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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, renements 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 signicant 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 specic 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-conned 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.
(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 reect either shared environmental and lifestyle risk factors, or a genetic mechanism, or indeed both. In order to address the inherent difculties 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 agged 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 rene the mapping of these regions to the gene level.
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 difculties, association studies have identied 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 dened, 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. Amplication 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 signicantly 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 efciently 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).
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 specic 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 specic 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 mRNAs: 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 signicant 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 reects broad errors in promoter recognition/transcription initiation. However, regulatory elements have been identied for a number of non-coding RNAs, including DD3/PCA3 and PCGEM1 see below.
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 broblasts, smooth muscle cells, vascular endothelium and bone-derived cells including osteoblasts . All of these cell types and the factors they secrete form the cells 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.
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 .
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
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
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
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, nasteride, and thalidomide .
2. IL-6 High levels of IL-6 secretion from prostate broblasts, 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 brolasts 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 dened (84). TGF-beta specic inhibitors have been developed and have been proposed to have utility in treatment of progressive prostate cancer .
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 MMPs particularly MMP2 enabling ECM degradation and tumour cell invasion .
3.MMPs: 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 signicant 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 conrmed 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 KLKs 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 IGFBs (IGFB-2, -3, -4 and -5) more efciently 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.
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
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 modications (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 conned prostate carcinoma was a signicant 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 proling may depend more on overexpressed molecules. Therefore, the activity of MMPs 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 efcacy 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 signicantly 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 rst 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-conned 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 identied 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 specic 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 specic 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-specic 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 specic 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 identied which may have utility as diagnostic and prognostic markers that do not t 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 RNAs 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 nding 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+ prole, 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 identied 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 identied by differential display technology in 1999 as a non-coding RNA highly specic to prostate cancer . Subsequently a number of researchers have conrmed 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 signicant improvements in detecting cancer compared with the use of PSA alone (169, 170). Tinzl (2004)(169) reported 82% sensitivity, 76% specicity for the uPM3 assay compared to 98% sensitivity, 5% specicity, 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 specicity was 61%, 80% and 70%, respectively (169). The Canadian-based study (170) sampled 517 patients undergoing biopsy at ve centres, for which 86% had an assessable sample. The overall uPM3 sensitivity and specicity 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 specicity 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 identied 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 signicantly 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 identication of individual markers to utilising combinations of known prostate cancer-specic 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 ngerprint 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 proling, 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 modications which are biologically signicant 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.
18
(ii) Lycopene
The relevance of the anti-oxidant lycopene, an isomer of -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)
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).
Pharmacological
(i) COX-2 Inhibition
Continuous use of Nonsteroidal anti-inammatory 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 nonspecic and specic COX-2 inhibitors act at this site, although some specic COX-2 inhibitors may have other actions as well. Specic 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 deciency of the 5--reductase type 2 enzyme do not develop prostate cancer, a 7-year randomised, controlled trial with the drug nasteride 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 nasteride, which inhibits conversion of testosterone to dihydrotestosterone (DHT) by targeting the 5--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 nasteride 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-signicant prostate cancer detection in this trial. They present a model of risk and benet that estimates the potential inuence of histological artefact (due to nasteride-induced effect on prostatic epithelial appearances) in the assignment of excess risk for high-grade disease and possible overdetection bias introduced by nasteride-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--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 nasteride study in which prostatic biopsies were recommended if the annual PSA (adjusted for the effect of nasteride) exceeded 4 ng/ml or if the digital rectal examination was abnormal. Recent research suggests that inhibition of the irreversible action of 5-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 3-diol and 3 -Adiol which do not bind to the androgen receptor but have a strong afnity for oestrogen receptors, the result of which is thought to have a direct effect on prostate development and homeostasis (206). The binding of 3 -Adiol to oestrogen receptor beta (ER ) 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
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 benecial effects are to be maximised.
