Prostate Cancer Therapy: Standard Management, New Options and Experimental Approaches

ANTICANCER RESEARCH 25: 551-562 (2005)

Review Prostate Cancer Therapy: Standard Management, New Options and Experimental Approaches

LUTZ TROJAN, KOBA KIKNAVELIDZE, THOMAS KNOLL, PETER ALKEN and MAURICE STEPHAN MICHEL

Department of Urology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany

Abstract. The management of prostate cancer is one of the The established therapeutic methods include purely core tasks for urologists today. This review focuses on surgical procedures (radical prostatovesiculectomy), radiotherapeutic options for the curative and palliative treatment of therapeutic methods (external beam irradiation, prostate cancer. Within the area of urological competence, brachytherapy) and medical treatment (hormonal ablation radical prostatectomy remains the standard procedure for the and chemotherapy). Several alternative minimally-invasive curative treatment of localised prostate cancer. Recently, interest therapeutic procedures have been developed over the last in minimally-invasive procedures such as brachytherapy, few years, such as high-intensity focused ultrasound (HIFU) focused ultrasound and cryotherapy has increased considerably. and cryoablation. Nevertheless, these must be rated as Established palliative treatment strategies include hormonal experimental procedures and should be performed only in treatment schemes as the gold standard. Chemotherapeutic medical centres and in a clinical trial setting. A special type regimes are used for the hormone refractory disease. In addition of prostate carcinoma treatment is "watchful waiting". This to both the standard and new urological therapeutic options, method rejects immediate therapeutic intervention against promising experimental systemic strategies for the generalised the malignancy, such action only being taken in the case of disease are presented in this review. a progressive disease.

There has been a rising incidence in prostate cancer over Radical prostatectomy the last 20 years, with the peak being reached in 1995. Prostate cancer is the second most frequent malignancy The standard method for the treatment of localised prostate among males in Western Europe and the most common cancer today is radical prostatectomy, which can be cancer in men in the United States (1, 2). Therefore, the performed as an open or a laparoscopic surgical procedure. different strategies being used to treat prostate cancer are It is usually carried out with a curative purpose in mind. In of increasing interest. Generally speaking, these are all cases, the whole prostate gland is removed. The excised divided into potentially curative procedures for localised specimen includes the proximal prostatic part of the carcinoma (T1-T2, N0, M0) and palliative procedures for urethra, some parts of the bladder neck and both seminal the treatment of locally advanced or generalised diseases. vesicles. Reconstruction of the urine passage is performed The TNM classification of the UICC, 1997 version, is used by an anastomosis between the stump of the proximal in this review. urethra and the bladder neck. Post-surgical infertility exists because both ductii deferentes are ligated. The duration of the operation depends on the surgical approach used (retropubic, perineal or lapraroscopic) and Correspondence to: Lutz Trojan M.D., Department of Urology, takes between 1.5 to 3 hours. The post-surgical University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, D- hospitalisation time in our clinic is about 7 days. The 68167 Mannheim, Germany. Tel: +49-621-3832629, Fax: +49-621- intraoperatively inserted balloon catheter is removed after 3831452, e-mail: [email protected] 7 or 14 days, depending on the operative technique chosen. Key Words: Prostate cancer, therapy, radical prostatectomy, The open surgical operation can be divided into the brachytherapy, cryotherapy, high intensity focused ultrasound, retropubic (extraperitoneal) and the perineal approach, watchful waiting, chemotherapy. depending on to the surgical incision used. Retropubic

0250-7005/2005 $2.00+.40 551 ANTICANCER RESEARCH 25: 551-562 (2005)

Table I. Oncological results after radical prostatectomy from 4 studies.

