Historically, bilateral orchidectomy has been the reference treatment for advanced prostate cancer which, by targeting the major source of androgen production, dramatically diminishes the number of tumour epithelial cells and accompanying neovasculature. LHRH agonists, after initially stimulating LH and hence testosterone synthesis by the testicles, occupy LHRH receptors to prevent subsequent production of both these hormones. In addition, LHRH agonists can have a a further action by targeting LHRH receptors on prostate tumour cells (563, 564).

The unwanted effects of bilateral orchidectomy and LHRH agonists are generally considered to be comparable apart from the fact that the former requires an operation, with physical and possible psychological consequences, and the latter necessitates regular interval injections and commencement of therapy has an accompanying risk of an initial surge in testosterone (the so-called flare reaction) due the drug initially stimulating production of luteinising hormone before blocking production.

Reduced libido and impotence are to be expected following surgical or medical castration together with a loss of bone substance and muscle mass. As a condition, osteoporosis is underdiagnosed in men and it is only relatively recently that its relationship with bilateral orchidectomy and LHRH agonists has been appreciated (565-567). The high prevalence of osteoporosis together with its debilitating consequence of bone fractures has prompted advocacy for the use of bisphosphonates in prostate cancer patients, especially those committed to longstanding castration (see below). Hot flushes can be problematic for many men and tiredness from anaemia can compound debility. A minority of men receiving LHRH analogues develop gynaecomastia.

The American Society of Clinical Oncology recommends bilateral orchidectomy or LHRH agonists as initial androgen suppression treatments (568). Non-steroidal anti-androgens 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 non-steroidal antiandrogens are common with gynaecomastia and breast pain troublesome for many: a cessation rate for these medications has been reported to be 4-10%, in particular with flutamide (568, 569). Hepatotoxicity is a potential problem with all antiandrogens but especially cyproterone acetate.( 568).

Green et al (2004) (570) reported the results of our study of 82 men randomised to leuprorelin (Lucrin™), goserelin (Zoladex™), cyproterone acetate (Androcur™) or watchful waiting, 62 of whom completed 12 months of follow-up. In addition to a non-treatment (watchful waiting) control group, a non-cancer community reference group was also evaluated. Findings were compared in relation to cognition and quality of life. Most patients had serum PSA levels between 30 and 60 ng/ml at baseline. Using well-validated and established instruments, they found that ~50% of men in all treatment groups, but none of the controls, had significant cognitive deterioration at 12 months, in particular in relation to complex information processing. Although the cognitive defects were of a magnitude comparable with sleep-deprivation or mild inebriation, there was no consistent association between subjective cognitive changes and objective deficits. In addition, there were more instances of a deterioration of quality of life for the men on hormonal treatments at 12 months, in particular in relation to sexual function (570).

Unlike other studies addressing cognition and quality of life, Green et al’s paper is important as all patients were randomised to management regimens which included a non-drug (control) arm and this study was completely independent of any industry-sponsorship. Consequently, these findings are much more compelling than those reported from less robustly designed studies and those trials sponsored or supported by industry (571-577)

Oral oestrogen therapy, the most common form of androgen suppressive medication for many years, is now rarely used as first line hormonal treatment because of associated cardiovascular complications with oral administration, although this route of delivery is employed not uncommonly in Japan for a short period to offset the flare effect of LHRH agonists (578). An increased cardiovascular morbidity was reported to be present with the oral form of oestrogens even in patients without overt cardiovascular disease affecting one quarter of such patients during their first year of treatment (579). However, a dose-response relationship is said to be present in terms of cardiovascular morbidity and mortality with one mg daily of diethylstilboestrol (DES) (with or without aspirin) stated to be comparable with bilateral orchidectomy in the treatment of advanced disease but without increased cardiovascular complications. Klotz et al (1999) (580) found that venous thrombosis was not prevented when DES was prescribed together with low-dose warfarin (580).