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 difcult 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 benets 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 dened 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 benets 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 difcult for both parties to achieve . There are, however, dened strategies and decision aids that can facilitate this process .
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 patients 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 patients personal preferences 6. Support the patients 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 nd 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 benet 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 patients values and personal preferences . Thus, Step 5 in Box 1 prompts the clinician to discuss each mans 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 clarication 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?
Im concerned that I might get prostate cancer I want the best chance of nding it early, if I do get it Im 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 theres no guarantee Id 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 mens 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.
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.
Chapter 10. PROSTATE CANCER basis of age-specic PSA reference ranges, Pelzer et al (2005) (266) focused on ndings 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 nding 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
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 nasteride 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 (1 antichymotrypsin and 2 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 uid is much higher than in serum, consistent with its physiological role in liquefaction (276). Levels of free-PSA but not complex-PSA in blood signicantly 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 mans 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
Deciencies 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 specicities 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 specicity were 66% and 89%, respectively. In men with a PSA level <4 ng/ml, the sensitivity was 74% and specicity 91%; for PSA levels 4-10 ng/ml, the sensitivity was 58% and specicity 91%; for PSA levels >10 ng/ml, the sensitivity and specicity 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.
Chapter 10. PROSTATE CANCER faeces are not infrequent sequelae with some men having difculty 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 rst 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 inltrating 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
Figure 2a. The presence of Gleason grade 4 or greater histology carries a signicantly poorer prognosis (297, 298). Stamey demonstrated that Gleason score 7 tumours can be stratied, 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 signicantly more aggressive phenotype.
31
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 nding 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 nding 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 insufcient for a patient to undergo either radical prostatectomy or radiotherapy.
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 patients 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 classications 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 conned 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
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/_les/cp88.pdf http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm http://www.uroweb.nl/les/uploaded_les/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 nd 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 inuenced 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 patients age and the extent of the urologists 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 afuent, 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 clinicians recommendation strongly inuences mens treatment choice . As well, lay health beliefs, such as the view that surgery is the best way to cure a cancer are a strong inuence, 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 benets 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 mens 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 specic 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 rst 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 Specic 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/
http://www.prostatecancersupport.info/
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 insignicant 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 insignicant disease which did not warrant treatment. As a result, Epstein et al (1994) (334) developed criteria to identify insignicant 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 conned disease, illustrating the problem of undercalling when relying on biopsy information for stratifying patients into a good prognostic group.
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 modied (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 ndings 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 ndings are useful to a degree. Post-operatively, however, incorporation of more denitive and comprehensive parameters obtained from pathology of the RRP specimen itself, enable formulation of more predictive nomograms (355). A number of studies have stratied patients with respect to likelihood of tumour progression with recurrent disease, if it does become evident, likely to do so for the rst time within 5 years after RRP. Partin et al were the rst to develop a simple biostatistical model equation which allowed categorisation of cases after RRP into 3 risk groups reecting a low, intermediate and high likelihood of PSA recurrence (356). After an extensive multifactorial regression analysis, they identied only 3 variables viz. a sigmoidal transformation of PSA, Gleason sum of the RRP specimen and margin status or tumour connement within the prostate. Other studies have conrmed 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
38
Chapter 10. PROSTATE CANCER 1. Digital rectal examination (DRE) Digital rectal examination understages organ-conned disease (245, 342-346). In a published series of 601 men undergoing RRP, of the 565 men with cT2 disease, only 52% had organ-conned tumours (248). By comparison, of 36 men with cT3 disease, 19% had organ-conned 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 organconned 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, DAmico 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 nal 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 ndings 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 ndings is very difcult 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 conrmed 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 rst-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 rst 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). Justication 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 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 mans 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 ofces. His Prostate and Me: A Couple Deals with Prostate cancer by Desiree Lyon Howe, Winedale Publishing Company, 2002. A womans 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 couples struggle to get their sex life back to normal after radical prostatectomy. The Lovin Aint 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
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 satised with their quality of life post-prostatectomy, than ever before (394, 395). The modern RRP evolved from a succession of anatomic dissections and modications 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.