Study Patients Oncological follow-up (n)

Stein et al. (1992) 230 10 years clinical recurrence-free survival if localised: 91%, capsular invasion: 79%, seminal vesical invasion: 58%

Walsh et al. (1994) 995 10 years biochemical recurrence-free survival if localised: 85%, focal capsular invasion: 82%, extended capsular invasion: 54%

Zinke et al. (1994) 3170 Cancer-specific survival 10 years: 90% 15 years: 82% Pound et al. (1997) 1623 Cancer-specific survival 5 years: 99% 10 years: 83%

access offers the advantage of carrying out an intraoperative function. Apical (distal part of the prostate) preparation of lymphadenectomy if the PSA value is >10 ng/ml and/or the prostate can cause damage to the function of the cross- lymph node metastasis is suspected. Lymph node metastasis striped external sphincter, which can consequently result in (as a sign of a generalised disease) can be normally excluded incontinency problems. Significant reduction in the by the pathologist by intraoperative analysis of the frozen perioperative morbidity rate, maintenance of the post- lymph node specimen. In the case of positive lymph node surgical erectile function and urinary continence are findings, the prostate is usually not removed and therapy for provided by anatomical studies of the prostate gland and the an advanced disease such as hormonal ablation is carried pelvis that were started more than 20 years ago (6, 7). out. A generalised disease will lead, despite surgical Today, in patients with a T2a tumor stage (tumor intervention, to tumor progression. For this reason, radical confined within the prostate capsule to one lobe of the operation of such patients is regarded as overtreatment and prostate), radical prostatectomy can be carried out as a should not be performed. Today, retropubic prostatectomy nerve-sparing procedure by identifying and preserving the can be considered as the standard approach. nerves responsible for erection. The neurovascular bundles, Over recent years, PSA screening has resulted in a rising which are located at the dorsolateral part of the prostate, number of early diagnosed (and therefore small) carcinomas can be spared on one or, in a few cases, on both sides. of the prostate, where lymphatic dissemination of the cancer Before the nerve-sparing technique was introduced, can be excluded statistically by means of nomograms (3). postoperative erectile dysfunction after radical There has, therefore, been an increasing interest in the less prostatectomy was nearly 100%, but this rate has now been invasive perineal intervention, where no intraoperative significantly reduced (8). Data from our clinic show that lymphadenectomy is performed. With the perineal potency was preserved in 43 to 50% of the patients after approach, there is no need to perform a laparotomy or to one-sided nerve-sparing operation, although the actual incise the endopelvic fascia and it avoids contact with the numbers depend heavily on the preoperative potency rate. penile dorsal vein complex and any subsequent severe It should be noted that, if a biopsy in both lobes indicates bleeding from it. Reasons for not using the perineal the presence of a carcinoma, a nerve-sparing prostatectomy approach are a large prostate gland (which can cause should be avoided for oncological reasons. Because prostate technical operative problems) or any probability of lymph cancer spreads out preferentially through the perineural node metastasis. sheaths into the periprostatic tissue (9), a nerve-sparing The long natural history of well-differentiated prostate procedure increases the risk of postoperative progression of cancer in the early stages of the disease results in a long the disease, but not among appropriately selected patients temporal latency (up to 10 years) before the appearance of (10, 11). It is necessary to discover the patient’s opinion on tumor-related morbidity and mortality (4, 5). Therefore, a preserving before the final decision on the treatment patient life expectancy of at least 10 years is a pre-condition modality is made. for performing the operation. As previously mentioned, urinary incontinence is one of Post-surgical functional deficits and complications of the undesirable functional complications after radical radical prostatectomy are mainly determined by the prostatectomy. In the past, this was a significant clinical anatomical structures surrounding the prostate. There is a problem, with 15% second-grade stress incontinence and high risk of damage to the neurovascular bundles, with 3% complete incontinence (12). An analysis done by means subsequent disturbance or failure of the penile erectile of a written questionnaire distributed to the last 182 patients

