Theo M. de Reijke 1, Jean J.M.C.H. de la Rosette 1, Cora N. Sternberg 2
- 1 Department Of Urology Academic Medical Center, Amsterdam
2 Department of Medical Oncology San Camillo And Forlanini Hospitals, Rome
prostate, prostate cancer, hormone refractory, chemotherapy, targeted therapy
- Patients with locally advanced or metastatic prostate cancer are being treated with different forms of androgen deprivation therapy. The median time progression of this treatment approach ranges between 14 and 30 months. Following biochemical or objective progression the prostate cancer cells can still be androgen dependent for some time. The different treatment approaches in this disease stage are being described, including the working mechanism and possible application as second line treatment. Inevitably, however, the patient will progress to a hormone refractory prostate cancer stage. Recently, for the first time it was reported that docetaxel-based chemotherapy resulted in a modest survival benefit of approximately 2 months in patients with hormone refractory prostate cancer. The question is at this moment when to start this palliative chemotherapy and in which patients. Clearly, an improvement of these survival rates is necessary and several other approaches have been or are being investigated in patients with hormone refractory prostate cancer. The current stage of these treatment modalities are being discussed and put into clinical perspective. The great challenge will be to select these treatment modalities from the abundance of new agents that are in the pipeline of the pharmaceutical companies. Which of these targeted therapies have the biggest potential to be active as mono- or combination therapy in patients with prostate cancer? The goal of the treatment using the new treatment modalities will be to convert prostate cancer from a proliferative into a chronic disease. It is clear that selection of patients, using e. g. nomograms, genomics/proteomics, and side effect profile will then be very important. It is obvious that most of these new treatments will be tested in patients with hormone refractory prostate cancer, but once there is proven activity an earlier start of the treatment should be investigated. The setup of clinical trials with other endpoints (not survival) should be discussed in order to speed up the introduction of these new treatment modalities.
Hormonal treatment is the treatment of choice for patients with metastatic prostate cancer. In 1940, Huggins and Hodges proved hormonal dependence of prostate cancer by hormonal manipulation . Since then, gonadal androgen suppression with or without anti-androgens or antiandrogens alone have been the treatments of choice for patients with metastatic prostate cancer. More recently these treatments are also being used in patients with relapsing disease after definitive local therapy.
Despite hormonal manipulation, development of progressive disease is inevitable because the tumour will become resistant to hormonal therapy and resume growth. The androgen-dependent period in patients with metastatic disease ranges from a median of 14 to 30 months depending on the extent of disease .
In spite of testosterone at castration levels, the disease progresses but secondary hormonal manipulations can still induce biochemical and clinical responses. Kelly et al first described a PSA decline following withdrawal of anti-androgens in men progressing during combined androgen blockade . This phenomenon can be induced due to alterations in the androgen signalling cascade, including mutations in the androgen receptor, resulting in the anti-androgen behaving as an activator, rather than an inhibitor of the androgen receptor . The median duration of this PSA decline is however only 3.5 to 6 months and phase III trials have shown that anti-androgen withdrawal happens rarely [5-9].
Following this Androgen Independent stage the patient will inevitably enter into the Hormone Refractory stage. Until recently, chemotherapy was not very effective for these patients. In a literature review the Yagoda and Petrylak reported an objective response rate for single agent chemotherapy of only 9% .
Median survival of patients with metastatic hormone refractory prostate cancer has been thought to be approximately 12 months, although this clearly depends upon the initial degree of pain and performance status . The mechanism of the acquisition of androgen independence is unclear. It has been postulated that the early hormone refractory state is due to an increased sensitivity of the androgen receptor (AR) pathway through mutations, over expression or alterations in cofactor expression. The end result is that the AR becomes super responsive, stimulating cancer growth despite very low in vivo levels of dihydrotestosterone (DHT), or in the presence of alternative ligands such as anti-androgens [12,13]. Many treatment modalities have been investigated for patients with hormone refractory prostate cancer (HRPC), all attempting to intervene upon different mechanisms in the development of prostate cancer.
