . The nature of these difﬁculties goes beyond the symptom of erectile dysfunction, although this is the effect most often described in the research literature. Physical effects men may experience include: 1. Erectile dysfunction 2. penile shortening 3. loss of sexual desire 4. less satisfying orgasms, and for a small percentage of men, 5. painful orgasms . The inability to achieve a spontaneous erection sufﬁcient for penetrative sex has an obvious direct impact upon intimate relations. However, this is more than just a physical consequence, with the domains of quality of life that may be affected by erectile dysfunction including impaired sexual performance; and changes in relationships with women, sexual imaginings and masculinity . For example, men who experience erectile dysfunction after treatment for prostate cancer describe fears about intimate contact with partners, embarrassment about the failure or potential failure to obtain an erection, and awkwardness about needing to use mechanical devices or penile injections within an intimate encounter . As well, men describe changes in the way they relate to women generally, with regards to losing the enjoyment of sexual feelings in response to women they ﬁnd attractive. This loss of desire and arousal is broader than changes in the men’s actual relationships and extends to sexual fantasies and imaginings. Men may experience a loss of feelings of masculinity and of self worth, as well as embarrassment and loss of self esteem about other related physical changes such as penile shortening. Studies suggest that an early return to sexual activity using intracavernous injections, speciﬁcally by three months after surgery, may increase the recovery rate of spontaneous erections after prostatectomy and improve men’s responses to erectile dysfunction treatments . However, problematically, after prostate cancer men may be reluctant to seek help for sexual difﬁculties, with studies ﬁnding that up to ﬁve years after treatment only about half of men seek medical treatment for erectile dysfunction . Further, for those men who do seek treatment, improvements in erectile function are modest. Thus, sexual dysfunction is an ongoing quality of life problem for many men after being treated for prostate cancer. Negative attitudes to help seeking for sexual problems are a barrier to men’s psychosexual adjustment, suggesting a potential role for a counselling intervention . In particular, normalising help seeking for sexual problems; setting realistic goals and expectations about sexual function after treatment; reinforcing the need for ﬂexibility, patience and persistence in managing erectile dysfunction; and encouraging and teaching a problem solving approach may be helpful. With regards to sources of help for sexual problems, men report a preference for help from their urologist or cancer specialist; written information about erectile dysfunction before and after treatment and one to one support . Including the man’s partner in medical consultations about sexual problems is also likely to be helpful. Table 8 lists internet sites and self help books that may be helpful to patients and clinicians. As well, prostate cancer support groups may also be helpful for some men. A further approach is the integration of elements of sex therapy, such as sexual communication and stimulation, with medical treatments for erectile dysfunction. In this regard, a recent pilot of a four session counselling program to enhance sexual rehabilitation after treatment for localised prostate cancer produced improved sexual satisfaction in both men and their partners at three month follow up, and increased 41

Chapter 10. PROSTATE CANCER utilisation of medical treatments for erectile dysfunction at three and six months . Improvements in sexual satisfaction were not maintained at six months. Contrary to expectations, the presence of the man’s partner during the intervention did not affect study outcomes. These authors are currently trialling an internet based version of this program in order to improve the acceptability of the program to men and study generalisability. Table 8. Examples of Internet Sites Relating to Prostate cancer and Sexuality Internet Sites Oncolink has links to chatlines for sexuality and cancer or fertility and cancer, and links to other useful sites. http://www.oncolink.upenn.edu/psychosocial/sexuality Cancer Source offers interactive tools and community resources. http://www.cancersource.com Association of Cancer Online Resources is a cancer online information system that offers access to electronic mailing lists and links to other sites. http://www.acor.org Andrology Australia has resources about sexual dysfunction. http://www.andrologyaustralia.org The Lions Prostate cancer Website has information on prostate cancertreatment and support groups, links t other sites, as well as an email advisory service. http://www.prostatehealth.org.au Books Sexuality and Fertility after Cancer by Leslie R. Schover, Ph.D., John Wiley & Sons, 1997. A how-to and educational book for all types of cancer. Sexuality & Cancer: For the Man Who Has Cancer and His Partner, prepared for the American Cancer Society by Leslie R. Schover, Ph.D. Large booklet available free of charge from ACS website and ofﬁces. His Prostate and Me: A Couple Deals with Prostate cancer by Desiree Lyon Howe, Winedale Publishing Company, 2002. A woman’s perspective of coping as a couple with prostate cancer. Making Love Again:Hope for Couples Facing Loss of Sexual Intimacy, by Virginia and Keith Laken, Ant Hill Press, 2002. An unusually open, emotional account of one couple’s struggle to get their sex life back to normal after radical prostatectomy. The Lovin’ Ain’t Over, The Couples guide to Better Sex after Prostate Disease by Ralph and Barbara Alterowitz, Health Education Literary Publisher, Westbury, NY.

Acknowledgment: We are grateful to Professor Lesley Schover for assistance in compiling this table

VIII. RADICAL RETROPUBIC PROSTATECTOMY (RRP)
There are two traditional approaches to the prostate for its total removal, retropubic and perineal. Throughout the world, the large majority of total (or so-called radical) prostatectomies are undertaken by the retropubic route with perineal prostatectomy performed by only a small number of urologists. The procedure of perineal prostatectomy is suited particularly to the removal of smaller prostates. 42

Chapter 10. PROSTATE CANCER Contemporary surgical management of prostate cancer has been shaped by two seminal events, development of the anatomic RRP by Walsh (393) and application of serum PSA as a means for early detection, resulting in many more young men being diagnosed with this condition than ever before. Consequently, there has been a concerted effort to improve long-term cancer control together with preservation of urinary and sexual function. Description of the anatomic RRP has improved understanding of prostatic and pelvic anatomy and of the structures involved in maintaining urinary continence and erectile function. As a result, more patients are cured of their cancers today and are satisﬁed with their quality of life post-prostatectomy, than ever before (394, 395). The modern RRP evolved from a succession of anatomic dissections and modiﬁcations to historical techniques (396, 397). The legacy of the anatomic RRP which permits preservation of the neurovascular bundle with maintenance of erections for many, better sphincter preservation with improved continence rates and more effective management of the dorsal vein complex resulting in less blood loss, has paved the way for not only faster and less morbid recovery (338) but also the newer adaptions of laparoscopic and robotic forms of RRP.

A. Preoperative Consultation and Care
In addition to having pathology and staging details reviewed together with their overall medical status, it is usual to provide candidates for RRP with detailed printed information and, as a routine, have concerns and questions addressed pre-operatively. Blood may be taken in advance to be used as needed peri-operatively as an autologous transfusion. It is standard procedure for compression stockings to be ﬁtted immediately before surgery with intermittent calf compression applied throughout and after the operation, as part of the prophylaxis against deep venous thrombosis. Since the small risk of peri-operative mortality (usually <0.5%) is mostly due to cardiovascular/respiratory complications, some surgeons insist on having all candidates for RRP evaluated with stress testing by cardiovascular physicians.

Delayed commencement of treatment
In terms of timing, it is not uncommon for surgery to be delayed 6 weeks after TRUS biopsies to permit resolution of biopsy-induced inﬂammation. Patients often are concerned that a delay in treatment is deleterious to the likelihood of the surgery being curative. Graefen et al (2005) (398) analysed data from 795 patients with clinically localized prostate cancer who underwent RRP between January 1992 and June 2000 in relation to the time from biopsy to the date of RRP as a potential prognostic factor. For a mean follow-up of 33 months (1-116 months), 25% of the patients failed on the basis of a postoperative PSA level >0.1 ng/ml. They concluded that a treatment delay in the investigated time span of a few months did not adversely affect recurrence free survival rates and recommended that patients can be reassured that they can evaluate their management options without compromising efﬁcacy due to a delay in initiation of treatment (398). Boorjian et al (2005 (399) reviewed 3,969 consecutive patients who underwent RRP for clinically localised cancer within one year of diagnosis. They reported that the time from biopsies to surgery did not inﬂuence the probability of biochemical recurrence, even for those considered to be at high risk of biochemical recurrence. The clinical and pathological features and not the delay were the important factors for estimating risk of biochemical recurrence (399).

43

Chapter 10. PROSTATE CANCER

B. Operative Technique
Most RRPs are performed under regional (epidural) or general anesthesia. Advantages of the epidural approach include diminished blood loss, decreased incidence of pulmonary embolus and improved post-operative analgesia. (400-402). If general anaesthesia is used, post-operative analgesia is usually delivered parenterally for at least 24 hours, often via patient controlled analgesia. Subsequently, oral analgesics such as NSAIDs are used as indicated. Commonly, a Pfannenstiel or a midline incision is made from the umbilicus to the pubis and continued through to the space of Retzius. The peritoneum is mobilized superiorly, enabling the surgery to be undertaken extraperitoneally. A lymphadenectomy is performed, if indicated (see below). The principles and techniques of the anatomic RRP (393) constitute the basis for the operative procedure with various modiﬁcations such as bladder neck preservation having been incorporated and used by some urologists. The entire operation is performed under complete visualization with meticulous dissection in a relatively bloodless ﬁeld, to facilitate optimal cancer control, maximize post-operative continence and, if nerve-sparing is attempted, retain potency. When the specimen is removed, it is examined intraoperatively to ensure completeness of the resection and exclude any evidence of grossly positive margins or violation of the prostatic capsule. An indwelling urethral catheter is left for 1-2 weeks to maximize optimal healing of the vesicourethral anastomosis. A drain is placed near the anastomosis site: it is usually left in position for several days.

C Nerve-sparing prostatectomy
Sexual function is important in middle aged and older men (403,404) as well as their partners. Helgason et al (1996) (403) reported physiological potency for 435 randomly selected Swedish men aged 50-59, 60-69 and 70-80 years to be 97%, 76% and 51%, respectively. Blanker et al (2001) (404) conﬁrmed this ﬁnding in data collected from 1688 men with the prevalence of signiﬁcant dysfunction ranging from 3% in 50-54 year olds to 26% in males between 70-78 years. Consequently, it is not surprising that potency problems rate highly as an important consideration not only in deciding whether or not to proceed to active treatment but in determining which treatment to pursue. The importance of sexual function as a consideration is illustrated by Singer et al (2001)(405) who reported that men undergoing treatment for prostate cancer were willing to exchange an approximate 20% chance of being cured of their cancers for an increased prospect of remaining potent after treatment (405). Consequently for many patients, the emphasis of RRP is no longer focused solely on cancer control, but extends to include lifestyle issues (394, 395, 406,407). This is not a dissimilar paradigm shift to that which has occurred with breast cancer treatment, as sexuality issues have taken a prominent role inﬂuencing treatment decisions with radical and partial mastectomies replaced by combination lumpectomy and adjuvant therapy. Potency and continence rates associated with nerve-sparing surgery vary among surgeons and academic centres (see Table 9). It is fair to say that a degree of scepticism is expressed regarding some of the claims made in respect to post-operative potency, in particular. However, explanations for inconsistencies in cited results include differences in surgical skill, patient selection and outcome measurement methodology. Among these, patient selection ranks particularly highly. Nonetheless, it is undisputed that increasing numbers of patients are sexually potent after surgery, albeit with the use of the phosphodiesterase inhibiting drugs (Viagra™, Cialis™ and Levitra™), as a result of the modiﬁcations incorporated into the technique of anatomic nerve-sparing RRP. Table 9. Potency rates after nerve-sparing radical prostatectomy Study 44 Potency Rate

Chapter 10. PROSTATE CANCER Study Jonler, et al (1994) (408) Fowler, et al (1993) (409) Heathcote, et al (1998) (410) Ojdeby, et al (1996) (411) Gaylis, et al (1998) (412) Talcott, et al (1997) (413) Sole-Balcells, et al (1992) (414) Davidson, et al (1996) (415) Ritchie, et al (1989) (416) Catalona, et al (1999) (417) Quinlan, et al (1991) (418) Leandri, et al (1992) (419) Noh, et al (2005) (420) Walsh, (2000) (421) Potency Rate 9% 11% 12% 14% 18% 21% 39% 43% 45% 67% 68% 71% 72% 86%

Although deﬁnitions for above parameters vary, quality of life studies indicate that the majority of patients are satisﬁed with the outcomes of their surgery (394, 395, 406, 407). Link et al (2005) (422) reported their experience with laparoscopic RRP using the validated EPIC and a 5-item International Index of Erectile Function questionnaires; 78.9% of men who were previously potent were having sexual intercourse, albeit with the use of phosphodiesterase inhibitors in most instances, 12 months following surgery. Sexual bother decreased to 64% of baseline at 3 months and did not show any signiﬁcant improvement subsequently. By contrast, the sexual function sub-domain, which refects erectile performance better, decreased to a mean of 36% at 3 months but showed improvement subsequently to 51% of baseline at 6 months and 64% of baseline at 12 months. Recovery of sexual function was not signiﬁcantly affected by age or pre-operative potency status, although the extent of nerve sparing was a signiﬁcant predictor of outcome (422).

(i) Anatomical Considerations of Nerve-sparing Surgery
Normal post-prostatectomy erectile function depends upon preservation of the autonomic cavernous nerves, located within the neurovascular bundles of the penis. These nerves are located immediately posterolateral to the prostatic capsule, within the periprostatic fascia at the junction of the lateral and posterior portions of the endopelvic fascia. At this position, the lateral pelvic fascia is comprised of two layers, the levator and the prostatic fascia. The neurovascular bundles pass between these layers bilaterally and can be preserved by entering the periprostatic fascia laterally and gently and meticulously dissecting them off the prostatic fascia. If both neurovascular bundles are preserved, potency (deﬁned as the ability to sustain sufﬁcient erections for sexual intercourse without any aids other than phosphodiesterase inhibitors) can be as high as 68- 86% (338, 417). When only one bundle is saved, potency rates diminish substantially (423). Given the importance of sexual function to many men with prostate cancer and the differences when only one bundle is spared instead of two, it is common practice for every effort to be made to preserve both neurovascular bundles whenever possible, as long as the potential of cure is not considered to be jeopardized – consistent with the wishes of the patient.

(ii) Effect of Nerve-Sparing Surgery on Cancer Control
The neurovascular bundles are mostly located outside of the prostatic capsule so, 45

Chapter 10. PROSTATE CANCER unless dissection violates the capsule, nerve-sparing radical prostatectomy should not compromise surgical cancer control if the tumour is organ-conﬁned. Epstein et al followed patients with positive surgical margins present only in the posterolateral region and determined that post-prostatectomy relapse was uncommon (424). In this study, of 507 men with cT1 and cT2 tumours, the most common sites of positive margins were distal (22%), posterior (17%), and posterolateral (14%). Rosen conﬁrmed these ﬁndings in 144 men undergoing radical prostatectomy (425). They demonstrated that, when positive margins were present, <10% had involvement in the region of the neurovascular bundles. Hence, in cases of extraprostatic extension, involvement of the posterolateral margin is less common than for other locations. Epstein also examined paired specimens from men with prostate tumors highly suspicious for posterolateral involvement who underwent nerve-sparing prostatectomy followed by excision of the neurovascular bundles on the suspect side (423). Cancer was found in the bundles in only 17.5% of the men. In men with clinically-suspicious but pathologically negative posterolateral margins, no tumour was found in the resected bundles.