552 Trojan et al: Update on Prostate Cancer Therapy operated on in our clinic revealed that only 4% of the (23). Because of PSA-screening programs, the number of patients needed more than 2 pads per day. This low patients in these three groups is rising significantly. The long incidence of postoperative incontinence can be related to doubling time of the early-stage tumor results in a low risk of advances in the operative techniques. Insufficiency of the cancer-related morbidity and mortality. Therefore, a anastomosis between the urethra and the bladder neck definitive curative therapy for these patients has to be requires prolonged catheterisation, as observed in 1.2 to 4% carefully evaluated, if not thoroughly questioned. One of the cases (12, 13). Strictures of the anastomosis requiring possible strategy for these patients is called ‘watchful waiting’ a transurethral incision of the bladder neck were noted in (24). The strategy involves waiting, without therapeutic 9% of the cases. The perioperative mortality rate is reported intervention, until a progression of the disease is noted. Then, as being between 0 and 2.1%. Bleeding that required blood after an initial waiting policy, a delayed hormone ablative transfusions was observed in up to 11.5% of cases (14, 12). therapy is applied if tumor progression occurs. Clinical and oncological long-term data of large cohorts The usefulness of the ‘watchful waiting’ strategy is of patients are now available. Ten years of data on the underlined by studies where progression rates of between 3 biochemical recurrence-free survival of organ-confined and 16% were observed among patients diagnosed with a diseases vary between 85 and 91%, while the disease-specific T1a tumor (small volume tumors), discovered during 10-year survival rate is reported as being between 90 and transurethral resection of the prostate due to BPH (25, 26). 96% (15, 16, 17). In most of the larger studies, there is a A recent prospective, randomised study (median follow-up strong correlation between the rate of recurrence with 6.2 years) showed no significant difference in the cancer- tumor staging and grading, as well as the preoperative PSA related mortality between ‘watchful waiting’ and primary levels. A summary of 4 studies is provided in Table I. curative treatment by radical prostatectomy in this special Preoperative neoadjuvant hormonal therapy was previously sub-group of patients (27). Comparable rates of disease- used to achieve a tumor ‘down-staging’. Despite the fact that specific survival have also been shown in earlier studies of this method significantly reduced the rate of positive patients treated by radical prostatectomy and of patients postoperative margins, the incidence of lymph node where the ‘watchful waiting’ strategy was used (28). One of metastases and tumor recurrence (by means of elevation of the shortcomings of this treatment policy is the need to PSA postoperatively) remained unchanged (18). Routine use provide multiple serum-PSA controls, which can result in to of a neoadjuvant hormonal therapy for prostate cancer is a psycho-emotional burden for the patient. Problems are restricted because of the undesirable effects on the anatomic also posed if the point of time when progression of the condition: preoperative hormonal ablation leads to a disease occurs is missed making curative treatment no regression of the prostate of up to 50% of its volume. longer possible. Consequently, there were technical difficulties with dissecting To bridge the gap between operative procedures as the the prostate and performing the nerve-sparing procedure. most radical curative therapy on the one hand, and Over the last few years, an increasing number of "watchful waiting" as a non-therapeutic strategy on the laparoscopic radical prostatectomies has been observed. other, different alternative minimally-invasive therapeutic Despite the fact that this procedure was introduced only 6 procedures with curative objectives have been developed years ago (19), data on large collectives are available. Data during recent years. Some of these methods, used for the on the 3-year survival without biochemical recurrence after treatment of patients with an organ-confined disease, are laparoscopic prostatectomy is 90.5%, with 12 months of highlighted below. median follow-up (20). Another study showed inferior results of 84.1% (21). A comparison of the different studies Modern minimally-invasive procedures is difficult because of the different tumor stages of the patients involved, although analysis of the postoperative Radical prostatectomy is recognised as the standard curative potency rate showed comparable results to the open therapy with good oncological long-term results for the procedure (22). Nevertheless, the final proof of oncological treatment of localised prostate cancer. Because of the equivalence between open and laparoscopic intervention invasiveness and postoperative morbidity of this open requires further study and long-term follow-up. surgical procedure, it is not suitable for certain groups of patients. Furthermore, alternative curative treatment Watchful waiting strategies had to be found for patients with a live expectancy of less than 10 years and for those who reject the ‘watchful Special attention must be paid to the type of treatment waiting’ concept and want to receive a definitive treatment chosen in the case of patients with a life expectancy of less instead. This has led to the development of alternative than 10 years and patients of an advanced age, as well as instrumental procedures that have a minimally-invasive patients with small and well-differentiated tumors at biopsy character. The purpose of all these procedures is the local