43
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 modications 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 eld, 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) conrmed this nding in data collected from 1688 men with the prevalence of signicant 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 inuencing 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 modications 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 denitions for above parameters vary, quality of life studies indicate that the majority of patients are satised 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 signicant 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 signicantly affected by age or pre-operative potency status, although the extent of nerve sparing was a signicant predictor of outcome (422).
Chapter 10. PROSTATE CANCER unless dissection violates the capsule, nerve-sparing radical prostatectomy should not compromise surgical cancer control if the tumour is organ-conned. 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 conrmed these ndings 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.
46
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).
47
Chapter 10. PROSTATE CANCER tissue at a distant and/or local site (444, 452, 465). Most PSA recurrences occur in the rst 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 denition of PSA failure of the American Society of Therapeutic Radiation and Oncologys (ASTROs) 1996 consensus statement (ie 3 consecutively rising PSA values, each obtained at least 3 months apart), DAmico 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 signicant 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). DAmico 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).
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)
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 inuencing 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 articial 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 ow 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.
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.sildenal/Viagra, tadalal/Cialis, vardenal/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 efcacy 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 benet 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 brosis 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 brosis 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%) efcacy 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 eld. 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
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.
Adjuvant radiotherapy
A number of retrospective comparative series have examined the potential benet 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 signicantly 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 signicantly 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 signicantly 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 dened 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 signicant 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 signicant). 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 dened, with no prospective studies of efcacy 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 benet from early referral for treatment regardless of PSA dynamics. Indeed, one series demonstrated an independent benet 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 efcacy 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 patients 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.
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 benet 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 benecial effect when given after radiotherapy for a duration of either 2 years (511), 3 years (375) or indenitely (512). An overall survival benet 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 benet to some patients. The precise explanation for this improvement in results is less clear though. Observational studies suggested a benet 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 signicant gains in loco-regional control, cancer-specic 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 benet shown for the use of 6 months NAAS (particularly in terms of freedom from BF and cancer-specic 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 signicant benet only when given prior to and during radiotherapy (rather than adjuvantly), and furthermore, only when combined with whole pelvic radiation elds (rather than prostate only) (518). As most of these trials showing a benet 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 t within the typical intermediate risk prole, will benet 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.
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 stula 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 gures. 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.
Chapter 10. PROSTATE CANCER midpoint of the PSA nadir and rst rise. This was largely based on the nding 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 conrmatory 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 difculty 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 uctuations (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 sufcient 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 dened last non-rising PSA date, the backdating effect was exaggerated to the theoretical extreme, further reinforcing the nding 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 denitions may be superior to the ACD. These have focused on the correlation of PSA dynamics and subsequent clinical events in the aim of nding a BF denition which is both sensitive in detecting recurrence early, yet specic 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 denitions 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, specicity 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 denition, for example, showed a sensitivity, specicity 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 denition 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 specicity 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 denitions (554). Analysis of the interaction of various BF denitions 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 conrmed by Zietman et al (2005) (547). It would also appear that the denition of the nadir + 2 ng/mL style will be relatively unlikely to be inuenced 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 sufcient level to trigger a false positive BF with this denition (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.
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 signicant 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 rst 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 ndings. RRP always led to a high QOL impact in terms of urinary continence and sexual dysfunction within the rst 6 months post-therapy. These both improve over the rst 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.
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 signicant adverse or unwanted effects.
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 are 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 ushes 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 utamide (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 signicant 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 decits. 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 als 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 ndings 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 rst 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 are 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 rst 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 signicantly 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.
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 benet with early treatment (594, 595).