(iii) Sural nerve grafting
In order to attempt to maximise preservation of the neurovascular bundles, technical modiﬁcations to RRP have been reported; many of these involve methods which improve visualisaton of the neurovascular bundles (420, 426, 427, 428). The potential problem of impotence, when preservation of the neurovascular bundle is not considered appropriate, has been addressed by sural nerve grafting, employing techniques established in the management of facial and peripheral nerve injuries (429, 430). Although this approach has met with a mixed reception by urologists, claimed success rates vary with one study having reported return of erectile activity in 75% of men with maximum return of function 14-18 months post-RRP (431). However, most Urologists cite much lower success rates.

(iv) Laparoscopic and Robotic prostatectomy
As expected, the recently introduced techniques of laparoscopic and robotic prostatectomy differ from open radical prostatectomy in that they have incorporated some adaptations for practical reasons. However, the principles of the prostatic cancer surgery remain the same and results to date are comparable (426, 432). Keyhole approaches are attractive to patients because of perceptions of reduced surgical trauma and morbidity with, by extrapolation, less post-operative pain - even though this is uncommonly problematic with the open approach. A recently reported prospective study of robot assisted laparoscopic prostatectomy (n = 159) is illustrative in that it did not provide a clinically meaningful decrease in post-operative pain compared with RRP (n = 154), which the authors ascribed primarily to the low pain scores reported in both groups. They concluded that outcomes other than pain will ultimately determine the role of laparoscopic radical prostatectomy and Robot assisted laparoscopic prostatectomy (433). Conceptually, better vision is afforded the surgeon with forms of endoscopic surgery to permit easier identiﬁcation of structures, particularly apically (434, 435), but there is the potential problem of delay if (the infrequent) conversion to an open procedure is required in the event of bleeding. Unlike laparoscopic surgery, roboticallyperformed procedures involve hand-eye coordination and hand positions which are more akin to those used in open surgery; in addition, the learning period appears to be shorter (436). Although the capital costs associated with robotic surgery are, at present, very large, these are likely to decrease with time.

46

Chapter 10. PROSTATE CANCER

D. Pelvic Lymphadenectomy
Following bone, the pelvic lymph nodes are the second most common site of prostate cancer metastases (437). While radionuclide bone scans provide a sensitive method for evaluating skeletal lesions, the sensitivity of CT scans to delineate lymph node metastases is poor (48, 49, 438). Pelvic lymphadenectomy prior to RRP to detect metastatic lymphatic involvement is limited to patients at high risk for tumour cell dissemination, then only proceeding to RRP if the lymph nodes are free of tumour. In the PSA-era of the past 15 years, the rate of positive lymph nodes in patients undergoing RRP has plummeted from approximately 25-30% to under 5% (439-442). Consequently, there has been considerable debate regarding which patients should have lymph node dissections. It is generally accepted that men with Gleason scores < 7 and PSA values <10 ng/ml do not require pelvic lymphadenectomy (424). Some investigators have increased these limits to include PSA values from 10-20 ng/ml and Gleason 7 tumours (443). The presence of a positive lymph node is a predictor of post-operative recurrence. Most studies demonstrate that such foci of cancer herald subsequent curative treatment failure: 10-year biochemical disease-free survival rates are low (361, 444). In a study designed to determine if early versus delayed hormonal ablation therapy in men with lymph node positive disease was advantageous, Messing et al (1999) (445) reported on 51 men with lymph node positive disease who were randomized to delayed therapy. At an average follow-up of 7 years, 16 percent had no biochemical or clinical evidence of disease and were never started on androgen ablation (445). Pelvic lymphadenopathy can be performed as a separate procedure through a "minilaparotomy" or by laparoscopy, or can be combined with RRP (446). All nodal tissue medial to the external iliac artery, from the junction of the external iliac and hypogastric arteries to the obturator foramen is removed with this procedure. It is then sent for frozen section histologic analysis. If lymphadenectomy is performed prior to a planned RRP and the frozen section report indicates that there is no cancer evident, it is usual to proceed with the prostatectomy. If there are tumour cells present in the specimen, the planned RRP is almost always aborted. Complications of pelvic lymphadenectomy are infrequent (415, 447-450). Injury to the obturator nerve can occur in 1% of patients causing an inability to adduct the thigh. If complete transection occurs, primary anastomosis can be performed. Bleeding from obturator and iliac vessels is uncommon as are ureteric injuries. A lymphocele may form in the pelvis which can become symptomatic and require sclerosis or formal drainage into the peritoneal cavity. (451).

IX. RESULTS OF RADICAL RETROPUBIC PROSTATECTOMY
A. Disease-free Recurrence and Survival
(i) Pre-operative PSA
The results of published series vary but, depending very much on the cases selected, survival rates at 10 years have been reported to exceed 90% (338, 452, 453) with a comparable percentage of continent and many men potent post-operatively (338). Lower preoperative PSA, pathologic stage, and Gleason grade are associated with high rates of cure after RRP. For patients with preoperative PSA values <10 ng/ml, Catalona demonstrated that 7-year disease-free survival was 76-93% (417). If PSA was >10 ng/ml, disease-free survival decreased to 51%. Similar results have been shown by others (247, 454, 455).

47

Chapter 10. PROSTATE CANCER

(ii) Stage & Grade
Not unexpectedly, the probability of cure is considerably greater for patients with localized, non-palpable, and well to moderately differentiated tumors. The risk of treatment failure rises in relation to increases in clinical and pathological stage and correlates with increasingly aggressive histologic patterns. Survival rates has been reported to decrease with increasing pathologic stage, from 81% for pT2 lesions, 76% for pT3 tumors and 19% for N(+) disease. As indicated above, survival rates also vary with grade. In a multi-institutional study, Gerber et al (1996) (456) demonstrated that 10 year progression-free rates correlated with grade with 87% of low-grade tumors, 68% of moderate and 52% of high-grade cancers progressing, with other authors reporting comparable results (339, 340, 455-457).

(iii) Positive margins
A positive surgical margins is present if the tumour extends to the edge of the specimen. Patients with positive surgical margins, whether surgically induced or not, have approximately a 2 fold higher recurrence rate compared with patients with negative margins. The progression-free probability at 5 years for men with negative margins at RRP has been reported to be ~80% compared with 42-64% for men with positive margins (297, 458)

(iv) Molecular markers
A number of molecular markers have been evaluated for their prognostic value but none has been adopted for routine use in practice. Amongst others, the potential of CD151, c-myc and calveolin-1 overexpression in predicting outcome has been discussed earlier in this chapter. Overexpression of p21 protein has been reported to be a predictor of response to salvage radiotherapy after RRP (459) and Fizazi et al (2002) (460) correlated p21 expression with progression to androgen independence. In addition, expression of p53 and the combined loss of PTEN and p27 have been shown to be predictive in the identiﬁcation of the likelihood of disease recurrence (461, 462). Fradet et al (2004) (463) demonstrated that expression of NF-κB in prostate cancer cells at the sites of positive margins was highly indicative of biochemical recurrence (463).

(v) Lymph node & seminal vesicle involvement
Although clearly in the minority, some men with microscopic N(+) disease have undetectable PSA levels at 5-10 years. Progression in N(+) disease appears to be related to the volume of tumour in the lymph nodes. As well, not all men with seminal vesicle involvement have poor outcomes (464). Despite the observation that seminal vesicle and lymph node involvement are associated with poor results post-prostatectomy, in the Catalona series, at seven years the disease-free survival rates were 26% for men with seminal vesicle involvement and 9% for men with N(+) disease (337). There also appears to be a difference if seminal vesicle involvement is a direct extension from the primary tumour, in which case it behaves more like an extracapsular extension rather than a separate metastatic focus which implies systemic involvement.

(vi) PSA monitoring
PSA serology is very useful in monitoring for disease recurrence post-RRP. If all cancer tissue is removed, PSA values should drop to the undetectable range (between 0-0.02 ng/ml). Understandably, patients become strongly focussed on their postoperative PSA values with raised levels following RRP indicating persisting prostatic 48

Chapter 10. PROSTATE CANCER tissue at a distant and/or local site (444, 452, 465). Most PSA recurrences occur in the ﬁrst few years after surgery and precede clinical evidence of disease by as much as 5 years. It is rare for the PSA to become detectable after levels have been undetectable for 5 years. The rate of PSA doubling time is an important predictor of poor prognosis (452, 466, 467). Biochemical Recurrence (BCR)/Biochemical(PSA) Failure (BF) Using the deﬁnition of PSA failure of the American Society of Therapeutic Radiation and Oncology’s (ASTRO’s) 1996 consensus statement (ie 3 consecutively rising PSA values, each obtained at least 3 months apart), D’Amico et al analysed 888 patients followed for a median time of 38 months (8-100) after RRP. Based on the medical literature, they established 3 groups using known prognostic factors (viz. PSA level, biopsy Gleason score and the American Joint Commission on Cancer [AJCC] staging system). Over 95% of the PSA failures were evident for the intermediate and highrisk groups by 4 years. Questioning the ASTRO guidelines, Amling et al reviewed 2,782 RPP patients followed for a median of 6.3 years. After examining four points of “PSA cut-off”, these authors concluded that a PSA >0.4ng/ml was most appropriate since a signiﬁcant number of patients with a lower PSA do not continue to increase or proceed to demonstrable metastases (468). Freedland et al (2003) (469) undertook a retrospective review of 358 men who underwent RRP between 1991 and 2001 to determine the most relevant cutpoint for determining biochemical recurrence. For patients with a detectable postoperative PSA value from 0.11 to 0.2 ng/ml, the 1 and 3-year risk of PSA progression was 64% and 93%, respectively. For men with a PSA value from 0.21-0.3 ng/ml, the 1 and 3-year risk of PSA progression was 86% and 100%, respectively. The 5-year risk of PSA recurrence using a greater than 0.1 ng/ml cutpoint resulted in a 43% risk of recurrence compared with only 23% for a greater than 0.5 ng/mL cutpoint (469). Contemporarily, it has become common practice to regard a PSA of >0.2ng/ml as the cutpoint to indicate BCR. Reporting on 213 men who had biochemical failure on the basis of a PSA of >0.2 ng/ml following RRP for a mean follow-up of 56 months (range 1 to 125), 99 of whom were treated with androgen ablation and/or radiation therapy at the time of detection of BF, Jhaveri et al (1999) (470) cited 10-year overall survival rates of 88% compared with 93% for those who did not have BF. They found no difference in survival rates in relation to age (>65 years), preoperative PSA >10 ng/ml, biopsy or specimen Gleason score >7, clinical Stage including the presence of extracapsular extension, positive surgical margins, and seminal vesicle invasion. (470).

(vii) Prognosis
Pound et al (1999) (452) reported in a retrospective study on the fate of 304 men with biochemical escape (PSA >0.2 ng/ml) following RRP, 103 of whom progressed to metastatic disease, not having had androgen suppressive therapy. The median actuarial time to metastases was 8 years from the time of PSA elevation and once patients developed metastases, the median actuarial time to death was 5 years. The time interval from surgery to the appearance of metastatic disease was predictive of the time until death (452). However, it is clear that BCR in itself is not a predictor of imminent demise from prostate cancer and, as alluded to above, PSA doubling time (PSADT) is becoming accepted increasingly as a preferred prognostic indicator (471). Albertsen et al (2004) reported that men who had a PSADT of <1 year had a high risk of dying of prostate cancer within 10 years of diagnosis, and conversely (472). D’Amico et al (2003) (473) examined the results of men who experienced BCR subsequent to RRP and radiation therapy. From their analyses of 5,918 men following RRP and 2,751 patients after radiation therapy, they concluded that a PSADT of <3months met the criteria of sur49

Chapter 10. PROSTATE CANCER rogacy in predicting death from prostate cancer at a median survival time of 6 years (473).

X. COMPLICATIONS OF RADICAL RETROPUBIC PROSTATECTOMY
A. Incontinence
Table 10. Continence rates after radical retropubic prostatectomy Study Percent Continent Average Post-operative Length of Time to Regain Continence 6 months 12 months 6 months 18 months 2 months 18 months 6 months 12 months

Shelfo et al (474) Lowe (475) Goluboff et al (476) Catalona et al (417) Kaye et al (477) Walsh et al (421) Seaman et al (478) Poore et al (479)

88% 85 to 100% 92% 92% 93% 93% 97% 100%

Continence rates from several institutions are represented in the table (above). In general, >90% of patients are continent by their reckoning at 12 months. Most men report little bother from urinary symptoms after RRP with socially acceptable continence achieved usually within 3-6 months of surgery, although, for some patients, regaining control can take up to 18 to 24 months. Factors inﬂuencing continence include maintaining the integrity of periurethral support, the precision of the vesicourethral anastomosis, patient age and co-morbidities, including pre-prostatectomy detrusor dysfunction which may persist post-operatively. Return of urinary control is considered to take longer in men over 65 years. Patients with atherosclerotic and diabetic vasculopathy are more prone to prolonged incontinence, probably the result of poor vascularization and healing of the periurethral and sphincteric tissues. Biofeedback and Kegel exercises have been reported to hasten the return of urinary control (480). If urinary control does not return, and the incontinence is demonstrated to be sphincter failure by urodynamics investigations, an artiﬁcial urinary sphincter may resolve the problem (481). Bladder neck contractures occur in less than 10% of patients and can cause symptoms ranging from poor urinary ﬂow to complete incontinence (482, 483). Bladder neck contractures can result from non-mucosa-to-mucosal anastomosis, following heavy intraoperative bleeding and after prolonged urinary extravasation, with a previous transurethral resection of the prostate possibly predisposing to this problem. Treatment can consist of simple dilatation, although surgical incision of the scarred tissue is usually performed. Urethral stricturing can also require dilatation and/or incision with formal urethroplasty rarely warranted.