553 ANTICANCER RESEARCH 25: 551-562 (2005) intraprostatic application of "energy", such as isotope techniques have advanced considerably. Improved radiation (brachytherapy), heat (high-intensity focused oncological results in recently published data reflect the ultrasound) and cold (cryoablation). advantages of this (35). A final conclusion on whether the long-term oncological results after brachytherapy are Brachytherapy. The importance of interstitial brachytherapy comparable with those after radical prostatectomy cannot, as a monotherapy for the treatment of prostate cancer is as yet, be drawn (36, 37). increasing. In comparison to external beam irradiation, brachytherapy allows higher doses of irradiation to be Cryotherapy. Cryoablation of the prostate gland was applied locally by means of an interstitial placement of introduced as early as 1964 as a therapy for prostate cancer radioactive bodies (seeds). There are two options here: (38). By applying very low temperatures to the prostate, the permanent seed implantation by the use of iod-125 or whole gland including the carcinoma is frozen and palladium-103 sources (low-dose radiation, LDR) and subsequently destroyed. The first two generations of devices temporary implantation (after loading procedure) of used for this resulted in a high rate of severe complications. iridium-192 bodies (high-dose radiation, HDR). The latter Recto-urethral fistulas were observed, for example, which should be carried out as a monotherapy only as a part of adversely affected the popularity of this method (39). The clinical studies (29). third generation of modern devices enables the Brachytherapy can be carried out in an outpatient setting simultaneous intraprostatic insertion of multiple small cold and/or under epidural anesthesia. It offers further probes using a transperineal approach. This allows the cold advantages over radical prostatectomy such as the duration to be applied uniformly to the individual size and form of of the procedure. Brachytherapy is an interdisciplinary the prostate gland (40, 41). The process of freezing is procedure and requires close collaboration between controlled by transrectal ultrasound. In addition, to avoid urologists, radiotherapists and medical physicists. Rigorous injury to the adjacent sensitive organs, such as the rectum indications have been introduced with increasing experience or the neurovascular bundles, special probes are used to of the procedure over the last 12 years. They are reflected in control the temperature between the prostate and the the recommendations of the German Society of Urology surrounding organs. (2002) and other institutions, such as the American The data available on cryotherapy and its long-term Brachytherapy Society (30, 31). In Germany, as well as in oncological results refer mostly to the second-generation many other countries all over Western Europe and in the devices. As has been observed with brachytherapy, patient USA, permanent seed implantation has established itself as collectives of these studies are often heterogenous and a curative therapy for organ-confined prostate cancer. include patients with locally advanced diseases. For this Nowadays, radioactive seeds implantation is considered reason, comparisons of the results have to be interpreted an appropriate method of treatment for the so-called "low- carefully. According to Long et al., the analysis of the largest risk prostatic cancers": clinical stage N0M0 with the tumor patient collective, with a median follow-up of 24 months, confined to one lobe of the prostate, Gleason score <7, showed a statistical 5-year biochemical recurrence-free preoperative PSA level <10 ng/ml and only one cancer- survival rate (PSA under 1.0 ng/ml) in 45% to 75% of the positive biopsy from at least six. Given these criteria, cases. The PSA recurrence-free survival rate in this adequate tumor control can be achieved (32). The relative collective was highly dependent on the staging and grading exclusion criteria for brachytherapy are a significant of the tumor (42). infravesical obstruction (temporary post-surgical worsening Severe complications as a result of cryotherapy include is likely) and a TUR-P before therapy (increase of the post- impotence, incontinence and the formation of recto-urethral surgical incontinence rates) (32). Possible postoperative fistulas, although the latter are rarely observed with the use complications include urinary retention or a bladder of third-generation devices (43, 44). Infravesical obstruction, tamponade after bleeding from the urinary bladder. which frequently develops after cryoablation of the prostate, Irradiation can also induce irritation of the urethra and the can be an indication for a TUR-P. Data published by bladder neck, with subsequent development of dysuria and Witzsch et al. showed a decrease of the serum-PSA level in urge-symptoms postoperatively. In most cases these all patients (n=27) treated with one of the third-generation symptoms regress to the preoperative status (33, 32). cryotherapy devices. In 6 patients from this series, TUR-P The oncological results of brachytherapy are promising in was carried out after cryotherapy and one patient suffered appropriately selected groups of patients: one study (10-year from stress incontinence. No fistula formation was observed follow-up) showed a 98% cancer-specific survival rate, in this patient collective (43). The results of 3 studies, although with a recurrence-free rate of only 46% (34). including the oncological results, rate of positive biopsies These data come from one of the early large collectives after cryotherapy and rate of complications, are summarised investigated. In the meantime, planning and implantation in Table II.