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 rst and second line hormonal manipulation. Although the administration of bisphosphonate and chemotherapeutic interventions may provide benet 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 insufciency 5. Lymphoedema 6. Rectal obstruction/inltration 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 patients 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% condence 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 signicant 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 benet 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 signicant 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 efcacy 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 signicantly 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 signicant benets 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 benet, 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 signicant benet 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 signicantly 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 rst 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 rst 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 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 rst 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 benets 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 efcacy 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 signicant difference in analgesic efcacy, although the occurrence of new areas of pain and analgesic requirements was signicantly reduced in two randomised series (622, 623), although one other suggested inferiority to EBRT (624). Similar efcacy 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 are (a temporary increase) in pain in the rst 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 efcacy in combination with chemotherapy (627, 628).
(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. T-cells 6. Cytotoxic CD8+ T-cells 7. 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 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 specic effector arms of adaptive immunity, namely CD4+ and CD8+ T-cells.
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 ( and ) T-lymphocytes (CTL) effect cell killing chiey 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, broblasts and inltrating cells, may also be an important target for cell-directed killing (640). Further, interferon (IFN ) 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
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-specic, and nave yet-to-be-primed, T cells must expand considerably in number before sufcient 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 inltrating 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 nave 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 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 sufcient for strong induction of nave 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 uid (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 conned to the inner plasma membrane leaet), marks them as targets for phagocytosis by DC. DC have the unique property of efciently 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 nave 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
Figure 4. Precise alignment of co-stimulatory & adhesion molecules required for T-cell recognition of presented antigen in MHC receptor
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. Signicantly 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)
(b) Non-specic 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 signicant 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-specic 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 nding, McNeel et al (2003) (654) reported a marked increase in DCs in the blood with vaccine preparations containing t3 ligand (654). 72
Chapter 10. PROSTATE CANCER An attenuated form of the tuberculosis bacilli, bacillus Calmete-Gurin (BCG), is a non-specic immune stimulant which was initially developed to vaccinate patients against tuberculosis. The major role for BCG oncologically is as an intravesical agent in supercial bladder cancer where it is administered to minimize tumour recurrences. However, it has potential utility in DC-based vaccines as a non-specic 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 specic antibodies were present in association with T cell proliferation (655). A further non-specic adjuvant we have used in one of our studies is keyhole limpet haemocyanin (KLH). However, one concern with the use of nonspecic 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. Specic 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 TNF (656). In addition to adjuvants specically included in vaccine preparations to enhance efcacy, other therapies may interact with patients immunological responses. Certain nitrogen-containing bisphosphonates such as paidronate and zoledronic acid are potent stimulators of V 9V 2 cells which constitute the majority of the small population of T-cells in the peripheral circulation. V 9V 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 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 signicant benet, 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 reect a sufciently comprehensive representation of antigenically relevant molecular changes common to all metastases which could be processed by DCs and presented to T cells to result in killing of all tumour cells.
2. Protein-based vaccines A more dened approach than using whole cells containing a variety of proteins and other factors, is to use agged proteins, in particular those which are predominantly prostate specic (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 modications being incorporated to enhance their immunogenicity with APC processing. Those examined have included prostate acid phosphatase (PAP) (662), and prostate specic antigen (PSA) (663-665) in particular.
3. Peptide-based vaccines As cytotoxic CD8+ T-cells and 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 specic peptides. Among the many molecular targets to which peptide sequences can be constructed, prostate specic 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 identied 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 identied (669) In order to permit this approach, techniques have been developed recently for highly efcient 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-specic 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 specic 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-specic cytotoxic Tcell lymphocyte (CTL) response with DCs transfected with amplied 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 nding was replicated in all patients, 6/7 of whom had a signicant 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), 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 specic 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 modications, 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 satised 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 benet 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 ndings.
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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/_les/cp88.pdf 7. http://www.nelh.nhs.uk/guidelinesdb/html/Prostate-ft.htm 8. http://www.uroweb.nl/les/uploaded_les/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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