It is generally accepted to continue on androgen deprivation treatment while administering other therapies such as chemotherapy, although the patient is in a hormone refractory stage of the disease [14,15]. The metastatic extent and location (s) determine the symptoms of the patient and especially in this situation it is important to discuss with the patient the chance of complications and possible palliative treatments. In case of local progression and subsequent voiding symptoms or hematuria a palliative transurethral prostate desobstruction (channel resection in order to prevent incontinence) or radiotherapy could be discussed [16,17]. In case of renal function deterioration due to bilateral hydronephrosis a high dose of corticosteroids could relieve the obstruction temporarily, the role of placement of a percutaneous nephrostomy tube is questionable due to the fact that patients are in an incurable stage and the nephrostomy tube (s) can induce side effects with a clear impact on the quality of life [18,19]. But, the option should be openly discussed with the patient and relatives. Bone pain due to metastases could be treated with palliative local irradiation (8 Gy) in case only a few painful metastases are present or radionuclide treatment (strontium-89, rhenium-86, samarium-155) or hemi body radiation in case of more extensive bone lesions [20-22]. In some instable fractures even emergency surgical stabilisation should be considered followed by local irradiation or in case of a vertebral fracture also in combination with corticosteroids to prevent oedema and paralysis . Important is to inform the patient on the early signs of spinal compression, e. g. a band-like pain in the abdomen, lower limb weakness, peripheral neuropathy . It is obvious that especially in this situation a multidisciplinary approach is essential in order to offer the best the best palliative care. In the following paragraphs current and investigational medical treatment modalities for patients with HRPC are described.
Definition and prognosis
Relapse, indicating the emergence of androgen independent cells, can be observed in different ways [25,26]. First, progressive disease can be defined as a consecutive rise in PSA level on 3 serial measurements of greater than 50% despite castrate levels of testosterone (Memorial Sloan-Kettering Cancer Center). Worsening of disease can be evidenced by a worsening of the radionuclide bone scan (new lesions), an enlarging soft tissue mass in a lymph node or visceral site, or tumour-related symptoms such as skeletal pain, obstructed voiding symptoms, fatigue and weight loss. Patients with a PSA rise only (biochemical progression) have a median survival time of more than 20 months when treated with chemotherapy . However, patients with painful bone metastases have a worse prognosis with a median survival time of some 6-9 months. Quality of life is as important to this group of patients as treatment with known survival benefits. Therefore, side effects should be well tolerated and eventually well treated and balanced against the palliative effect of the therapy.
Evaluation of response is usually difficult since the majority of patients have bone-only disease which is not very reliable in terms of response evaluation. Measurable disease (soft tissue lesions) is present in only 10 to 20% of the patients. Kelly et al defined a decline of PSA of ł50% as a useful surrogate for improved long-term outcome, but this has been hotly debated by others .
The Prostate-Specific Antigen Working Group recommended employing PSA response confirmed again after 4 weeks in the absence of clinical or radiological progression. PSA progression was defined as a 25% increase and an absolute PSA increase by at least 5 ng/mL . Response and progression of measurable disease are evaluated by the RECIST criteria . These definitions are being revisited by a new Working Group (Scher et al Prostate Cancer ASCO, February 2007, in press).
Secondary hormonal treatment modalities in patients with HRPC
Ketoconazole is an antifungal agent which in high doses inhibits testicular and adrenal androgen synthesis and also has a direct cytotoxic effect on prostatic cancer cells in vitro . Several trials have shown PSA responses with ketoconazole in men with HRPC, and up to 62.5% an objective response . Adrenal insufficiency should not be a limiting factor if patients are given concomitant hydrocortisone therapy. Very few well-designed clinical studies, have been reported .
Aminoglutethimide blocks several cytochrome p450-mediated hydroxylation steps, resulting in decreased production of adrenal glucocorticoids, mineral corticoids, estrogens and androgens . This second-line hormonal therapy has been directly compared to cytotoxic chemotherapy in a few studies, all in combination with the use of hydrocortisone . The addition of aminoglutethimide is rarely used today.
Glucocorticoids (prednisone, dexamethasone, and hydrocortisone) reduce the pituitary production of ACTH, resulting in suppression of adrenal steroid genesis, including adrenal androgens. There may be direct inhibition of tumour growth by disruption of intracellular signalling pathways . In one study, prednisone resulted in pain relief in 21-40% of men with HRPC, however, the median duration was short (2-3 months) .