554 Trojan et al: Update on Prostate Cancer Therapy

Table II. Complications of cryotherapy of prostate cancer from 3 studies.

Study Patients PSA (ng/ml) Negative biopsy Impotence Incontinence Fistulas (n) post-op post-op

De la Taille (2000) 35 73% (<1.0), 3 Mo n.a. n.a. 6% 0 68% (<1.0), 9 Mo

Long (2001) 975 45-76% (<1.0) 82% 93% 7.5% 0.5% Median F/U: 24 Mo

Han (2002) 102 84%(<0.4), 3 Mo n.a. 70% 4-8% 0% 76%(<0.4), 12 Mo

High-intensity focused ultrasound (HIFU). Clinical studies on For this reason, they represent a therapeutic challenge for the the treatment of localised prostate cancer with high-intensity urologist. Palliative systemic therapy can be divided into the focused ultrasound (HIFU) were first published 7 years ago three groups: endocrine manipulations (hormonal therapy), (45). The principle of HIFU ablation is based on the chemotherapy and new experimental approaches, with the conversion of high-energy ultrasound waves into heat by tissue first group playing the major role in treatment. absorption in a small focus. The applied energy results in the vaporisation of fluids from the tissue and necrosis. After using Hormonal therapy. The proliferation and apoptosis of benign transrectal diagnostic ultrasound to plan HIFU ablation, high- prostatic epithelial and prostate cancer cells are androgen- energy ultrasound waves are focused in the prostate by dependent processes. After androgen deprivation, the parabolically arranged piezo-crystals, causing the temperature division of hormone-sensitive cancer cell clones is within the tissue to rise to 85ÆC, which leads to coagulation suppressed. The effectiveness of hormonal therapy is usually necrosis. In contrast to the radiotherapeutic approach, it is restricted in time. After 12 to 18 months of hormonal routinely possible to repeat the procedure, if the treatment therapy of the metastatic disease, prostate cancer cells in fails in the first place. Initial results have shown a 56% part escape the androgen-dependent status and progress response rate among treated patients (response defined as 6 (47). At that point, latent androgen-independent tumor cell negative biopsies, PSA <4ng / ml; (46)). The results of two clones develop from the androgen-independent stem cells recent studies are summarised in Table III. of the prostate, forming tumor masses that will not respond Cryoablation and HIFU treatment represent new to hormonal therapy. methods for prostate cancer. Like brachytherapy, they can In order to prolong the hormone-sensitive stage and to also be carried out as an outpatient procedure. The initial extend the latency until hormonal resistance to prostate results are promising. Nevertheless, one can assume further cancer develops, delayed or intermittent hormonal development of these technologies and a subsequent therapeutic strategies have been evaluated. It should be improvement in the oncological results and safety of both noted that, in studies where immediate hormone therapy procedures. One of the potential future applications of was used on patients with advanced disease, but with no these methods may be the treatment of local tumor clinical symptoms of metastases, there was a significant recurrence as a "salvage" therapy after radical prostatectomy reduction in the tumor-associated complication rate and or radiotherapy. Before cryotherapy and/or HIFU become survival (48). The development of a hormonal-resistant standard treatment options for prostate cancer, however, status in prostate cancer is inevitable after hormonal randomised and prospective studies with long-term follow- ablation. The attempt to delay hormonal resistance led to ups must be completed. Because of the high cost of the the introduction of the so-called intermittent hormonal devices required, it is also questionable whether these therapy. Theoretically, an interrupted application of procedures can be widely used in urological departments. androgen deprivation can impede the overgrowth of hormone-resistant cell clones. The final results of the Drug therapies for the management of advanced EORTC phase III randomised study-30985 will hopefully disease clarify these theoretical suggestions. However, the advantages of intermittent hormonal therapy over As a general rule, neither locally advanced prostate cancer nor continuous therapy are already uncontroversial and make it the generalised disease are curable and can only be restrained. possible to improve the quality of life (49, 50).