The increased susceptibility to cardiovascular complications in patients taking oestrogens appears to be critically related to the route of administration. This predeliction is reported to be significantly reduced (581) or avoided by parenteral delivery. An increased synthesis of coagulation factors, in particular Factor VII, results from oral oestrogen therapy and this is thought to be responsible for the increased rate of cardiovascular problems in these patients (582, 583). Consequently, many investigators have advocated a re-evaluation of oestrogen treatment (584-587), especially since all forms of oestrogen, including parenteral and transdermal patch preparations, are cheap (588) and, unlike bilateral orchidectomy and LHRH agonists in particular, this medication is not considered to induce osteoporosis ( 581). Furthermore, oestrogens may have a role in ameliorating agitation in some men receiving LHRH agonists.

Ockrim et al (2003) (589) reported their experience with 20 men with newly diagnosed locally advanced or metastatic prostate cancer treated with transdermal estradiol patches in particular in relation to bone mineral density. They found that at 1 year that the mean bone mineral density had increased by 3.6% and concluded that transdermal estradiol protects against bone loss in men with prostate cancer and may improve bone density in those at risk for osteoporotic fracture. Local experience with this form of delivery has been that patch displacement can occur with sweating, especially in active men: serial serum testosterone levels may be used to optimise the frequency and duration of patch application.

Despite many attempts to demonstrate otherwise, there is no clear evidence that commencing androgen suppression therapy early improves survival (568, 590). Early commencement does, however, increase the likelihood and duration of unwanted effects. Since in terms of lifestyle effects, commencing androgen suppression is likely to adversely affect libido, potency, physical mobility and strength, body habitus, cognition and liver function (with anti-androgens), a body of clinicians advocates carefully delaying commencement by balancing the unwanted effects of treatment with those of the disease being treated. In conjunction with patients’ wishes, PSA doubling times and development of lesions on bone scans can be helpful in deciding when to commence androgen suppression.

By upsetting homeostasis at a molecular level, androgen suppressive therapies may in fact contribute to tumour progression in those remaining prostate cancer cells after commencement of treatment (38). Unlike androgen receptors which are sited in prostate epithelial cells, oestrogen receptors are present in both epithelial and stromal cells. Compartmentalisation of the two ERs is reported with ERα exclusively in stroma and ERβ predominantly in the epithelial compartment (38, 591). ERβ is considered to have a role against prostate cancer dedifferentiation in contrast to the proliferative effect of ERα and androgens (592). In prostatic epithelial cells, testosterone is reduced by 5α-reductase to dihydrotestosterone which, in turn, is converted into 3α-diol and 3β-Adiol. Unlike testosterone and dihydrotestosterone, these two metabolites do not bind to the androgen receptor but possess high affinity for oestrogen receptors. By binding to estrogen receptor β (ERβ), 3β-Adiol induces expression of the cell adhesion molecule E-cadherin, the presence of which in prostate cancer cell membranes is associated with a less aggressive phenotype. Decreased expression of many C-CAMs including E-cadherin, have been associated with the progression of prostate cancer (38,107).

However, there are many clinicians and patients who become pre-occupied with lowering the serum PSA levels at all costs. A survey of American Urologists indicated that 68% recommended hormone suppression therapy for an elevated PSA after radical prostatectomy (562, 593). Thus, an increasing PSA often serves as the trigger for commencement of what translates into long-term androgen suppressive therapy for a large proportion of patients in spite of a lack of clear evidence of a survival benefit with early treatment (594, 595).

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

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

Once prostate cancer metastasizes following effective androgen suppression therapy, its toll, with regard to pain, suffering, and disability, can be considerable due to incapacitating sequelae of disseminated and hormone-refractory disease, for which no curative treatments currently exist. PSA evidence of hormone escape usually precedes other barometers of disease progression and metastasis. Newling et al (1993) (598) reported that, for men with newly diagnosed metastatic prostate cancer who were randomised in the EORTC study 30853 to receive goserelin and flutamide or bilateral orchidectomy, the median time for survival following PSA progression was 52 weeks compared with 41 weeks for bone metastases and 28 weeks and 33 weeks for progression of regional and distant lymph nodes, respectively (598). However, as suggested by a reducing mortality rate for this condition in many countries, these estimates may no longer be accurate for a variety of reasons addressed throughout this chapter.