B. Impotence (& sexual dysfunction – see section VII. E)
Spontaneous post-prostatectomy erectile function depends upon preservation of at 50

Chapter 10. PROSTATE CANCER least one neurovascular bundle. While surgical skill is an important factor in the successful outcome of nerve-sparing prostatectomy, patient selection is paramount. Younger men (<60-65 years old) with small, non-palpable, and low-grade tumours have the best outcomes (421). Phosphodiesterase inhibitors (e.g.sildenaﬁl/Viagra™, tadalaﬁl/Cialis™, vardenaﬁl/Levitra™), intracorporeal injection of vasoactive drugs such as prostaglandin E1 or Alprostadil, transurethral vasodilators (medicated urethral system for erection [MUSE]) and vacuum constriction devices (VCD) all have a role in erectile rehabilitation (484, 485). Although patients clearly prefer oral medications (391), these may be less effective in the short term, particularly if temporary neurovascular damage (neuropraxia) is present following RRP (485) as well as following external beam radiotherapy, (389). The results of the various treatment approaches were reviewed recently by Raina et al (2005) (485). They reported that VCD efﬁcacy rates range from 60-80% with compliance at 12 months between 50% and 70%. Tightness or pain from the constriction ring and decreased sensation of the penis, in particular the glans, were common causes for noncomliance. Approximately 50% of men were afforded beneﬁt from MUSE using Alprostadil with some non-nerve sparing RRP patients also able to achieve tumescence satisfactory for vaginal penetration. In addition to not achieving satisfactory penile tumescence, urethral pain and burning were cited causes for discontinuation. Intracorporeal penile injection therapy with PGE1 or Alprostadil is claimed to provide adequate rigidity in >75% of patients but ~50% of men do not continue with the treatment long-term. In addition to a lack of success with the technique, physical and emotional problems in addition to pain with with the injection were promoted as reasons for discontinuation. Penile ﬁbrosis is reported to occur in up to 15% of men (485). Avoidance of penile hypoxia through regular tissue oxygenation via erections is considered to lessen the likelihood of lacunar ﬁbrosis and, ultimately, erectile incapacity. Thus, there is a vogue currently to advocate a return to penile tumesence with the early commencement of one or a combination of the above treatments following RRP. Not unexpectedly, the use of oral phospodiesterase inhibiting drugs is most popular in this regard but, especially in the early post-operative period, other methods may be more effective. Despite high (>75%) efﬁcacy and satisfaction rates, penile implant surgery is restricted to only those men with persisting erectile failure after having exhausted all less invasive options and all hope of spontaneous erectile recovery (485, 486).

C. Bleeding
The anatomic approach to RRP has improved awareness of, and abilities to control, the venous plexuses surrounding the prostate. Consequently, massive blood loss is rare. nevertheless, during nerve-sparing surgery it is not uncommon for 600-1200 mL of blood to be lost. Many patients are encouraged to donate autologous blood preoperatively in case a transfusion is required intraoperatively or in the immediate post-operative period. The need for transfusion may be lessened by the use of a ‘cellsaver’ during the operative procedure.

D. Infection
Despite using an iodine or alcohol-based skin preparation preoperatively, any time a skin incision is made there is the risk of both local and systemic infection. For this reason, it is usual to administer antibacterial drugs prophylactically. During RRP, the bladder is opened and, inevitably, urine spills into the surgical ﬁeld. Several strategies can be used to diminish the risk of infection. Preoperative urinalysis and urine cultures identify patients with potential urinary tract infections which can be treated. After the vesicourethral anastomosis is completed, lavaging the pelvis with saline may help and post-operative drainage as a routine decreases the likelihood of localised sepsis occurring. 51

Chapter 10. PROSTATE CANCER

E. Visceral Injuries
Rectal injuries occur in under 1% of RRPs and may be more likely subsequent to previous rectal surgery or pelvic irradiation (415, 448, 482). If a rectal injury does occur, it can be repaired easily in most instances by oversewing the rectal wall. It is for this reason that some surgeons suggest that all patients are given a bowel preparation prior to surgery, to minimise wound contamination and lessen the need for a covering colostomy should an injury occur. Although extremely rare, ureteric injuries can happen during transection of the bladder neck and dissection of the seminal vesicles. Correction usually consists of a ureteroneocystotomy with insertion of a ureteric stent.

F. Deep vein thrombosis, pulmonary embolus & other problems
Deep vein thrombosis and pulmonary embolus are diagnosed in approximately 1% of men having a RRP (415, 448, 482, 487). Their probability can be reduced by ensuring adequate hydration peri-operatively, using elastic compression stockings with sequential compression applied during and after surrgery and encouraging early ambulation. Subcutaneous heparin or clexane is also commonly used. All peri-operative complications are increased in patients with conditions characterised by impaired healing or reduced pelvic tissue vascularity (482). Thus, prior pelvic radiation, previous rectal surgery, inﬂammatory bowel disease, past procedures on the prostate, urethra, or bladder, diabetes mellitus, and vasculopathies can contribute to prolonged incontinence, impotence, hemorrhage, infection, and visceral injuries. In addition, co-morbid cardiac and respiratory conditions can contribute to perioperative morbidity and mortality.

XI. TREATMENT OF POST-PROSTATECTOMY RECURRENCES
Overall, approximately 35% of men undergoing RRP will have a recurrence of their prostate cancer within 5 to 10 years (342-346). The following preoperative ﬁndings are associated with a high risk of surgical failure: cT3 lesions, cT1 or cT2 tumors with >Gleason grade 4 number on prostate biopsy, and serum PSA >10 ng/ml. Additional risk factors for recurrence after attempted deﬁnitive therapy include such additional pathologic determinants as tumor volume, vascular invasion, seminal vesicle or lymph node involvement, and positive surgical margins. The location of the positive margin can inﬂuence the likelihood of tumor recurrence and must be taken into consideration (292). The use of post-operative radiotherapy has been the focus of extensive investigation in recent years, including both retrospective and randomised prospective studies. The use of radiotherapy post-RRP can be with either adjuvant or salvage intent. Adjuvant radiotherapy is that used immediately post-operatively, in the aim of eliminating potential but as yet unidentiﬁable residual disease. Salvage therapy is conducted when recurrence is suspected - typically when a PSA rise is seen - although the immediate use of radiotherapy when an undetectable post-RRP PSA is not returned may also be regarded in this category.

Adjuvant radiotherapy
A number of retrospective comparative series have examined the potential beneﬁt to adjuvant radiotherapy. Unselected series have suggested biochemical control rates in the combined surgery plus adjuvant radiotherapy cases of 52-93% compared to surgery only rates of 25-74% (488-492). More concordant results were seen in two published matched pair analyses which showed surgery only freedom from bio52

Chapter 10. PROSTATE CANCER chemical failure (FFbF) of 55-59% which was increased to 88-89% with the addition of radiotherapy (493, 494). Three randomised studies of adjuvant therapy have now been announced in abstract or publication form. These trials have focused on a subset of men at high risk of having residual disease with inclusion requiring either pathologically involved surgical margins or pathological stage T3 disease. The EORTC 22911 trial (495) randomised 1005 such patients to observation or post-RRP radiotherapy (60Gy) from 1992-2001. 30% of these had a detectable post-operative PSA. At a median follow-up of 5 years, biochemical progression-free survival was signiﬁcantly improved in the irradiated arm (74.0% versus 52.6%; hazard ratio 0.48 [95% CI 0.37-0.62]). Clinical progression and loco-regional failure were also signiﬁcantly improved. Too few death events have been recorded as yet to show a difference, although approximately twice as many deaths from prostate cancer had occurred in the observation arm compared with the irradiated. Grade 3 toxicity was uncommon, and not signiﬁcantly different between the treatment arms (4.2% and 2.6% cumulative incidence rate at 5 years for the radiotherapy and observed arms respectively). In a detailed companion study, urinary incontinence (as deﬁned by patient reported questionnaires and pad weight measurements) was found to not be increased by the addition of radiotherapy (496). Two additional similar randomised studies have been presented in abstract form to date. The German Cancer Society trial (ARO 96-02 / AUO AP 0995) was designed to asses to impact of adjuvant radiotherapy in those with pT3 disease or positive margins who achieved an undetectable PSA post-RRP (497). With a median follow-up of over 3 years, the results from 261 patients showed a better than 20% absolute improvement in the biochemical failure rate in the radiotherapy arm (hazard ratio 0.40 for the addition of radiotherapy when analysed by treatment received, p<0.0001). Grade 3 rectal toxicity was not observed in either group. Similarly, the Southwest Oncology Group study (SWOG 8794) randomised 419 pT3 and margin positive men to have either observation or radiotherapy (498). 55% had a detectable post-RRP PSA. The risk of biochemical recurrence was reduced by 56% by adding adjuvant radiotherapy, and prospective quality of life assessment suggested no signiﬁcant differences in the gastrointestinal, urinary and sexual domains at 5 years. The risk of needing future salvage androgen suppression therapy was reduced by 56% also and clinically apparent relapse by 38% (both statistically signiﬁcant). Distant metastasis and survival events were too infrequent in both studies to make meaningful assessment. This combination of randomised trial data (amounting to level 1 evidence) suggest that there is an unequivocal capacity for post-RRP adjuvant radiotherapy to approximately halve the chance of having a future PSA-detectable tumour recurrence in pT3 / margin positive patients, while maintaining a low level of toxicity. More maturity to the data is awaited to determine the overall impact this has on distant metastases or survival.

Salvage radiotherapy
The role of salvage radiotherapy is far less clearly deﬁned, with no prospective studies of efﬁcacy or toxicity to guide decisions. Retrospective analyses suggest that the PSA level prior to initiating the salvage radiotherapy is strongly predictive of outcome (499-501), with some series suggesting that treatment at PSA levels below 1 ng/mL do substantially better than those above this level (502). This PSA effect has been shown to be independent of the PSA doubling time (503), potentially indicating that these patients beneﬁt from early referral for treatment regardless of PSA dynamics. Indeed, one series demonstrated an independent beneﬁt to the use of immediate adjuvant therapy rather than waiting until requiring salvage (504). Other prognostic factors which have described, although not consistently, have included seminal vesicle invasion, margin positivity, post-operative PSA nadir level, high gleason grade, and radiation dose (501-503). Larger series typically show a 5 year biochemical control rate in the order of 50% typically (501, 505), and over 70% for those with a pretreatment PSA of less than 1 ng/mL and an operative Gleason score of 7 or lower 53

Chapter 10. PROSTATE CANCER (502). Despite the apparent ability to provide a substantial chance for long-term control in relapsed men, there is concerning data that post-RRP radiotherapy may be under-utilised. Only 55% and the 38% of the biochemical failures in the observation arms of the EORTC and SWOG randomised trials respectively underwent potentially curative salvage radiotherapy, with the remaining being treated palliatively with observation or androgen suppression therapy. Prospective efﬁcacy and toxicity data will be required to fully appreciate the therapeutic ratio of radiotherapy in this group of men.

XII. RADIOTHERAPY
A. Introduction
Contemporary radiation therapy can result in cure of prostate cancer in a substantial proportion of cases. Deliberation continues regarding when it is best used rather than other radical treatments, in particular, RRP. Direct randomised evaluation of them would appear unlikely to ever happen, given that a highly anticipated and well funded international trial comparing radical surgery with seed brachytherapy recently closed due to poor accrual (ACOSOG Z0070 – the “SPIRIT” trial). Without such evidence, non-randomised data describing both tumour control and quality of life issues must be balanced against each patient’s concerns and overall health status. Multidisciplinary clinics should be regarded as the standard forum for helping patients balance these issues. Irrespective of the perceived tumour biology, men under 60 years of age are offered surgical therapy in many centres based on, amongst other issues, the practical advantages of ascertainment of pathological tumour stage (discussed above), more accurate grading and a more dependable early PSA endpoint of success in most cases. Many patients, however, will be offered radiotherapy preferentially. This may be on the basis of advancing age, a high risk of not achieving surgical complete clearance or patient preference. Evidence to help determine appropriate therapy is now available for many clinical scenarios within this group of men.

B. Stratiﬁcation of risk of progression & metastases
In many cases, radiotherapy treatment decisions are now driven by the patient’s risk proﬁle tumour containment. These proﬁles were typically developed using historical data, and either externally validated or conﬁrmed as clinically relevant by stratiﬁcation levels in prospective trials. The most simple of these is a three tiered system with (506): 1. Low risk: PSA≤10 ng/mL and Gleason Score 2-6 and stage cT1-cT2a 2. High risk: either cT3 or cT4 or PSA>20 ng/mL or Gleason Score 8-10 3. Intermediate risk falls between these levels While nomogram models (507) have been shown to have more reliable discrimination of outcome, the three level model serves well in relation to known therapeutic option categories. These may involve combinations of external beam radiotherapy (EBRT), brachytherapy (BT) or androgen suppression (AS) therapy.

C. External Beam Radiotherapy
For those with low risk prostate cancer, modern EBRT techniques appear to be highly efﬁcacious (508, 509). PSA control would be expected in over 85% of such cases 54

Chapter 10. PROSTATE CANCER presently. These treatments are typically delivered using conformal 3D techniques, or intensity modulated radiotherapy (IMRT) where these more complex treatments may aid in controlling toxicity, especially at higher doses. These excellent results are yet to have an additional demonstrated beneﬁt when combined with therapies such as AS. High risk prostate cancer traditionally has been a disease with a poor outcome when treated with radiotherapy alone (as with surgery). In the days before PSA detection of tumours, biochemical recurrence rates were typically over 80% using radiotherapy as primary therapy (510). With the risk of both local and metastatic progression being of concern, randomised trials investigated the role of adjuvant AS in what are now known to be typically high risk patients. Published trials of locally advanced disease showed AS to have a beneﬁcial effect when given after radiotherapy for a duration of either 2 years (511), 3 years (375) or indeﬁnitely (512). An overall survival beneﬁt of 16% at 5 years was seen in the Bolla et al trial when compared with radiotherapy alone. Hence, most men today with advanced cancers will have this style of treatment offered as a minimum. Fit men in this group may also be offered therapy on a clinical trial, as the improved results in this group are continuing to be optimised. Intermediate risk prostate cancer, however, appears to have a lesser reliance on treatment of sub-clinical metastatic disease present at diagnosis, as borne out in trials evaluating the value of local therapy intensity. Responses to increasing radiation doses (“dose escalation”) have now been shown in a randomised trial. For the subset of PSA 10-20 ng/mL, the freedom from failure rate at 6 years increased from 43% to 62% when the radiation dose was increased from 70Gy to 78Gy (513). This supports the results of other dose escalation observational series (509, 511, 514). Additionally, short-term use of AS combined with EBRT has shown to be of beneﬁt to some patients. The precise explanation for this improvement in results is less clear though. Observational studies suggested a beneﬁt predominately to intermediate and possibly high risk men (515). A number of randomised trials also now exist which, to some extent, cover this group of men. The mature RTOG 86-10 trial examined the role of 2 months of complete AS before as well as during radiotherapy in patients with bulky primary tumours and was conducted prior to the wide availability of PSA. The subanalysis by grade showed signiﬁcant gains in loco-regional control, cancer-speciﬁc and overall survival in the Gleason 2-6 tumours, also further reinforcing that bulky high-grade cancers should be approached as high risk disease. Another trial has recently reported a freedom from failure together with a survival advantage to having 6 months of neoadjuvant AS (NAAS) prior to 70Gy of EBRT in intermediate and high risk men (516). Somewhat disparate though are the results from the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial which compared radiotherapy of 66Gy alone to the same dose in combination with either 3 or 6 months of neoadjuvant maximum androgen blockade. Looking at the risk subsets of men from this study shows that the beneﬁt shown for the use of 6 months NAAS (particularly in terms of freedom from BF and cancer-speciﬁc mortality) was primarily limited to the high risk men. The power to detect a difference, however, was limited by the small proportion of intermediate risk patients (517). Also somewhat confounding matters is a large 2x2 phase III trial of men with a calculated risk of nodal positivity >15% showing that 4 months of AS was a signiﬁcant beneﬁt only when given prior to and during radiotherapy (rather than adjuvantly), and furthermore, only when combined with whole pelvic radiation ﬁelds (rather than prostate only) (518). As most of these trials showing a beneﬁt to AS in combination with radiotherapy have employed lower doses of radiation than used presently, the precise indications for combination therapy in this group are unclear, it does appear that a subgroup of men, who usually ﬁt within the typical intermediate risk proﬁle, will beneﬁt from short term neoadjuvant therapy. Toxicity: The major concerns with EBRT are damage to normal tissues at risk viz. the rectum, bladder/urethra as well as the neurovascularity involved with erectile function. Modern planning systems have capabilities to produce detailed descriptions of 55

Chapter 10. PROSTATE CANCER the dose to structures of interest (dose-volume histograms). Applying accurate constraints to these parameters is partly the explanation for the observation that serious toxicity from modern 3D EBRT is uncommon, with evidence suggesting that it is less common now than with previous EBRT planning and treatment techniques, even those previously using much lower doses (519). During a typical radical course of EBRT, symptomatic urinary toxicity occurs in most men which can be a combination of so-called irritative or obstructive symptoms. Grade I-II toxicity typically not requiring any or only minor medical intervention happens in approximately 50%, while serious problems potentially requiring invasive intervention happen in less than 1%. Urethral stricturing is a major concern after radiotherapy in high doses, and occur in approximately <1% presently. Towards the end of a course of radiotherapy, most men will be aware of some rectal urgency associated with frequency. Rectal bleeding during or soon after therapy occurs in 0-2% of men in modern series (519) with the late bleeding rate being approximately 1% also. A measurable, but not clinically problematic, change in bowel habit will be observed in 10-20% (519). Changes in erectile function related to increases in radiation dose are yet to be adequately documented in long-term data from large scale randomised dose trials. Observational series do suggest that in those with adequate erections prior to radiotherapy, 50% will maintain erectile function for more than 2 years (520). The control arm (radiation alone to 66Gy) of a large Australian randomised trial showed that 1 year after radiotherapy, approximately half of the patients sexually active prior to treatment remained active (376). This trial also showed that the addition of AS to radiotherapy does not appear to increase the toxicity of radiotherapy beyond that seen with radiation alone, in agreement with other published results (521).