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Hormonal therapy is indicated in patients with positive is one of the explanations for the so-called anti-androgen lymph node findings or metastases, and also in the case of a withdrawal syndrome first described by Scher et al. (60), locally advanced carcinoma or where primary curative when about 30% of patients receiving MAB responded to therapy has failed. However, no final recommendation on an the cessation of anti-androgens for a short time (3-6 months) optimal method of hormonal treatment can be given as yet. with a decrease in serum PSA level and, less frequently, with Generally, there are two ways of administering primary symptomatic disease-related improvement (61). hormonal therapy: i) The suppression of testosterone production either by bilateral orchiectomy (surgical Alternative medical therapy. In the systemic disease phase castration) or by the use of LHRH agonists (disturbance of especially, patients are on the look out for alternative the pulsatile GnRH emission from the hypophysis – treatment options and methods. Two therapeutic strategies chemical castration) and estrogens. Synthetic LHRH that can be assigned to the field of "hormonal therapies" are agonists, before suppression, initially induce a stimulation widely available and, in the era of the internet, easily of LHRH production. After this, the testosterone level rises obtained. (biochemical ‘Flare-Up’) and can lead to a flare-up or PC-SPES is produced from Chinese plants which contain progression of the disease (clinical ‘Flare-Up’). To avoid high amounts of phyto-estrogens. The cost of this therapy is this undesired effect, the use of steroidal or non-steroidal approx. 450 € / month and has to be met, at least in anti-androgens 1-2 weeks before and 3-4 weeks after the Germany, by the patient. The effect is a reduction of the first injection of LHRH agonists was proposed (51). LHRH serum testosterone to castration level, like conventional antagonists have recently been investigated in clinical estrogen-therapy. Side-effects such as gynecomasty are often studies (52, 53). Such therapy can prevent the occurrence of observed. Clinical studies did not show any advantage over the so-called ‘Flare-Up’ effect, which always appears initially either of the above-mentioned classical hormonal with the use of LHRH agonists. ii) The effect of androgens therapeutic concepts (62). at the cellular level of the prostate can be influenced by the The Triple Therapy (introduced by Leibowitz) did not blockage of the androgen receptor and is known as anti- show sufficient effectiveness in treating systemic prostate androgen therapy. There are two types of anti-androgens: cancer in a clinically controlled setting. Patients are initially steroidal and non-steroidal, or ‘pure’ anti-androgens. treated with three medications (LHRH analogs, anti- Because of their gestagenic properties, steroidal anti- androgens and 5-alpha-reductase inhibitor) for 13 months, androgens induce a reduction of serum testosterone to the followed by 5-alpha-reductase inhibitor maintenance therapy castration level and can be used as a monotherapy. ‘Pure’ (63). The authors believe that this triple androgen blockade anti-androgens can be administered as a monotherapy only could be a ‘promising alternative’ for the treatment of local or in selected patients (young men with locally advanced locally advanced prostate cancer. In our opinion, it could only disease or low metastatic burden) and should be used with be an alternative treatment for selected patients with a local caution (54). These different forms of medical treatment disease where definitive treatment is contraindicated. can be applied as a continuous monotherapy and have to be considered as the standard for hormonal therapy. Combination of local therapy and systemic hormonal The combination of surgical or chemical castration and anti- manipulation (neoadjuvant and adjuvant hormonal therapy). androgen therapy is known as a maximal androgen blockade Some patients who receive potentially curative treatment, (MAB) and has been investigated in numerous studies. LHRH such as radical prostatectomy or radiotherapy, develop agonists suppress testicular androgen production, but 5 to 10% biochemical and clinical recurrences. The incidence of such of the androgens circulating in men are of adrenal origin failure is closely related to several risk factors: Gleason’s (androstenedione, dehydroepiandrostesterone). MAB was Score, the presence of positive margins after surgery and intended to eradicate the influence of adrenal androgens on postoperative tumor staging (64, 65). the prostate and increase the efficacy of hormonal therapy. Neoadjuvant hormonal therapy is one of the attempts to The advantage of MAB is controversial: there was no improve the results of the curative procedures. Most studies significant improvement in most randomised trials. Meta- have shown that only the rate of positive margins was analysis of 27 randomised trials showed an average advantage significantly reduced after neoadjuvant therapy. No in 5-year survival of 2 months at 25.4 months versus 23.4 improvement in oncological outcome has been observed. (statistically insignificant) (55). In 3 of the 27 studies, there was (66-68). An additional factor that has to be taken into a significant improvement in survival (56-58). consideration is that neoadjuvant hormonal therapy induces In this context, a possible paradoxical effect of the anti- tissue fibrosis, which can have undesirable effects on the androgen treatment has to be mentioned: after the mutation surgical procedure. In conclusion, neoadjuvant therapy for of the androgen receptor, anti-androgens may act on the localised prostate cancer before radical prostatectomy receptor as agonists, thus accelerating the disease (59). This cannot be considered as a standard (68).