As outlined above, prostate cancer has a particular predilection for androgens that serve as this malignancy’s preferred ligand. When androgen suppression is invoked initially, the tumour regression effect can be dramatic with both epithelial cells and tumour neovasculature being affected significantly (599). However, tumour repression is not permanent with a median time to relapse of 18 months (600). Nevertheless, maintaining suppression of circulating androgens remains important as the androgen receptor pathway continues to be very active in ‘hormone escape’ patients. Amplification and overexpression of the androgen receptor gene, as well as post-translational modifications to the AR occur, resulting in the cancer cells becoming ‘super-sensitive’ to androgens (601-603).

In conjunction with these changes is activation of other genes that, through signal transduction pathways, facilitate receptivity to a variety of ligands including other hormones and drugs, especially antiandrogens (604). Consequently stopping an antiandrogen may afford a temporary respite to tumour regression manifested by a reduction of serum PSA in some patients (605).

Paradoxically, for those patients receiving monotherapy in the form of LHRH agonists or a previous bilateral orchidectomy, the addition of an antiandrogen may cause a clinical regression for a short time and this is often recommended before proceeding to chemotherapy or radiotherapy in the form of radio-isotopes or local external beam treatment to isolated troublesome secondary deposits. Recent research has provided support for modulation of the oestrogen receptor axis in disease no longer responding to androgen suppression by LHRH agonists, bilateral orchidectomy or antiandrogens by targeting oestrogen receptors in metastatic disease (606).

Hormone-refractory prostate cancer is said to be present when there is evidence of progression despite the use of first and second line hormonal manipulation. Although the administration of bisphosphonate and chemotherapeutic interventions may provide benefit in the short term (see below) these palliating approaches merely serve to temporise the situation in this subterminal/terminal phase of the disease. Clarke (2003) (607) divided the urological issues to be considered into:

It is this last point in particular which needs to be considered paramount so that unreasonable attempts to prolong life are not undertaken, especially when these are not in concert with individual patient’s wishes. For example, it may be preferable not to treat ureteric obstruction and allow the patient to die painlessly from uraemia than protract his demise for a short but miserable period by instigating various interventions. A number of other disciplines are often involved at this stage as indicated, which include medical and radiation oncology, interventional radiology, pain management specialists and palliative care clinicians amongst others. It is important that pastoral care support is available as appropriate.

A further web-site is:

http://www.cancer.gov/cancertopics/understanding-prostate-cancer-treatment/page6

Of the various treatment approaches being examined for prostate cancer, nothing seems to have captured the public’s imagination quite as vividly as have vaccines. Although considerable advances have been made in understanding the processes involved with different vaccine approaches, overall clinical results remain modest so, with changes being implemented continually this form of therapy must still be regarded as experimental.

Historically, the prostate was considered to be an “immunologically privileged” site (629, 630) and was regarded as lacking a network of intraprostatic (631) and afferent lymphatics (632) . Although neither McCullough nor Gittes was able to demonstrate extraprostatic lymphatic drainage following intra-glandular injections of iodinated emulsified oils and India ink carbon particles, respectively (629), Gardiner et al in 1979 described lymphoscintigraphic evidence of lymphatic drainage following intra-glandular injections of technetium labelled antimony sulphide colloid into clinically benign prostates of volunteer patients (633, 634) That intraprostatic lymphatics do exist was elegantly demonstrated by Zeng et al (2004, 2005) (635, 636) who showed recently that, not only does the prostate contain lymphatics, but peritumoural lymhangiogenesis is demonstrable within prostates harbouring cancer. Furthermore, they found a relationship between peri-tumoural lymphatic vessel density and the presence of lymph node metastases (635, 636).