D. Brachytherapy
Brachytherapy (BT) for prostate cancer can involve 2 forms of interstitial implant therapy, either permanent low dose-rate (LDR) radioactive seed implant or a temporary high dose-rate (HDR) implant.

(i) LDR seed implant
For men with early stage prostate cancer, the use of seed BT has increased dramatically over the past decade with potentially a quarter of all early cancers now being treated this way in the USA (522). The modern technique uses accurate imaging and guidance systems to place metal seeds, containing either Iodine125 or Palladium103 as the radioactive source, in a planned array within the prostate to deliver a conformal dose of radiotherapy. Typically a TRUS unit is used to image the prostate in real-time (with CT or MRI used in some centres) and a template utilised to guide needles loaded with the seeds into the prostate transperineally. The procedure is usually relatively simple and brief from the patient’s viewpoint, often administered in an outpatient setting, making it attractive to many. A number of series have now reported both PSA and toxicity outcomes for many thousands of men treated this way (523, 524). Although the longterm results published for this procedure amount to beyond 10 years at only a few centres (525, 526), the tumour control rates appear to be similar to those of surgery. Biochemical control rates for those in the low risk group are presently greater than 85% (524, 525, 527), and shown to be equivalent or better than results of similar EBRT treated cohorts. Moving beyond the low risk category, the use of seed BT as the sole treatment modality almost universally shows an increase in the biochemical failure (BF) rates. In these cases, recommendations range from using seed BT in combination with EBRT, in combination with AS, or using EBRT only. No randomised evidence exists to help with this decision, however, there is considerable experience using seed BT in combination with EBRT indicating potential for good outcomes in this group 56

Chapter 10. PROSTATE CANCER (528). High risk men typically do poorly with seed BT alone and are rarely considered suitable for this therapy. Toxicity Following a seed implant, the dose of radiation is delivered over some months, depending on the half-life of the isotope. The predominant toxicity of the implant is that of urinary irritation, and typically the symptoms peak at 2-10 weeks (isotoperelated) and the majority will have returned to normal at 12 months (529). These initial symptoms can be troublesome, with most series reporting rises in the International Prostate Symptom Score of 7-12 units at their worst, indicating moderate bother (373, 530, 531). Rectal toxicity is uncommon, with bleeding or ﬁstula formation occurring in <1% (532). Erectile function maintenance has been reported in a number of prospective brachytherapy studies. The highly conformal dose distribution of seed BT theoretically may reduce the dose of radiation to the structures important for maintaining erectile function, and this seems to be demonstrated in the relatively early ﬁgures. The loss of adequate erectile function rates appears to occur in 30-50% of patients by 3 years (533, 534) and longer term results are awaited.

(ii) HDR temporary implant
HDR brachytherapy of the prostate has been utilised in a number of centres now for well over a decade (535-541). Proponents of the technique are in favour of the highly conformal nature of the radiation dosimetry able to be achieved with HDR, as well as a theoretical biological advantage in prostate cancer (542). It is performed by placing a series of ﬁne BT catheters in the prostate transperineally, using a technique similar to the guidance of the needles for LDR seed BT. These are subsequently loaded with a radioactive source which sits at various positions in the catheters for various durations to build up a dose of radiation as predetermined by a computer planning system. It is typically used in combination with a truncated course of EBRT, although there are experimental protocols in place for using it as monotherapy. Results using this technique are encouraging, and would appear to justify the theoretical basis of its use. Series routinely report freedom from biochemical failure results of better than 90% and better than 80% for low and intermediate risk patients respectively (537, 539, 540). Late urinary complications (grade 3) appear to occur in about 5%, and are typically ‘obstructive’ symptoms. Signiﬁcant rectal toxicity is uncommon; the maintenance of erectile function is poorly reported to date.

E. Deﬁning biochemical failure (BF) after radiotherapy
The deﬁnition of therapeutic failure based on the post-radiotherapy PSA proﬁle (“biochemical failure”) is a more difﬁcult prospect than following radical prostatectomy. After surgery, essentially all the PSA-secreting tissue is removed, and hence an undetectable level is considered desirable. Naturally, this situation does not exist following radiotherapy; with the prostate remaining in situ with variable residual function. Early after the inception of PSA testing, the publication of BF results was based on a variety of interpretations which were felt by individuals to describe a high likelihood of recurrent disease. In response to concerns regarding the potential lack comparability of such published results, an ASTRO consensus panel was convened in 1996 to discuss future BF publication criteria. The panel considered data from a number of clinical databases, all treated with external beam therapy. The subsequently published deﬁnition of BF, known as the ASTRO consensus deﬁnition (ACD), stipulated BF to have occurred when three consecutive PSA rises are seen and the date of failure to be retrospectively backdated to the 57

Chapter 10. PROSTATE CANCER midpoint of the PSA nadir and ﬁrst rise. This was largely based on the ﬁnding that three consecutive PSA rises was followed by a further rise in 89% of cases, plus the clinically plausible argument that the recurrence actually commenced well prior to the conﬁrmatory third rise. Relatively little was known at the time regarding the relationship between the ACD BF status and clinical endpoints (543). The ACD has been widely embraced for the analysis of post-radiotherapy results. A large number of concerns about its performance have been raised however. Although BF would appear to occur rarely after 5 years using the ACD, the reliability of the results are known to be highly dependent on the duration of follow-up. Practically this has shown to potentially worsen the derived freedom from BF (FFBF) rate by approximately 25% when the same data is analysed at a median follow-up of 6 years against that obtained at 2 years (544). This creates difﬁculty when examining the results of more recent series (for example, a new treatment technique) with historical data; the contemporary data will be favourably biased. This phenomenon is known to be an artefact of the backdating in the ACD. Furthermore, the known independent prognostic value of ACD BF and overall survival (relative risk 1.27) is substantially weakened by backdating (545). The ACD has also been criticised for having unpredictable results when applied to treatment modalities other than EBRT, for which it was not planned to be utilised. False positive results can be problematic with seed brachytherapy, where benign PSA ﬂuctuations (“bounces”) are seen in approximately one-third of cases (546). Similarly, when the testosterone recovers after combined AS and radiotherapy there may be a concurrent PSA rise of a level sufﬁcient to trigger ACD BF in up to approximately 20% of cases (547, 548). There is poor applicability to surgical data, with backdating particularly creating differences in the late risk of failure (468). A further surgical analysis suggested that the ACD may underestimate the risk of BF by as much as 30%, however this study illustrates the propensity for the ACD to be misinterpreted (549). By stipulating the nadir date to be the date of surgery, rather than the deﬁned last non-rising PSA date, the backdating effect was exaggerated to the theoretical extreme, further reinforcing the ﬁnding that the there are multiple areas of potential misinterpretation in the ACD (550), and that original publication guidelines are poorly adhered to (551). A number of analyses of very large and mature patient cohorts have been published which suggest alternative BF deﬁnitions may be superior to the ACD. These have focused on the correlation of PSA dynamics and subsequent clinical events in the aim of ﬁnding a BF deﬁnition which is both sensitive in detecting recurrence early, yet speciﬁc to those factors which are likely to be clinically relevant in the future – data which was unknown at the time of the original consensus meeting. The most ambitious undertaking was that of Thames et al (2003) (552). This study assimilated PSA and clinical outcomes of 4839 T1-T2 prostate cancer patients from nine USA institutions treated with EBRT without planned AS. A total of 102 different definitions of BF were assessed using a variety of quantitative measures of prediction of clinical failure. A number of deﬁnitions were found to have substantially better performance than the ACD. In particular, nadir (the lowest level to date) plus either 2 or 3 ng/mL showed good sensitivity, speciﬁcity and predictive indices in relation to clinical failure without resorting to backdating and prospective in nature (that is, it used only the PSA data available prior to failure, as would happen in the clinic). The nadir + 2 ng/mL deﬁnition, for example, showed a sensitivity, speciﬁcity and relative risk of clinical failure of 0.74, 0.84 and 58.4 respectively, while the ACD had respective values of 0.61, 0.80 and 7.0. Similarly, Kestin et al (2004) (553) used the mature data of 727 men to show the nadir + 2 ng/mL deﬁnition had a 73% versus 3% rate of clinical failure at 10 years for those who were deemed as BF or not respectively, while the ACD had 64% against 14%. Further analysis of the sensitivity and speciﬁcity characteristics using receiver operating characteristics show that the optimum balance appears with the nadir + 2 ng/ml or an absolute level of 3 ng/ml deﬁnitions (554). Analysis of the interaction of various BF deﬁnitions and AS therapy have been per58

Chapter 10. PROSTATE CANCER formed by Pickles et al (2003) (548). The nadir + 2 ng/mL performed better in terms of predicting clinical failure in their cohort of 1490 patients, and especially so in those previously receiving AS, and this was also conﬁrmed by Zietman et al (2005) (547). It would also appear that the deﬁnition of the nadir + 2 ng/mL style will be relatively unlikely to be inﬂuenced by PSA bounces related to seed brachytherapy, given the median bounce level is 0.4-0.7 ng/mL (546) and less than 3% are of sufﬁcient level to trigger a false positive BF with this deﬁnition (555). In view of the considerable advances in the understanding of PSA biology following radiotherapy, another consensus meeting to discuss an update to the ACD was convened in January 2005. Results from this meeting are expected soon.

F. Management of local failure after radiotherapy
A detectable and rising PSA above the nadir value following radiation therapy may represent local or distant failure, or both. Determining the site or sites of tumour, although highly desirable, is notoroiously difﬁcult with currently available diagnostic techniques with BF often preceding clinically evidence of metastases by several years. Consequently, a diagnosis of localized disease without metastases, can be only inferred. However, selecting the most appropriate therapeutic approach may be aided by reference to initial clinical staging, PSA and Gleason score from TRUS biopsies. In addition to pre-treatment clinical and post-treatment pathological factors, PSA kinetics and, speciﬁcally, a pretreatment PSA velocity >2 ng/ml/year, an interval to PSA failure <3 years and a post-treatment PSA doubling time <3 months place a man at increased risk for metastases and subsequent prostate cancer-speciﬁc mortality, making these patients poor candidates for local-only salvage therapy. Men with any Gleason 8-10 tumour in their TRUS biopsy cores or those whose cores indicated seminal vesicle involvement are also very likely to have non-localised disease. As a result, Lee and D’Amico (2005) (556) identiﬁed an optimal candidate for local-only salvage therapy as one whose pretreatment PSA velocity was <2 ng/ml/year, interval to PSA failure exceeded 3 years, post-treatment PSA doubling time was at least 12 months and whose TRUS biopsy cores contained a Gleason score of less than 8 (556). Touma et al (2005) (557) reviewed the current status of local salvage therapies following radiation failure for prostate cancer, reporting that salvage RRP offered 5-year biochemical relapse-free rates of 55 to 69%. They identiﬁed a life expectancy of at least 10 years, pre-radiation and pre-operative PSA <10 ng/ml and localized preoperative stage as desirable factors for RRP after radiotherapy failure. However, patients need to be aware that higher complication rates are to be expected compared with primary RRP, which include rectal injuries, bladder neck contracture and urinary incontinence (557). As discussed above in Section VII, the most appropriate application of cryotherapy is for patients with bulky local disease and local recurrence after radiation therapy (315). Touma et al (2005) (557) noted that urinary incontinence, impotence, pelvic pain and urinary retention were the major side effects of salvage cryotherapy cited and considered salvage cryotherapy to be a valid option in hormonally naïve patients with preoperative PSA <10 ng/ml, Gleason score <8 and clinical stage <T3, being especially suitable for older men with some comorbidities but who are still considered to be reasonable anesthetic risks (557). HIFU (also addressed brieﬂy in Section VII) may have a role in these types of patients but relevant data to make this assertion are not yet available (313). Apart from local treatments, androgen suppression treatments may be considered (detailed in Section XIII, below).

G. Quality of life issues in prostate cancer radiotherapy
Considerable interest exists regarding the treatment modality in early prostate cancer, and the impact it has on the patient’s quality of life (QOL). Once more, randomised 59

Chapter 10. PROSTATE CANCER data are lacking, although at least three large prospective series have now been published comparing treatment modalities (413, 558, 559). EBRT was typically associated with the most bowel dysfunction, which settles over 1-2 years, and then tends to be stable. Acute urinary bother is mild, but signiﬁcant worsening of symptoms at later stages (beyond 5 years) has been reported and requires further investigation (559). Sexual function consistently deteriorated over time in all series after EBRT, although notably, at the same rate as the untreated controls of one series. Seed BT has initial elevation of urinary bother that settles to a large degree in the ﬁrst 2 years. There is however, the suggestion that there may be subsequent deterioration of continence over the next 4 years. This has not been corroborated in other studies to date (560). Rectal morbidity, although typically minor, is documented to steadily settle with time. Erectile function deteriorates in the initial 1-2 years typically, but the longer term results of one series suggest little change in the QOL impact of this beyond that time. Each of these series had a RRP control arm for comparison, which yielded consistent ﬁndings. RRP always led to a high QOL impact in terms of urinary continence and sexual dysfunction within the ﬁrst 6 months post-therapy. These both improve over the ﬁrst 2 years, but should be considered likely to remain stable beyond that time. Long-term follow-up comparisons in well designed trials will be required to ultimately decide the overall QOL trade-offs with each particular therapy.