556 Trojan et al: Update on Prostate Cancer Therapy

Table III. Complications of HIFU therapy of prostate cancer from 3 studies.

Study Patients PSA (ng/ml) Negative biopsy Impotence Incontinence Fistulas (n) post-op post-op

Thueroff (2001) 136 97%(<4.0) 80% 33-66% Stress incontinence 0.5-3.1% 61%(<0.5) 0.9-24%

Gelet (2001) 102 No disease 75% n=25 Stress incontinence n=1 progression: 66% av. F/U: 19 Mo (of 41) Gr.1:9, Gr.2:10 Gr.3:4

The effectiveness of adjuvant hormonal therapy after was also investigated (76-78). PSA doubling time is one of curative radiotherapy was proven by RTOG and EORTC the criteria for assessing the effectiveness of chemotherapy. randomised studies. One advantage of radiotherapy plus In favourable cases, an interval of more than 80 days is hormonal ablation over radiotherapy alone in terms of achieved. Compared to the early stage disease, cancer disease-free survival was evident among patients with progression is more apparent in the advanced stages. unfavourable prognosis (locally advanced cancer or lymph Whether the individual patient will benefit from these new node-positive) (69, 70). The EORTC trial also showed an chemotherapeutic regimes is still unclear (79, 92). improvement in overall survival (71). The difference in disease-free and overall survival remained significant even New experimental approaches for systemic disease after the results were updated in 2002 (66 months follow- up): 74% vs 40% (p=0.0001) and 78% vs 40% (p=0.0002), The process of carcinogenesis is complex and includes respectively (72). several alterations at the genetic and molecular levels. A Most retrospective studies have demonstrated an better understanding of these changes will open up new improvement in long-term results when radical possibilities for the treatment of malignant diseases, prostatectomy was combined with immediate hormonal including prostate cancer. deprivation (orchiectomy or LHRH agonists) among patients with lymph node metastases (73, 74). However, as Antiangiogenic therapy. Solid tumors of more than 1-2mm in yet there has been no prospective randomized study to diameter require a blood supply via the formation of new evaluate the role of adjuvant hormonal therapy after radical vessels. Inhibition of this process of neoangiogenesis seems to prostatectomy, so this treatment concept can still not be be an attractive and universal target of anticancer therapy. considered as the standard approach. The advantage of such therapy is the absence of the side- Because of the minor impact on the quality of life, the effects and toxicity symptoms usually observed in conventional use of pure anti-androgens in the adjuvant setting has an chemotherapy. The effectiveness of different anti-angiogenic advantage over LH-RH agonists. Whether the efficacy of agents has been documented in experimental and clinical this approach is adequate remains to be evaluated, but studies (80). Thalidomide, for example, was initially designed initial results are promising. The risk of biochemical as a sedative drug, but was subsequently discovered to possess progression was significantly reduced in patients who potent anti-angiogenic properties. It is currently being underwent radical prostatectomy and radiotherapy, where investigated in clinical trials for the treatment of hormone adjuvant 150mg bicalutamide was used immediately after refractory prostate cancer. The initial results are promising, definitive therapy (75). especially where Thalidomide was used in combination with conventional therapeutics such as docetaxel (81). Chemotherapy. The use of chemotherapy in the treatment of prostate cancer is still restricted because of the lack of Gene therapy – Antisense technologies. Antisense effectiveness against hormone-refractory carcinoma. oligonucleotide (ASO) therapy is a promising concept for Nevertheless, there are numerous trials where the the treatment of different solid tumors, including prostate effectiveness of mitoxantrone-based, estramustine cancer. Antisense oligonucleotides are single-stranded phosphate-based, or docetaxel-based regimes have been DNA, usually 12-20 bases in length, complementary to the evaluated. The value of these drugs as a single agent therapy sequence of the target m-RNA. Common targets for