Further endorsement of Zeng et al’s findings (635, 636) in relation to finally destroying the myth of the prostate being an ‘immunologically privileged’ site, is Vesulainen et al’s report that lymphocytic infiltrates correlate with an improved 10-year survival for patients with primary prostate cancer (637). This observation by Vesalainen et al (1994) (637) also serves to encourage approaches to enhance lymphocytic infiltration with enhancement of its cytotoxic activity through prostate cancer immunotherapy.

Active vaccination strategies can exploit a number of candidate immunological cells as effectors or mediators for immunological therapies (638). These include:

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

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

Figure 3. Production of peptides for presentation on MHC receptors for T-cell recogntion. The 9-11 amino-acid peptides displayed by MHC class I receptor molecules on the cell surface are generally, but not exclusively, derived from endogenous proteins made by the antigen-presenting cell. A process called cross priming may also allow external proteins to be presented via the class I pathway.

The 12-20 amino-acid peptides displayed by the MHC class II receptor molecules on the cell surface are typically derived from extracellular proteins taken up by the antigen presenting cell.

CD4 and CD8 T cells are referred to as the adaptive arm of the cellular immune response because the relevant antigen-specific, and naïve yet-to-be-primed, T cells must expand considerably in number before sufficient are present to be effective. This expansion occurs in the specialised environment of lymph nodes, in response to antigen presented by antigen presenting cells (APCs). One obvious possibility is that tumour cells infiltrating lymph nodes might act as APC, and cause this expansion (642). However, most reports support mature dendritic cells (DC) as the only APCs with the ability to prime naïve T-cells, and from the perspective of therapeutic potential, most recent attention has concentrated on directly or indirectly targeting antigen to these. Nonetheless, a recent report indicates that γδ T-cells may also have this capacity (643) being able to simulate mature DC function by processing and displaying antigens as well as providing co-stimulatory signals sufficient for strong induction of naïve αβT-cell proliferation and differentiation.

DCs constitute only ~0.2% of the circulating white blood cell population (644) but are distributed throughout tissues where they act as sentinels. They function as biological vacuum-cleaners by pinocytosing, endocytosing and phagocytosing extracellular antigens, processing up to 4 times their own volume of extracellular fluid (ECF) in 1 hour, and converting proteins into peptide (645). A more important source of antigens may be apoptotic or necrotic cells; their display of aberrant surface molecules (such as phosphatidyl serine, usually confined to the inner plasma membrane leaflet), marks them as targets for phagocytosis by DC. DC have the unique property of efficiently cross-presenting antigens: that is, they are capable of processing antigens derived from other cells, and presenting derived peptide fragments on their MHC class I molecules, for presentation to CD8 T cells. Like other “professional” APC such as monocytes, they can also present extracellular antigens via MHC class II, for presentation to CD4 T cells.

Highly motile DCs with their captured antigens migrate via lymphatic channels to lymph nodes where the antigen is presented to prime naïve T-cells or re-activate resting memory T-cells. Signalling through pattern-recognition receptors on DC, such as Toll-Like Receptors (TLR), facilitates their migration, and subsequent secretion of IL-2 & IL-12, which appear to be crucial cytokines for the development of a successful cellular response. Early interactions with activated NK cells and CD4 T cells in the lymph node may further contribute to the effectiveness of the priming process (646-649).

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

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

Successful prostate tumours ‘evolve’ genetically, epigenetically, or environmentally to evade detection and destruction by immune defence mechanisms. Strategies include:

The current status of vaccine studies in prostate cancer was recently reviewed by McNeel and Malkovsky (2005) (652): a brief outline of the various approaches available is provided below. A major limitation with immunotherapy studies is a lack of known antigens recognized by T cells and expressed by prostate cancers. This deficiency is related to the difficulty of generating cell lines from patients’ tumours. Antigens validated thus far (such as hTERT, survivin, PSMA, PSA) have been first proposed on the basis of selective overexpression in tumours, rather than discovered ab initio using T cells recognizing tumour cells. We thus have no knowledge of their relative importance in T cell mediated immunity. Nonetheless, the prostate is a highly specialized organ, and therefore (if tolerance can be overcome) potentially expresses many putative specific targets for an immune response.

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.