XIII. SYSTEMIC THERAPIES
Although much attention is focussed on early diagnosis and localised disease, a considerable proportion of patients continues to present with extra-prostatic disease (561). In addition, approximately 25% of men treated initially with curative intent experience prostate speciﬁc antigen (PSA) failure or develop clinically detectable metastases within 5 years following therapy (562). The cornerstone of treatment for patients with prostate cancer metastases is hormonal manipulation: approximately 80% of patients have a durable clinical regression with androgen suppression therapy.

A. Hormonal Therapy
It is now well over 60 years since Huggins and Hodges reported their observation (308, 309) that prostate cancer was an androgen dependent tumour which regressed following bilateral orchidectomy. In the interim, a number of alternative methods have become available for achieving castrate testosterone levels. These include bilateral orchidectomy/orchiectomy (regarded as the reference treatment), Luteinising Hormone Releasing Hormone (LHRH) agonists, antiandrogens and oestrogens, all of which have signiﬁcant adverse or unwanted effects.

(i) Bilateral orchidectomy/orchiectomy, LHRH agonists & antiandrogens:
Historically, bilateral orchidectomy has been the reference treatment for advanced prostate cancer which, by targeting the major source of androgen production, dramatically diminishes the number of tumour epithelial cells and accompanying neovasculature. LHRH agonists, after initially stimulating LH and hence testosterone synthesis by the testicles, occupy LHRH receptors to prevent subsequent production of both these hormones. In addition, LHRH agonists can have a a further action by targeting LHRH receptors on prostate tumour cells (563, 564). The unwanted effects of bilateral orchidectomy and LHRH agonists are generally considered to be comparable apart from the fact that the former requires an opera60

Chapter 10. PROSTATE CANCER tion, with physical and possible psychological consequences, and the latter necessitates regular interval injections and commencement of therapy has an accompanying risk of an initial surge in testosterone (the so-called ﬂare reaction) due the drug initially stimulating production of luteinising hormone before blocking production. Reduced libido and impotence are to be expected following surgical or medical castration together with a loss of bone substance and muscle mass. As a condition, osteoporosis is underdiagnosed in men and it is only relatively recently that its relationship with bilateral orchidectomy and LHRH agonists has been appreciated (565567). The high prevalence of osteoporosis together with its debilitating consequence of bone fractures has prompted advocacy for the use of bisphosphonates in prostate cancer patients, especially those committed to longstanding castration (see below). Hot ﬂushes can be problematic for many men and tiredness from anaemia can compound debility. A minority of men receiving LHRH analogues develop gynaecomastia. The American Society of Clinical Oncology recommends bilateral orchidectomy or LHRH agonists as initial androgen suppression treatments (568). Non-steroidal antiandrogens may be considered alternatives but the steroidal anti-androgen cyproterone acetate should not be offered as monotherapy (568). The UK Committee on the Safety of Medicines recommends that, because of the risk of hepatotoxicity, cyproterone use in prostate cancer should be restricted to short courses unless patients are unresponsive to or intolerant of other treatments. Unwanted effects with nonsteroidal antiandrogens are common with gynaecomastia and breast pain troublesome for many: a cessation rate for these medications has been reported to be 4-10%, in particular with ﬂutamide (568, 569). Hepatotoxicity is a potential problem with all antiandrogens but especially cyproterone acetate.( 568). Green et al (2004) (570) reported the results of our study of 82 men randomised to leuprorelin (Lucrin™), goserelin (Zoladex™), cyproterone acetate (Androcur™) or watchful waiting, 62 of whom completed 12 months of follow-up. In addition to a non-treatment (watchful waiting) control group, a non-cancer community reference group was also evaluated. Findings were compared in relation to cognition and quality of life. Most patients had serum PSA levels between 30 and 60 ng/ml at baseline. Using well-validated and established instruments, they found that ~50% of men in all treatment groups, but none of the controls, had signiﬁcant cognitive deterioration at 12 months, in particular in relation to complex information processing. Although the cognitive defects were of a magnitude comparable with sleep-deprivation or mild inebriation, there was no consistent association between subjective cognitive changes and objective deﬁcits. In addition, there were more instances of a deterioration of quality of life for the men on hormonal treatments at 12 months, in particular in relation to sexual function (570). Unlike other studies addressing cognition and quality of life, Green et al’s paper is important as all patients were randomised to management regimens which included a non-drug (control) arm and this study was completely independent of any industry-sponsorship. Consequently, these ﬁndings are much more compelling than those reported from less robustly designed studies and those trials sponsored or supported by industry (571-577)

(ii) Oestrogens
Oral oestrogen therapy, the most common form of androgen suppressive medication for many years, is now rarely used as ﬁrst line hormonal treatment because of associated cardiovascular complications with oral administration, although this route of delivery is employed not uncommonly in Japan for a short period to offset the ﬂare effect of LHRH agonists (578). An increased cardiovascular morbidity was reported to be present with the oral form of oestrogens even in patients without overt cardiovascular disease affecting one quarter of such patients during their ﬁrst year of treatment (579). However, a dose-response relationship is said to be present in terms of cardiovascular morbidity and mortality with one mg daily of diethylstilboestrol 61

Chapter 10. PROSTATE CANCER (DES) (with or without aspirin) stated to be comparable with bilateral orchidectomy in the treatment of advanced disease but without increased cardiovascular complications. Klotz et al (1999) (580) found that venous thrombosis was not prevented when DES was prescribed together with low-dose warfarin (580). The increased susceptibility to cardiovascular complications in patients taking oestrogens appears to be critically related to the route of administration. This predeliction is reported to be signiﬁcantly reduced (581) or avoided by parenteral delivery. An increased synthesis of coagulation factors, in particular Factor VII, results from oral oestrogen therapy and this is thought to be responsible for the increased rate of cardiovascular problems in these patients (582, 583). Consequently, many investigators have advocated a re-evaluation of oestrogen treatment (584-587), especially since all forms of oestrogen, including parenteral and transdermal patch preparations, are cheap (588) and, unlike bilateral orchidectomy and LHRH agonists in particular, this medication is not considered to induce osteoporosis ( 581). Furthermore, oestrogens may have a role in ameliorating agitation in some men receiving LHRH agonists. Ockrim et al (2003) (589) reported their experience with 20 men with newly diagnosed locally advanced or metastatic prostate cancer treated with transdermal estradiol patches in particular in relation to bone mineral density. They found that at 1 year that the mean bone mineral density had increased by 3.6% and concluded that transdermal estradiol protects against bone loss in men with prostate cancer and may improve bone density in those at risk for osteoporotic fracture. Local experience with this form of delivery has been that patch displacement can occur with sweating, especially in active men: serial serum testosterone levels may be used to optimise the frequency and duration of patch application.

(iii) Commencement of hormone therapy
Despite many attempts to demonstrate otherwise, there is no clear evidence that commencing androgen suppression therapy early improves survival (568, 590). Early commencement does, however, increase the likelihood and duration of unwanted effects. Since in terms of lifestyle effects, commencing androgen suppression is likely to adversely affect libido, potency, physical mobility and strength, body habitus, cognition and liver function (with anti-androgens), a body of clinicians advocates carefully delaying commencement by balancing the unwanted effects of treatment with those of the disease being treated. In conjunction with patients’ wishes, PSA doubling times and development of lesions on bone scans can be helpful in deciding when to commence androgen suppression. By upsetting homeostasis at a molecular level, androgen suppressive therapies may in fact contribute to tumour progression in those remaining prostate cancer cells after commencement of treatment (38). Unlike androgen receptors which are sited in prostate epithelial cells, oestrogen receptors are present in both epithelial and stromal cells. Compartmentalisation of the two ERs is reported with ERα exclusively in stroma and ERβ predominantly in the epithelial compartment (38, 591). ERβ is considered to have a role against prostate cancer dedifferentiation in contrast to the proliferative effect of ERα and androgens (592). In prostatic epithelial cells, testosterone is reduced by 5α-reductase to dihydrotestosterone which, in turn, is converted into 3α-diol and 3β -Adiol. Unlike testosterone and dihydrotestosterone, these two metabolites do not bind to the androgen receptor but possess high afﬁnity for oestrogen receptors. By binding to estrogen receptor β (ERβ ), 3β -Adiol induces expression of the cell adhesion molecule E-cadherin, the presence of which in prostate cancer cell membranes is associated with a less aggressive phenotype. Decreased expression of many C-CAMs including E-cadherin, have been associated with the progression of prostate cancer (38,107). However, there are many clinicians and patients who become pre-occupied with lowering the serum PSA levels at all costs. A survey of American Urologists indicated that 68% recommended hormone suppression therapy for an elevated PSA after radical prostatectomy (562, 593). Thus, an increasing PSA often serves as the trigger for 62

Chapter 10. PROSTATE CANCER commencement of what translates into long-term androgen suppressive therapy for a large proportion of patients in spite of a lack of clear evidence of a survival beneﬁt with early treatment (594, 595).

(iv) Combined androgen Blockade (CAB)/Maximum Adrogen Blockade (MAD)
Since bilateral orchidectomy and LHRH analogue treatment address testicular androgen production exclusively and a small contribution to overall androgen levels is made by adrenal androgens, CAB was initiated. However, despite extensive trialling, only a modest survival beneﬁt has been demonstrated but at the cost of a higher sideeffect proﬁle for patients (596). The limited survival beneﬁt appears to be associated with the use of non-steroidal antiandrogens and only becomes evident after 5 years of therapy. This topic has been reviewed recently by Loblaw et al (2004) (568).

(v) Intermittent Androgen Blockade (IAB)
Intermittent hormone therapy was instituted to lessen the duration of unwanted effects from androgen suppression therapy, usually being limited to those patients who demonstrate a pronounced PSA response and ﬁnd the unwanted effects of androgen suppression problematical. However, this approach to androgen delivery begs the question, why was the treatment started when it was since, most often, IAB seems to be used for men who commenced their androgen suppression very early. Other issues with IAB are that not all the adverse affects of androgen suppression are reversible and recovery of the hypothalamic-pituitary-testicular axis is variable, especially after prolonged LHRH administration. Indeed, castrate levels of testosterone and LH may persist for up to 1 year (or even longer) after discontinuing LHRH agonist treatment (597).

(vi) Hormone escape
Once prostate cancer metastasizes following effective androgen suppression therapy, its toll, with regard to pain, suffering, and disability, can be considerable due to incapacitating sequelae of disseminated and hormone-refractory disease, for which no curative treatments currently exist. PSA evidence of hormone escape usually precedes other barometers of disease progression and metastasis. Newling et al (1993) (598) reported that, for men with newly diagnosed metastatic prostate cancer who were randomised in the EORTC study 30853 to receive goserelin and ﬂutamide or bilateral orchidectomy, the median time for survival following PSA progression was 52 weeks compared with 41 weeks for bone metastases and 28 weeks and 33 weeks for progression of regional and distant lymph nodes, respectively (598). However, as suggested by a reducing mortality rate for this condition in many countries, these estimates may no longer be accurate for a variety of reasons addressed throughout this chapter. As outlined above, prostate cancer has a particular predilection for androgens that serve as this malignancy’s preferred ligand. When androgen suppression is invoked initially, the tumour regression effect can be dramatic with both epithelial cells and tumour neovasculature being affected signiﬁcantly (599). However, tumour repression is not permanent with a median time to relapse of 18 months (600). Nevertheless, maintaining suppression of circulating androgens remains important as the androgen receptor pathway continues to be very active in ‘hormone escape’ patients. Ampliﬁcation and overexpression of the androgen receptor gene, as well as posttranslational modiﬁcations to the AR occur, resulting in the cancer cells becoming ‘super-sensitive’ to androgens (601-603). In conjunction with these changes is activation of other genes that, through signal transduction pathways, facilitate receptivity to a variety of ligands including other 63

Chapter 10. PROSTATE CANCER hormones and drugs, especially antiandrogens (604). Consequently stopping an antiandrogen may afford a temporary respite to tumour regression manifested by a reduction of serum PSA in some patients (605). Paradoxically, for those patients receiving monotherapy in the form of LHRH agonists or a previous bilateral orchidectomy, the addition of an antiandrogen may cause a clinical regression for a short time and this is often recommended before proceeding to chemotherapy or radiotherapy in the form of radio-isotopes or local external beam treatment to isolated troublesome secondary deposits. Recent research has provided support for modulation of the oestrogen receptor axis in disease no longer responding to androgen suppression by LHRH agonists, bilateral orchidectomy or antiandrogens by targeting oestrogen receptors in metastatic disease (606). Hormone-refractory prostate cancer is said to be present when there is evidence of progression despite the use of ﬁrst and second line hormonal manipulation. Although the administration of bisphosphonate and chemotherapeutic interventions may provide beneﬁt in the short term (see below) these palliating approaches merely serve to temporise the situation in this subterminal/terminal phase of the disease. Clarke (2003) (607) divided the urological issues to be considered into: 1. Lower urinary tract dysfunction 2. Ureteric obstruction 3. Skeletal, dysfunction 4. Bone mrrow insufﬁciency 5. Lymphoedema 6. Rectal obstruction/inﬁltration 7. Pain 8. Psychological dysfunction/impaired quality of life. It is this last point in particular which needs to be considered paramount so that unreasonable attempts to prolong life are not undertaken, especially when these are not in concert with individual patient’s wishes. For example, it may be preferable not to treat ureteric obstruction and allow the patient to die painlessly from uraemia than protract his demise for a short but miserable period by instigating various interventions. A number of other disciplines are often involved at this stage as indicated, which include medical and radiation oncology, interventional radiology, pain management specialists and palliative care clinicians amongst others. It is important that pastoral care support is available as appropriate. A further web-site is: http://www.cancer.gov/cancertopics/understanding-prostate-cancertreatment/page6

B. Chemotherapy
In reports published to 1991, the rates of objective clinical response of prostate cancer to available cytotoxic agents were disappointingly poor. A summary overall response rate of just 8.7% (with a 95% conﬁdence interval of 6.4-9.0%) was responsible for Yagoda and Petrylak (608) concluding hormone-refractory prostate cancer to be unresponsive to conventional chemotherapy of the time. Initial randomised data for the use of mitoxantrone chemotherapy in prostate cancer (thought to be the most effective agent of the period) became available in 1996 with the publication by Tannock et al (609). By randomising 161 men with symptomatic hormone-refractory disease, they were able to show a signiﬁcant reduction in the need for analgesia (the primary end-point) in those who received mitoxantrone plus 64