557 ANTICANCER RESEARCH 25: 551-562 (2005) antisense strategies are m-RNA encoding for proteins systemic prostate cancers are suited to drug therapy, with associated with proliferation, apoptosis, angiogenesis and hormonal therapy as the gold standard. Nevertheless, this metastatic progression (82). concept provides only a temporary improvement of the In vivo application of ASO is limited due to the disease. Chemotherapeutic approaches have failed to achieve susceptibility of the original phosphodiester backbones to the desired therapeutic success up to now, and so the long- degradation caused by cellular nucleases. Much effort has term progression of the disease has to be considered as a been directed at increasing the stability and specificity of serious problem that must be overcome. New experimental ASO compounds, which would allow the use of ASO concepts are promising and may well fill this gap in the future. therapy more widely in clinical, patient-orientated trials. Second and third generation ASO with phosphorothioate References and phosphorodiamidate backbones are currently being investigated (83). To date, antisense therapy has been used 1 Farkas A, Schneider D, Perrotti M, Cummings KB and Ward for prostate cancer in clinical trials against different targets, WS: National trends in the epidemiology of prostate cancer, such as PKC-alpha, Protein Kinase A, Bcl2, c-myb etc. (84- 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. Urology 52: 444-8 1998. 86). Many other possible targets for treating prostate cancer 2 Smart CR: Results of prostate carcinoma screening in the U.S. with ASO are being investigated in preclinical studies, to as reflected in the surveillance, epidemiology, and end results include the inhibition of androgen receptor expression, the program. Cancer 80: 1835-44, 1997. deprivation of different growth factors and their receptors 3 Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI as well as an antitelomerase therapy (87). and Pearson JD: Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Oral selective inhibitors of protein kinases. The epidermal Urology 58: 843-8, 2001. 4 Albertsen PC, Fryback DG, Storer BE and Kolon TF: Long- growth factor receptor (EGFR) seems to be one of the main term survival among men with conservatively treated localized pathways for the stimulation of androgen receptors in the prostate cancer. JAMA 274: 626-631, 1995. setting of androgen deprivation. The high levels of EGFR 5 Albertsen PC, Hanley JA, Gleason DF and Barry MJ: expression observed in prostate tumors (88) and preclinical Competing risk analysis of men aged 55 to 74 years at diagnosis investigation suggest that non-steroid-hormone signal managed conservatively for clinically localized prostate cancer. transduction pathways, such as the EGFR signalling JAMA 280: 975-980, 1998. pathway, can activate the androgen receptor in the 6 Lepor H, Gregerman M, Crosby R, Mostofi FK and Walsh PC: Precise localization of the autonomic nerves from the pelvic environment of clinical androgen deprivation. Tyrosine plexus to the corpora cavernosa: a detailed anatomical study of kinases are the signal transduction trigger for the EGFR the adult male pelvis. J Urol 133: 207-12, 1985. ® (89). ZD 1839 (IRESSA ) is an oral selective inhibitor of 7 Walsh PC and Donker PJ: Impotence following radical the epidermal growth factor-tyrosine kinase (EGFR-TKI) prostatectomy: insight into etiology and prevention. J Urol 128: and is currently under investigation in clinical phase II and 492-7, 1982. III studies as a monotherapy or in combination with 8 Walsh PC, Lepor H and Eggleston JC: Radical prostatectomy conventional therapeutic options for the treatment of with preservation of sexual function: anatomical and pathological considerations. Prostate 4: 473-85, 1983. prostate cancer, including hormone refractory disease (90). 9 Villers AA, McNeal JE, Redwine EA, Freiha FS and Stamey Another oral protein kinase inhibitor (PTK-ZK), which TA: The role of perineural space invasion in the local spread of is selective for the vascular endothelial growth factor prostatic adenocarcinoma. J Urol 142: 763-8, 1989. 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