Chapter 10. PROSTATE CANCER prednisone compared with the control arm of prednisone only. Analgesic responses were also substantially longer in the chemotherapy arm. In a subsequent CALGB trial looking at survival end-points, no survival beneﬁt was shown when mitoxantrone was added to hydrocortisone, although there was an overall improvement in the quality of life and duration of analgesic response (8 months on average) in those on the chemotherapy arm (610). Further preclinical activity had also been suggested when prostate cancer was exposed to taxanes, a class of microtubule stabilising agents. Predominately, these agents work by blocking the ability of cells to depolymerize the microtubule cytoskeleton during normal mitosis, thus inducing a lethal cell cycle arrest at the G2M phase. In particular, docetaxel appeared the most active form and was taken to clinical testing. A number of phase I/II trials were conducted using either single agent docetaxel or in combination with estramustine, an agent thought to possibly potentiate the taxane effect by acting on a different microtubule pathway. Used as single agent therapy, docetaxel showed signiﬁcant PSA responses (a PSA level decline of greater than 50%) in 38-48%, and up to 68% in the combination therapy trials (611). Responses in measurable soft tissue disease ranged from 20-55%. Neutropenia was a feature in over two-thirds of the patients treated on a three weekly single agent docetaxel schedule, and less common when given weekly. Similar toxicity was seen with the combination therapy trials, except for the addition of thrombo-embolic complications in up to 10% related to the estramustine. Large randomised trials to comprehensively test the efﬁcacy of docetaxel in advanced hormone-refractory prostate cancer, in comparison with mitoxantrone, have now been published. The TAX 327 trial of Tannock et al (612) randomly allocated 1006 patients to one of three treatment arms, the ‘control reference’ being three weekly mitoxantrone plus prednisone (M/P): the docetaxel arms were given either weekly for 5 of 6 weeks or three weekly with prednisone (D/P). The three weekly schedule of D/P showed a signiﬁcantly improved overall survival compared with M/P, with the risk of death reduced by 24% (95% CI 0.62-0.94, p=0.009) leading to a median survival prolongation of 2.5 months (18.9 against 16.5 months). Other signiﬁcant beneﬁts were seen in the decrease of PSA levels, analgesic responses and the patientreported quality of life assessment in the D/P group. Toxicity was lowest in the M/P arm, while the highest in the weekly D/P group. As this group did not, however, show a survival beneﬁt, it was concluded that the three weekly schedule of D/P was optimal. The other phase III trial was conducted by the SouthWest Oncology Group (SWOG) and accrued 674 eligible patients to either receive M/P or docetaxel and estramustine (D/E) three weekly (613). Using the primary overall survival endpoint, a signiﬁcant beneﬁt was found for the D/E arm, with the median survival increasing from 15.6 to 17.5 months associated with a hazard ratio of 0.80. PSA declines of >50% were seen in 50% of D/E men, and 27% of those on M/P (p<0.001). Pain relief was not signiﬁcantly different between the arms and there was substantially more toxicity in those having D/E, although the neutropenia rates were comparable. The consistency of the results between these large trials has demonstrated that alteration of the natural history of hormone-refractory prostate cancer can be made using cytotoxic agents, and survival advantages, albeit small, can be made. Therefore, in the context of a patient with a rising PSA on hormonal therapy, the ﬁrst line use of docetaxel-based chemotherapy is considered standard of care by many. For those not medically suitable for this therapy, mitoxantrone-based therapy should still be considered for its known palliative capacity in those with symptomatic disease, along with lesser toxicity.

C Bisphosphonates
Bisphosphonates were initially examined for the prophylaxis and treatment of os65

Chapter 10. PROSTATE CANCER teoporosis, particularly in women (614) but, more recently, for osteoporosis in men following androgen deprivation +/- external beam radiotherapy (614, 615). Bisphosphonates inhibit osteoclast activity so, in addition to their potentially protective effect with respect to the development of osteoporosis there is a possible role in metastatic bone disease. Osteoclast activity is an integral part of the metastatic process for both osteolytic and, more commonly, osteoblastic bone metastases in prostate cancer (616). Most experience with bisphosphonates in cancer has been with multiple myeloma and breast cancer patients but results from these studies cannot be extrapolated to men with prostate cancer. In addition, not all bisphosphonates are equal with studies with the ﬁrst generation compound Clodronate failing to show a clear advantage compared with placebo (617). However, the third generation bisphosphonate zoledronic acid did demonstrate increased apoptosis in prostate cancer cell lines in vitro and inhibited growth of osteoblastic and osteolytic metastases in vivo (618). Furthermore, Zoledronate has been shown recently to expand γδ T cells which exhibit cytolytic activity independent of MHC (see next section; (619). Saad et al (2002) (620) reported their experience with 4 mg and 8 mg of zoledronic acid given intravenously 3-weekly over 5 minutes initially, but subsequently 15 minutes to increase renal safety, in a double-blind randomised controlled trial for 15 months. A total of 643 patients with documented bone metastases were randomised to one of the 3 groups. Only 98/214 (45.8%) and 77/221 (35.3%) of the patients who initially received 4 mg and 8 mg of zoledronic acid, respectively, received at least 12 months of study drug compared with 77/208 (37%) randomised to placebo. The 8 mg dose was reduced to 4 mg during the study because of renal toxicity. The reasons for discontinuation were withdrawal of consent, adverse events and death, most common in the 8/4mg zoledronic acid group, and unsatisfactory therapeutic effect, especially in the placebo group. During the study, at least one skeletal-related event occurred in 71 (33.2%) compared with 92 (44.2%) of patients randomised to 4 mg zoledronic acid and placebo, respectively. Pain and analgesic scores increased more in patients who received placebo than zoledronic acid but there were no differences in disease progression, performance status or quality-of-life scores among the groups (620). Saad et al (2004) (621) subsequently reported the results from 122 men who completed a total of 24 months on study. Fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%). The median time to the ﬁrst skeletal related event was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36%. These authors concluded that long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical beneﬁts for men with metastatic hormone-refractory prostate cancer. Since the optimal timing for commencing administration of zoledronate may be at an earlier phase in the disease, trials are underway with patients with hormone sensitive rather than refractory disease.

D Bone-seeking radio-isotopes
Widespread skeletal metastases may not be easily amenable to relatively localised external beam radiotherapy. The systemic use of bone-seeking radio-isotopes can be useful in this situation, with proven efﬁcacy for two agents – Strontium89 and Samarium153-ethylenediaminetetramethylene (EDTMP). Strontium89 (Sr89) is an agent which behaves biologically in a manner analogous to calcium (with which it shares a relationship on the periodic table of elements), and hence is incorporated into sclerotic bone metastases avidly. It is a pure beta emitter, with a half-life of approximately 50 days, although half is typically excreted from the body in 2 weeks (mainly in the urine). Samarium153 is chelated to EDTMP to enable preferential binding to bone. Physically it has a much shorter half-life (46 hours) than strontium89 and has gamma as well as beta emissions, enabling imaging on 66

Chapter 10. PROSTATE CANCER gamma cameras. Producing radiation damage for only a short distance in tissues, these agents concentrate effect in bone metastases with little deposition of dose in soft tissues. Following intravenous administration, maximal effect on pain is usually seen in 24 weeks. Randomised trials comparing Sr89 against or in combination with EBRT showed no signiﬁcant difference in analgesic efﬁcacy, although the occurrence of new areas of pain and analgesic requirements was signiﬁcantly reduced in two randomised series (622, 623), although one other suggested inferiority to EBRT (624). Similar efﬁcacy is reported for Samarium153 (625, 626), with both typically reducing pain to some degree in 70% of patients, an effect which lasts for 3-4 months on average. A small percentage of patients will experience a ﬂare (a temporary increase) in pain in the ﬁrst week. The predominate toxicity of these agents is that of bone marrow suppression, and in particular, most patients will have a measurable decrease in the platelet count (on average a 30% drop) or white cell count. Repeat doses must therefore be given with caution (especially within 3 months) and close monitoring of the blood count will be required. This will be a prime concern in patients being considered for chemotherapy. These agents are presently being further investigated for their efﬁcacy in combination with chemotherapy (627, 628).

E. Emerging Therapies: Vaccines in Prostate cancer
(i) Introduction
Of the various treatment approaches being examined for prostate cancer, nothing seems to have captured the public’s imagination quite as vividly as have vaccines. Although considerable advances have been made in understanding the processes involved with different vaccine approaches, overall clinical results remain modest so, with changes being implemented continually this form of therapy must still be regarded as experimental. Historically, the prostate was considered to be an “immunologically privileged” site (629, 630) and was regarded as lacking a network of intraprostatic (631) and afferent lymphatics (632) . Although neither McCullough nor Gittes was able to demonstrate extraprostatic lymphatic drainage following intra-glandular injections of iodinated emulsiﬁed oils and India ink carbon particles, respectively (629), Gardiner et al in 1979 described lymphoscintigraphic evidence of lymphatic drainage following intraglandular injections of technetium labelled antimony sulphide colloid into clinically benign prostates of volunteer patients (633, 634) That intraprostatic lymphatics do exist was elegantly demonstrated by Zeng et al (2004, 2005) (635, 636) who showed recently that, not only does the prostate contain lymphatics, but peritumoural lymhangiogenesis is demonstrable within prostates harbouring cancer. Furthermore, they found a relationship between peri-tumoural lymphatic vessel density and the presence of lymph node metastases (635, 636). Further endorsement of Zeng et al’s ﬁndings (635, 636) in relation to ﬁnally destroying the myth of the prostate being an ‘immunologically privileged’ site, is Vesulainen et al’s report that lymphocytic inﬁltrates correlate with an improved 10-year survival for patients with primary prostate cancer (637). This observation by Vesalainen et al (1994) (637) also serves to encourage approaches to enhance lymphocytic inﬁltration with enhancement of its cytotoxic activity through prostate cancer immunotherapy.

(ii) Effector arms available for recruitment for cell killing in tumour vaccines
Active vaccination strategies can exploit a number of candidate immunological cells as effectors or mediators for immunological therapies (638). These include: 67

Chapter 10. PROSTATE CANCER 1. B cells with production of antibodies 2. Monocytes/macrophages 3. Natural killer (NK) cells 4. NK T-cells 5. γδ T-cells 6. αβ Cytotoxic CD8+ T-cells 7. αβ CD4+ Helper T-cells A primitive level of tumour target recognition can be employed by monocytes, involving interactions with overabundant or aberrant cell surface molecules on cancers. NK cells, which provide the earliest effector mechanism against disseminated blood-borne metastases, identify absence of self on the basis of aberrant or absent expression of major histocompatibility (MHC) class I antigens. NKT and some γδ T-cells subsets recognize lipid antigens presented on CD1c, which is related in evolution to the major histocompatibility complex (MHC) molecules (see below). The balance between interactions with numerous inhibitory and activating receptors for MHC and other MHC-related molecules governs the outcome of NK-mediated recognition of tumour cells. However, the major roles of these more broadly reactive (and therefore immediately responsive) cell types in tumour immunity may be in directing the initial phase of activation of more speciﬁc effector arms of adaptive immunity, namely αβ CD4+ and CD8+ T-cells.

(iii) Methods of cell killing
1. Antibody-directed cell killing The interleukins (IL) 4, 5, 6 & 10 activate or inﬂuence B lymphocyte differentiation to antibody-making plasma cells. However, cell killing via antibodies is dependent upon more than just attachment of the binding Fab fragment of the immunoglobulin molecule to its speciﬁc target epitope. Additional requirements include activation of complement to induce phagocytosis, or interaction with NK-cells, polymorphonuclear leucocytes, or monocytes to provide antibody dependent cell-mediated cytotoxicity (ADCC). These mechanisms may also contribute to the success of clinically available immunotherapies based on the passive administration of monoclonal antibodies to destroy targeted cancer cells, such as Herceptin®, used in cancer of the breast. Unlike in breast cancer, Her-2neu does not appear to be overexpressed frequently in prostate cancer (639) so that the drug has little role here. Speciﬁc antibodyrelated mechanisms which trigger cell death in prostate cancer are under development, but are not yet available clinically. Despite correlations between survival and levels of anti-tumour antibodies, there is little evidence that antibodies actively induced by immunization can induce tumour regression.

2. Cell-directed killing Macrophages, which are the archetypical phagocyte, destroy cells by releasing reactive oxygen intermediates and tumour necrosis factor (TNF). By contrast, NK, NKT and cytotoxic (αβ and γδ ) T-lymphocytes (CTL) effect cell killing chieﬂy through the release of perforin and granzymes, or by ligating Fas on the tumour cell surface to cause apoptosis of targets. As well as malignant epithelial cells, tumour stroma, including endothelial cells, ﬁbroblasts and inﬁltrating cells, may also be an important target for cell-directed killing (640). Further, interferon γ (IFNγ ) production by T and NK cells may be crucial in tumour immunity, either by inhibiting stromal functions (e.g., angiogenesis) or enhancing tumour cell recognition by CTL, for example by upregulating MHC antigens. 68

Chapter 10. PROSTATE CANCER

(iv) αβ Cytotoxic T-cells, Helper T-cells and Dendritic Cells:
Both αβ CD8+ Cytotoxic T-cells and CD4+ Helper T-cells are unable to recognise naked antigen, requiring it to be presented to them on a platter that, for the former is the MHC class I receptor and for CD4+ Helper T-cells is the MHC class II receptor. The antigen is recognised by CD8+ and CD4+ T cells in the form of short, 8-10 or 12-20 amino acid fragments of proteins, respectively. Critically, the antigen may not be cell-surface associated, but may be derived from any intracellular compartment. Indeed, defective ribosomal products (including mistranslated proteins) are preferential targets for CD8+ T cells (641), while membrane-associated proteins are frequent targets for CD4+ T cells.

Figure 3. Production of peptides for presentation on MHC receptors for T-cell recogntion. The 9-11 amino-acid peptides displayed by MHC class I receptor molecules on the cell surface are generally, but not exclusively, derived from endogenous proteins made by the antigen-presenting cell. A process called cross priming may also allow external proteins to be presented via the class I pathway. The 12-20 amino-acid peptides displayed by the MHC class II receptor molecules on the cell surface are typically derived from extracellular proteins taken up by the antigen presenting cell. CD4 and CD8 T cells are referred to as the adaptive arm of the cellular immune response because the relevant antigen-speciﬁc, and naïve yet-to-be-primed, T cells must expand considerably in number before sufﬁcient are present to be effective. This expansion occurs in the specialised environment of lymph nodes, in response to antigen presented by antigen presenting cells (APCs). One obvious possibility is that tumour cells inﬁltrating lymph nodes might act as APC, and cause this expansion (642). However, most reports support mature dendritic cells (DC) as the only APCs with the ability to prime naïve T-cells, and from the perspective of therapeutic potential, most recent attention has concentrated on directly or indirectly targeting antigen to these. Nonetheless, a recent report indicates that γδ T-cells may also have this capacity (643) being able to simulate mature DC function by processing and displaying 69

Chapter 10. PROSTATE CANCER antigens as well as providing co-stimulatory signals sufﬁcient for strong induction of naïve αβ T-cell proliferation and differentiation. DCs constitute only ~0.2% of the circulating white blood cell population (644) but are distributed throughout tissues where they act as sentinels. They function as biological vacuum-cleaners by pinocytosing, endocytosing and phagocytosing extracellular antigens, processing up to 4 times their own volume of extracellular ﬂuid (ECF) in 1 hour, and converting proteins into peptide (645). A more important source of antigens may be apoptotic or necrotic cells; their display of aberrant surface molecules (such as phosphatidyl serine, usually conﬁned to the inner plasma membrane leaﬂet), marks them as targets for phagocytosis by DC. DC have the unique property of efﬁciently cross-presenting antigens: that is, they are capable of processing antigens derived from other cells, and presenting derived peptide fragments on their MHC class I molecules, for presentation to CD8 T cells. Like other “professional” APC such as monocytes, they can also present extracellular antigens via MHC class II, for presentation to CD4 T cells. Highly motile DCs with their captured antigens migrate via lymphatic channels to lymph nodes where the antigen is presented to prime naïve T-cells or re-activate resting memory T-cells. Signalling through pattern-recognition receptors on DC, such as Toll-Like Receptors (TLR), facilitates their migration, and subsequent secretion of IL-2 & IL-12, which appear to be crucial cytokines for the development of a successful cellular response. Early interactions with activated NK cells and CD4 T cells in the lymph node may further contribute to the effectiveness of the priming process (646649).

70

Chapter 10. PROSTATE CANCER

Figure 4. Precise alignment of co-stimulatory & adhesion molecules required for T-cell recognition of presented antigen in MHC receptor

(v) Ignorance, Tolerance to self, and autoimmunity
Autoimmune disorders tell us that the immune system can effectively target self antigens. Some self-reactive T cells escape deletion in the thymus (i.e., central tolerance) and inactivation in the periphery (i.e., peripheral tolerance), for example via regulatory T cells. Insufﬁcient presentation of antigen or access to target tissues could account for “ignorance”, in which potentially self-reactive T cells remain in a resting state. For immunological purposes, most tumour antigens (with the possible exception of mutated or aberrantly translated proteins) fall into these categories. The challenge for tumour vaccine strategies is to convince the immune system that these antigens are legitimate targets for attack.

(vi) Some strategies employed by tumours to thwart cytotoxicity
Successful prostate tumours ‘evolve’ genetically, epigenetically, or environmentally to evade detection and destruction by immune defence mechanisms. Strategies include: 1. Reduced MHC class I expression 71

Chapter 10. PROSTATE CANCER 1. Loss of co-stimulatory molecules 1. Antigen negative variants 1. Production of mucins to disguise antigens 1. Tumour production of Fasl 1. Signiﬁcantly reduced DC numbers 2. Expression of activation markers by only a small subset of DCs (650) 3. Suppression of T-cell proliferation by PSA in a dose-dependent manner (651)

(vii) Immunotherapeutic strategies
The current status of vaccine studies in prostate cancer was recently reviewed by McNeel and Malkovsky (2005) (652): a brief outline of the various approaches available is provided below. A major limitation with immunotherapy studies is a lack of known antigens recognized by T cells and expressed by prostate cancers. This deﬁciency is related to the difﬁculty of generating cell lines from patients’ tumours. Antigens validated thus far (such as hTERT, survivin, PSMA, PSA) have been ﬁrst proposed on the basis of selective overexpression in tumours, rather than discovered ab initio using T cells recognizing tumour cells. We thus have no knowledge of their relative importance in T cell mediated immunity. Nonetheless, the prostate is a highly specialized organ, and therefore (if tolerance can be overcome) potentially expresses many putative speciﬁc targets for an immune response. (a) Passive immunisation Although passive immunization with in vitro-activated anti-tumour T cells is used against other tumours, in particular for lymphomas as a result of Epstein-Barr viral infections following organ transplantation, the relative difﬁculty of generating and validating anti-tumour T cells has discouraged this approach in prostate cancer.

(b) Non-speciﬁc immune stimulants & adjuvants 1. Cytokines The use of cytokines such as GM-CSF and IL-2 therapeutically was initially in the form of unphysiological doses delivered intravenously and, as such, was associated with signiﬁcant systemic side-effects. More recently, cytokine activities have been harnessed more discretely as part of other treatments rather than as therapies in their own right. GM-CSF, in particular, is an important component in many vaccines, regulating growth and differentiation of haemopoietic cells and acting at several sites in the generation of the immune response. These include activation of ADCC of neutrophils, chemo-attraction of eosinophils and induction of differentiation of DCs (652).

2. Non-speciﬁc Adjuvants Flt3 ligand, is a growth and differentiation factor for DCs. In a transgenic murine model, Flt3 ligand on its own was able to result in prostate cancer regression (653) In support of this ﬁnding, McNeel et al (2003) (654) reported a marked increase in DCs in the blood with vaccine preparations containing ﬂt3 ligand (654). 72

Chapter 10. PROSTATE CANCER An attenuated form of the tuberculosis bacilli, bacillus Calmete-Guérin (BCG), is a non-speciﬁc immune stimulant which was initially developed to vaccinate patients against tuberculosis. The major role for BCG oncologically is as an intravesical agent in superﬁcial bladder cancer where it is administered to minimize tumour recurrences. However, it has potential utility in DC-based vaccines as a non-speciﬁc immune stimulant. Another mycobacterium, mycobacterium vaccae was administered in combination with irradiated cell lines by Eaton et al (2002) (655) in 60 men with prostate cancer: although there was absence of a clinical response, some increases in speciﬁc antibodies were present in association with T cell proliferation (655). A further non-speciﬁc adjuvant we have used in one of our studies is keyhole limpet haemocyanin (KLH). However, one concern with the use of nonspeciﬁc adjuvants such as Flt3 ligand, BCG and KLH is that, although they may invoke proliferation and expansion of dendritic or T-cells, these may not induce/include those particularly relevant lymphocytes to produce the desired response for effective tumour cell killing.

3. Speciﬁc Adjuvants Ligands for the Toll-Like Receptors (TLRs), pattern recognition receptors of the immune system, have received much attention recently, in particular deoxycytidyl-deoxyguanosin oligodeoxynucleorides (CpG). CpG which mediates its activities via TLR-9 induces DC activation and proliferation, increased co-stimulatory molecule expression and secretion of IFN, Il-1, 6 &12 and TNFα (656). In addition to adjuvants speciﬁcally included in vaccine preparations to enhance efﬁcacy, other therapies may interact with patients’ immunological responses. Certain nitrogen-containing bisphosphonates such as paidronate and zoledronic acid are potent stimulators of Vγ 9Vδ 2 cells which constitute the majority of the small population of γδ T-cells in the peripheral circulation. Vγ 9Vδ 2 cells recognise non-peptide antigens and, as they are not reliant upon antigen presentation via the MHC receptor, are able to effect target cell killing rapidly (657).

(c) Active immunization The recent expansion of interest in vaccines has been largely focused on DCs together with αβ Cytotoxic CD8+ T-cells and Helper CD4+ T-lymphocyte recruitment and activation. Potential sources of DC cells for vaccine production are umbilical cord blood, bone marrow and peripheral blood. The discovery that myeloid DCs can be generated readily from monocytes or very early (CD34+) precursors has served as a great boost with most studies using monocyte-derived DCs (MoDCs) which are loaded with antigen in-vitro. This topic has been reviewed recently in an excellent article by Figdor et al (2004) (644). To date, the large majority of prostate cancer vaccine studies have been phase I trials undertaken on patients with advanced disease. Large tumour burdens and the heterogeneity of these patients’ cancers together with potential sub-optimal immunocompetence of the vaccine recipients may serve to understate the real potential of this therapeutic approach. In contrast to cytotoxic chemotherapy regimens, a striking feature has been just how well these vaccines have been tolerated with a virtual absence of serious adverse events. Heiser et al (2002) (658) examined escalating doses of PSA mRNA-transfected DCs in their vaccines without any evidence of dose-related toxicity or adverse effects and Ridgway et al (2003) (659) reported that, in 100 trials which involved >1000 patients, there was a complete absence of severe adverse events (659) Certainly, the concern of inducing serious auto-immune reactions has not been seen, at least in the short-term.

73

Chapter 10. PROSTATE CANCER 1. Whole cell vaccines As clinical studies with re-injection of irradiated autologous tumour cells alone did not demonstrate a signiﬁcant beneﬁt, immune stimulants were introduced and used concomitantly. Simons reported injection of autologous cancer cells transfected with retroviral construct to express GM-CSF into patients with advanced prostate cancer (660) as a prelude to the use of the androgen dependent and PSA producing LNCaP and androgen independent and non-PSA secreting PC3 cell lines transfected to express GM-CSF (661). Because of the limited number of prostate cancer cell lines available for use as a source of antigens for presentation to T cells, one strategy to increase the number and variety of antigens has involved culturing freshly obtained prostatic tumours which are then transfected after several passages to confer immortality (Onyvax™). Although this approach promises to provide a greater range of readily available and suitable antigens, that the cells are transfected virally is likely to limit their utility to patients with advanced disease, at least initially. In order to overcome the limitations imposed by cell lines, we have been harvesting soft tissue metastases from men with progressing hormone-escape cancer. The tumour is then processed, which includes a sub-lethal dose of radiation, prior to being made available to DCs derived from cells of the monocyte lineage (MoDCs) in vitro. In this ongoing trial, we have had one man who has demonstrated a complete response at 12 months with total resolution of large lymph node metastases radiologically and a PSA which has decreased from 150 ng/ml at baseline to 4.7 ng/ml. Other patients have demonstrated partial responses - approximately 20% overall – but most have not. Amongst other explanations for the variability in response, this may indicate that harvested tumours did not reﬂect a sufﬁciently comprehensive representation of antigenically relevant molecular changes common to all metastases which could be processed by DCs and presented to αβ T cells to result in killing of all tumour cells.

2. Protein-based vaccines A more deﬁned approach than using whole cells containing a variety of proteins and other factors, is to use ﬂagged proteins, in particular those which are predominantly prostate speciﬁc (lineage markers) as the source of antigens for priming DCs. Unlike whole cell preparations, these have the potential advantage of being recombinant with the added possibility of subtle modiﬁcations being incorporated to enhance their immunogenicity with APC processing. Those examined have included prostate acid phosphatase (PAP) (662), and prostate speciﬁc antigen (PSA) (663-665) in particular.

3. Peptide-based vaccines As αβ cytotoxic CD8+ T-cells and αβ helper CD4+ T-cells recognize antigens as processed 8-10 or 12-20 amino acids, respectively, by APCs through their appropriate MHC receptors, so vaccines have been produced with speciﬁc peptides. Among the many molecular targets to which peptide sequences can be constructed, prostate speciﬁc membrane antigen (PSMA) peptides were used most widely especially in early phase I-II trials, with reported response rates of 20-30% (666, 667) Unlike PSA which, at a cellular level, is expressed more strongly in non-cancerous cells, PSMA is overexpressed in most prostate cancers as well as in tumour neovasculature (138). Although peptides are very attractive in the sense that they can be synthesized and made available as ‘off-the shelf’ preparations, they have the huge disadvantage that patient responses are MHC restricted. Consequently, people who do not have the appropriate HLA phenotype, which for PSMA peptides is HLA-A2+ (constituting ~40% of populations in many western countries), are unlikely to mount a TH1 response if they are administered vaccines based on PSMA peptides. 74

Chapter 10. PROSTATE CANCER In order to overcome this problem, Noguchi et al (2003) (668) tested 10 men with hormone escape prostate cancer to determine whether or not cytotoxic T cell precursors were detectable for 14 peptides. As these peptides were HLA-A24 restricted, all ten were shown to express the HLA-A24+ phenotype before commencement of the study. Patients were then vaccinated subcutaneously with up to 4 types of peptides to which their pre-vaccination peripheral blood mononuclear cells reacted. Four of the 10 men developed increased cytotoxic T-cell responses to peptides and cancer cells with anti-peptide IgG antibodies identiﬁed in 7 patients. One man developed a partial response with an 89% decrease in PSA. Stable disease was demonstrated in 5 of the 10 patients for a median duration of 2 months (668).

4. RNA Recently, use of RNA has attracted much attention for a number of reasons, not least of which is the need for only minute amounts of tumour tissue or recombinant material required. Tumour RNA potentially encodes multiple epitopes for many HLA alleles and, consequently, extends the scope of vaccination to cancers in which potent T cell epitopes have not been identiﬁed (669) In order to permit this approach, techniques have been developed recently for highly efﬁcient RNA transfection of DCs by electroporation (670-672). RNA taken up by DCs is translated and the resulting polypeptides have the potential to bind to MHC molecules for presentation to T cells. Cytoplasmic antigens in somatic cells, as a result of intracellular degrading processes, are channelled preferentially via the Class-I presentation pathway, thereby activating primarily antigen-speciﬁc CD8+ T cells (673). By contrast, membrane-associated antigens are more likely to be shunted through the endosomal pathway and peptides presented on MHC-Class II receptor for CD4+ T-cell recognition (Figure 3). The importance of mounting both a CD4+ and a CD8+ response for effective tumour killing has been highlighted recently. Furthermore, the importance of activating speciﬁc CD4+ T cells concurrently to facilitate initiation, potentiation & maintenance of an effective anti-tumour immune response may be harnessed more precisely via RNA (674-676). Heiser et al (2001) (677) reported induction of a polyclonal CaP-speciﬁc cytotoxic Tcell lymphocyte (CTL) response with DCs transfected with ampliﬁed tumour RNA (677). Subsequently the same group published their experience with a vaccine consisting of DCs transfected with mRNA encoding PSA. They found a potent T-cell mediated anti-tumour response in-vitro prompting a phase I study in which this ﬁnding was replicated in all patients, 6/7 of whom had a signiﬁcant decrease in the log slope of PSA (644). More recently, a strategy to curtail immortality of tumour cells was reported by Su et al (2005) (669) who targeted telomerase, the enzyme that prevents telomeres on the ends of chromosomes from shortening (669). By priming DCs with the human teleomerase reverse transcriptase (hTERT), αβ CD8+ cytotoxic T-cells can be primed to target tumours. Although this strategy, which can be engineered to obtain both CD8 and CD4 responses, is likely to be comprehensive in targeting most tumour cells, a theoretical concern is that other immortal cells such as non-cancer stem cells also may be affected by vaccines targeting telomerase (669).

5. Carbohydrates Tumours expressing high levels of certain carbohydrate antigens exhibit a greater propensity for progressing and metastasising, which is manifested in a reduced survival rate. In prostate cancer, globo-H, MUC1,GM2 and Thompson-Friedenreich antigen have been found to be preferentially expressed (678,679) in this regard and this has led to vaccine trials with combination carbohydrate-KLH conjugates (680, 681). 75

Chapter 10. PROSTATE CANCER 6. Viruses Based on the observation that a number of viral pathogens are able to elicit potent cytotoxic T-cell responses, viral constructs which express speciﬁc epitopes have been used. These include recombinant vaccinia and fowlpox viruses expressing PSA and B7.1 co-stimulatory genes (682, 683) In addition, DNA plasmids which encode for selelcted genes, have been used to produce immune responses to the gene products (684).

(viii) Summary
Although considerable advances are being made in vaccine therapies, they remain experimental and, as such, need to be integrated into clinical management in the form of research trials. However, it is hoped that the promise they bring will be realised increasingly so that they become an established form of therapy in the foreseeable future.

XVII. CONCLUSIONS
The contemporary management of prostate cancer has been shaped the utilization of PSA serology for prostate cancer detection and monitoring. One result of PSA early detection programmes is that younger patients are being diagnosed with and treated for prostate cancer. Consequently, there has been a concerted effort to improve long-term cancer control while preserving urinary and sexual function. This has been facilitated by the anatomic radical prostatectomy with, more recently, endoscopic modiﬁcations, as well as by advances in radiotherapy and other treatments. Consequently, increasing numbers of men are being cured of their prostate cancers and, by tailoring therapy to accomodate patients’ wishes, more and more are able to be satisﬁed with their quality of life throughout what is often a long period of management. The past 10 years has witnessed a surge in basic, clinical, and translational research in prostate cancer. Fortunately, we are in the midst of a period of unprecedented collaboration between scientists and clinicians placing patients in a most favourable position to beneﬁt from advances in basic science and experimental therapeutics. Even if a cure is not imminent, the welfare and quality of life of those diagnosed with this condition promises to continue to improve at an exponential rate through the careful and critical application of research ﬁndings.

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Chapter 10. PROSTATE CANCER 264. Hessels D, Verhaegh GW, Schalken JA, Witjes JA. “Applicability of biomarkers in the early diagnosis of prostate cancer.” Expert Rev Mol Diagn,2004; 4:513-26. 265. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman CA Jr. “Operating characteristics of prostate-speciﬁc antigen in men with an initial PSA level of 3.0 ng/ml or lower.” JAMA,2005; 294(1):66-70. 266. Pelzer AE, Tewari A, Bektic J, Berger AP, Frauscher F, Bartsch G, Horninger W. “Detection rates and biologic signiﬁcance of prostate cancer with PSA less than 4.0 ng/mL: observation and clinical implications from Tyrol screening project.” Urology, 2005; 66(5):1029-33. 267. Aus G, Damber JE, Khatami A, Lilja H, Stranne J, Hugosson J. “Individualized screening interval for prostate cancer based on prostate-speciﬁc antigen level: results of a prospective, randomized, population-based study.” Arch Intern Med,2005; 165(16):1857-61. 268. Roobol MJ, Roobol DW, Schroder FH. “Is additional testing necessary in men with prostate-speciﬁc antigen levels of 1.0 ng/mL or less in a population-based screening setting?” (ERSPC, section Rotterdam). Urology, 2005; 65(2):343-6. 269. Oesterling JE, Jacobsen SJ, Klee GG, Pettersson K, Piironen T, Abrahamsson PA, Stenman UH, Dowel B, Lovgren T, Lilja H. “Free complexed and total serum prostate antigen: the establishment of appropriate reference ranges for their concentrations and ratios.” J Urol, 1995; 154:1090-5. 270. Fang J, Metter EJ, Landis P, Chan DW, Morrell CH, Carter HB. “Low levels of prostate-speciﬁc antigen predict long-term risk of prostate cancer: Results from the Baltimore longitudinal study of aging.” Urology, 2001; 58:411-6. 271. Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC. “Longitudinal evaluation of prostate –speciﬁc antigen levels in men and without prostate disease.” JAMA, 1992; 267:2215-20. 272. Ornstein DK, Smith DS, Humphrey PA, Catalona WJ. “The effect of prostate volume, age, total prostate speciﬁc antigen level and acute inﬂammation on the percentage of free serum prostate speciﬁc antigen levels in men without clinically detectable Prostate cancer.” Journal of Urology, 1998; 159(4):1234. 273. Yuan JJ, Coplen DE, Petros JA, Figenshau RS, Ratliff TL, Smith DS, Catalona WJ. “Effects of rectal examination, prostatic massage, ultrasonography, and needle biopsy of prostate-speciﬁc antigen levels.” Journal of Urology, 1992; 147(6):810. 274. Guess HA, Heyse JF, Gormley GJ, Stoner E, Oesterling JE. Effect of ﬁnasteride on serum PSA concentration in men with benign prostatic hyperplasia: results from the North American Phase III clinical trial. Urologic Clinics of North America, 1993; 20(4):627. 275. de la Taille A, Katz A, Bagiella E, Olsson CA. O’Toole KM. Rubin MA. Perineural invasion on prostate needle biopsy: an independent predictor of ﬁnal pathologic stage. Urology, 1999; 54(6):1039. 276. Clements JA, Merritt T, Devoss K, Swanson C, Hamlyn L, Scells B, Rohde P, Lavin MF, Yaxley J, Gardiner RA. “Inactive free : total prostate speciﬁc antigen ratios in ejaculate from men with suspected and known prostate cancer, compared with young control men.” BJU Int.2000; Sep;86(4):453-8. 277. Savblom C, Malm J, Giwercman A, Nilsson JA, Berglund G, Lilja H. “Blood levels of free-PSA but not complex-PSA signiﬁcantly correlates to prostate release of PSA in semen in young men, while blood levels of complex-PSA, but not free-PSA increase with age.” Prostate.2005; Sep 15;65(1):66-72. 278. Lilja H. “Signiﬁcance of different molecular forms of serum PSA.” Urologic Clinics of North America, 1993; 20(4):681. 279. Carter, HB, Pearson, JD. “PSA velocity for the diagnosis of early prostate cancer.” Urologic Clinics of North America, 1993; 20(4):665. 92

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Chapter 10. PROSTATE CANCER 417. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. “Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies.” Journal of Urology, 1999; 162(2):433. 418 Quinlan DM, Epstein JI, Carter BS, Walsh PC. “Sexual function following radical prostatectomy: inﬂuence of preservation of neurovascular bundles.” Journal of Urology, 1991; 145(3):998. 419. Leandri P, Rossignol G, Gautier JR, Ramon J. “Radical retropubic prostatectomy: morbidity and quality of life. Experience with 620 consecutive cases.” Journal of Urology, 1992; 147(3):883. 420. Noh C, Kshirsagar A, Mohler JL. “Outcomes after radical retropubic prostatectomy.” Urology, 2003; 61(2): 412-6. 421. Walsh PC, Marschke P, Ricker D, Burnett AL. “Patient-reported urinary continence and sexual function after anatomic radical prostatectomy.” Urology, 2000; 55(1):58. 422. Link RE, Su LM, Sullivan W, Bhayani SB, Pavlovich CP. “Health related quality of life before and after laparoscopic radical prostatectomy.” J Urol, 2005; 173(1): 175-9; discussion 179. 423. Epstein JI. “Evaluation of radical prostatectomy capsular margins of resection. The signiﬁcance of margins designated as negative, closely approaching, and positive.” American Journal of Surgical Pathology, 1995; 14(7):626. 424. Epstein JI, Pizov G, Walsh PC. “Correlation of pathologic ﬁndings with progression after radical retropubic prostatectomy.” Cancer, 1993; 71(11):3582. 425. Rosen MA, Goldstone L, Lapin S, Wheeler T, Scardino PT. “Frequency and location of extracapsular extension of positive surgical margins in radical prostatectomy specimens.” Journal of Urology, 1992; 142(2):331. 426. Roumeguere T, Bollens R, Vanden-Bossche M, Rochet D, Bialek D, Hoffman P, Quackels T, Damoun A, Wespes E, Schulman CC, Zlotta AR. “Radical prostatectomy: a prospective comparison of oncological and functional results between open and laparoscopic approaches.” World J Urol, 2003; 20(6): 360-6. 427. Chuang MS, O’Connor RC, Laven BA, Orvieto MA, Brendler CB. “Early release of the neurovascular bundles and optical loupe magniﬁcation lead to improved and earlier return of potency following radical retropubic prostatectomy.” J Urol, 2005; 173(2): 537-9. 428. Porpiglia F, Ragni F, Terrone C, Renard J, Musso F, Grande S, Cracco C, Ghignone G, Scarpa RM. “Is laparoscopic unilateral sural nerve grafting during radical prostatectomy effective in retaining sexual potency?” BJU Int, 2005; 95(9): 1267-71. 429. Kim ED, Scardino PT, Hampel O, Mills NL, Wheeler TM, Nath RK. “Interposition of sural nerve restores function of cavernous nerves resected during radical prostatectomy.” J Urol, 1999; 61(1): 188-92. 430. Scardino PT, Kim ED. “Rationale for and results of nerve grafting during radical prostatectomy.” Urology, 2001; 57(6): 1016-9. 431. Kim ED, Nath R, Slawin KM, Kadmon D, Miles BJ, Scardino PT. “Bilateral nerve grafting during radical retropubic prostatectomy: extended follow-up.” Urology, 2001; 58(6): 983-7. 432. Joseph JV, Vincente I, Madeb R, Erturk E, Patel, HRH. “Robot-assisted vs laparoscopic radical proatatectomy: are there any differences?” BJU Int, 2005; 96:39-42 433. Webster TM, Herrell SD, Chang SS, Cookson MS, Baumgartner RG, Anderson LW, Smith JA Jr. “Robotic assisted laparoscopic radical prostatectomy versus retropubic radical prostatectomy: a prospective assessment of postoperative pain.” J Urol.2005; Sep, 174(3):912-4; discussion 914.

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Chapter 10. PROSTATE CANCER 434. Ahlering TE, Eichel L, Edwards RA, Lee DI, Skarecky DW. “Robotic radical prostatectomy: a technique to reduce pT2 positive margins.” Urology, 2004;64(6): 1224-8. 435. Touijer K, Kuroiwa K, Saranchuk JW, Hassen WA, Trabulsi EJ, Reuter VE, Guillonneau B. “Quality improvement in laparoscopic radical prostatectomy for pT2 prostate cancer: impact of video documentation review on positive surgical margin.” J Urol, 2005; 173(3): 765-8. 436. Costello AJ, Haxhimolla H, Crowe H, Peters, JS. “Installation of telerobotic surgery and initial experience with telerobotic radical prostatectomy.” BJU Int, 2005; 96:34-8. 437. Pienta K, Redman B, Hussain M. “Phase II study of estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.” Journal of Clinical Oncology, 1994; 12(10):2005. 438. Chung LWK. “Implications of stromal-epithelial interaction in human prostate cancer growth, progression and differentiation.” Semin Cancer Biol, 1993; 4: 183-192. 439. Labrie F, Candas B, Cusan L, Gomez JL, Diamond P, Suburu R, Lemay M. “Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-speciﬁc antigen.” Urology, 1996; 47(2):212. 440. Arai Y, Kanamaru H, Yoshimura K, Okubo K, Kamoto T, Yoshida O. “Incidence of lymph node metastasis and its impact on long-term prognosis in clinically localized prostate cancer.” International Journal of Urology, 1998; 5(5):459-65. 441. Ekman P. “Predicting pelvic lymph node involvement in patients with localized prostate cancer.” European Urology, 1997; 32(Suppl 3):60-4. 442. Danella JF, deKernion JB, Smith RB, Steckel J. “The contemporary incidence of lymph node metastases in prostate cancer: implications for laparoscopic lymph node dissection.” Journal of Urology, 1993; 149(6):1488-91. 443. Alagiri M, Colton MD, Seidmon EJ, Greenberg RE, Hanno PM. “The staging of pelvic lymphadenectomy: implications as an adjunctive procedure for clinically localized prostate cancer.” British Journal of Urology, 1997; 80(2):243-6. 444. Partin AW, Pearson JD, Landis PK, Carter HB, Pound CR, Clemens JQ, Epstein JI, Walsh PC. “Evaluation of serum prostate-speciﬁc antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastasis.” Urology, 1994; 43(3):649. 445. Messing EM, Manola J, Sarodsy M, Wilding G, Crawford ED, Truno D. “Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenopathy in men with node positive prostate cancer.” New Engl J Med, 1999; 341(24):1781. 446. Steiner MS, Marshall FF. “Mini-laparotomy staging pelvic lymphadenectomy (minilap). Alternative to standard and laparoscopic pelvic lymphadenectomy.” Urology, 1993; 41(3):201. 447. Wagner JR, Russo P. “Urologic complications of major pelvic surgery.” Seminars in Surgical Oncology, 2000; 18(3):216. 448. Heinzer H, Graefen M, Noldus J, Hammerer P, Huland H. “Early complication of anatomical radical retropubic prostatectomy: lessons from a single-center experience.” Urologia Internationalis, 1997; 59(1):30. 449. Paul DP, Loening SA, Narayana AS, Culp DA. “Morbidity from pelvic lymphadenectomy in staging carcinoma of the prostate.” Journal of Urology, 1983; 129(3):1141. 450. McCullough DL, McLaughlin AP, Gittes RF. “Morbidity of pelvic lymphadenectomy and radical prostatectomy for prostatic cancer.” Journal of Urology, 1977; 117(2):206. 102

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Chapter 10. PROSTATE CANCER 680. Musselli C, Livingston PO, Ragupathi G. “Keyhole limpet hemocyanin conjugate vaccines against cancer: the Memorial Sloan Kettering experience.” J Cancer Res Clin Oncol, 2001: 127 Suppl 2: R20-6. 681. Slovin SF, Ragupathi G, Musselli C, Olkiewicz K, Verbel D, Kuduk SD, Schwarz JB, Sames D, Danishefsky S, Livingston PO, Scher HI. “Fully synthetic carbohydratebased vaccines in biochemically relapsed prostate cancer: clinical trial results with alpha-N-acetylgalactosamine-O-serine/threonine conjugate vaccine.” J Clin Oncol, 2003; 21(23): 4292-8. 682. Sanda MG, Smith DC, Charles LG, Hwang C, Pienta KJ, Schlom J, Milenic D, Panicali D, Montie JE. “Recombinant vaccinia-PSA (PROSTVAC) can induce a prostatespeciﬁc immune response in androgen-modulated human prostate cancer.” Urology, 1999; 53(2): 260-6. 683. Cavacini LA, Duval M, Eder JP, Posner MR. “Evidence of determinant spreading in the antibody responses to prostate cell surface antigens in patients immunized with prostate-speciﬁc antigen.” Clin Cancer Res, 2002; 8(2): 368-73. 684. Raz E, Carson DA, Parker SE, Parr TB, Abai AM, Aichinger G, Gromkowski SH, Singh M, Lew D, Yankauckas MA. “Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses.” Proc Natl Acad Sci USA, 1994; 91(20): 9519-23.

Notes
1. http://www.andrologyaustralia.org/ 2. http://www.prostatehealth.org.au/ 3. http://www.cdc.gov/cancer/prostate 4. http://www.cancerbacup.org.uk/ 5. http://www.bostwicklaboratories.com/ 6. http://www.nhmrc.gov.au/publications/_ﬁles/cp88.pdf 7. http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm 8. http://www.uroweb.nl/ﬁles/uploaded_ﬁles/2005ProstateCancer.pdf 9. http://www.cancer.gov/cancertopics/understanding-prostate-cancertreatment/page5 10. http://www.prostatehealth.org.au/ 11. http://www.ohri.ca/decisionaid

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