Hydrocortisone has been evaluated in phase III trials in combination with chemotherapy, sometimes with a hydrocortisone control arm. Hydrocortisone alone compared with hydrocortisone plus suramin in men with HRPC showed a decline in serum PSA of 16% and 28% had improved bone pain . Another trial compared mitoxantrone plus hydrocortisone to hydrocortisone alone. There was no difference in survival between the treatment arms. In the group treated with hydrocortisone alone, 22% showed a greater than 50% decline in serum PSA . This trial may also have been underpowered to demonstrate a survival difference.
Diethylstilbestrol (DES) competes with androgens for the androgen receptor, and may have a cytotoxic effect on human androgen-sensitive and androgen - insensitive prostate cancer cells in vitro . DES has been evaluated in men failing first-line androgen deprivation. Because of lethal cardiovascular toxicity in 11 percent of 185 men in 2 EORTC trials using DES, it is not longer been used .
The herbal supplement PC-SPES, a combination of 8 herbal compounds, has been found to contain diethylstilbestrol (DES) as well as warfarin. In a prospective randomized phase II trial, PSA decreases of >50% were found in 40% of men receiving PC-SPES treatment, compared with 24% receiving DES . However, the use of PC-SPES was associated with bleeding and an elevated prothrombin time and it is therefore no longer available in the United States .
Chemotherapy in HRPC
Chemotherapy was previously considered to be relatively ineffective in HRPC . Estramustine phosphate (EMP) is a combination of nor-nitrogen mustard and oestradiol. As a single agent, EMP has minor activity in HRPC. Starting with EMP alone is usually not very effective . EMP appears to have a greater potential in combination chemotherapy regimens. When EMP was combined with vinblastine a trend toward improved survival (12.5 versus 9.4 months) was observed [46,47].
Mitoxantrone/prednisone combination therapy was the first chemotherapy regimen approved for the palliative treatment of symptomatic metastatic prostate cancer . In this trial there was no difference in overall survival for prednisone alone or the combination of mitoxantrone plus prednisone, there was a significant improvement in pain relief response. The quality of life findings were confirmed by Kantoff et al combining mitoxantrone with hydrocortisone .
However, newer regimens are associated with higher rates of both objective and biochemical (PSA) response, and importantly median survival durations of 18 to 19 months. Moreover, particularly important in patients with HRPC, quality of life endpoints are also being evaluated.
Taxanes bind to tubulin subunits and inhibit the disassembly of microtubules that normally occurs during cell cycle progression. Taxanes also inactivate the anti-apoptotic protein bcl-2 phosphorylation, thereby promoting apoptosis.
The Southwest Oncology Group (SWOG 99-16) study was a multicenter randomized trial which compared estramustine-docetaxel with mitoxantrone-prednisone in men with HRPC . Median survival was modestly but significantly better with estramustine-docetaxel (17.5 and 15.6 months, respectively) as well as median progression-free survival and PSA rate. Warfarin and aspirin were used as prevention of thrombo-embolic events.
Tannock et al compared docetaxel, either every 3 weeks or weekly plus prednisone 5 mg twice daily with mitoxantrone 12 mg/m˛ every 3 weeks combined with prednisone 5 mg twice daily . The median survival rates were 18.9, 17.3, and 16.4 months, respectively. This means a 24% reduction in the risk of death for those patients treated with docetaxel-prednisone compared with mitoxantrone-prednisone. Patients treated with a three-weekly regimen of docetaxel-prednisone demonstrated a survival benefit as well as a superior quality of life score. This regimen has now been approved as a new standard of care for men with HRPC by the United States Food and Drug Administration and by the EMEA in Europe.
Chemotherapy has now been proven to induce a survival benefit in advanced HRPC. Optimal timing, combinations such as cytotoxic therapy plus bisphosphonates or targeted therapies and sequencing of cytotoxic therapies in HRPC require further investigation [51,52]. Research should be done in offering docetaxel-based therapy in earlier stages, for example for hormone naďve patients (STAMPEDE Trial), or in patients with biochemical recurrence after androgen deprivation therapy or even earlier in high risk patients after radical prostatectomy. These studies might include patients with a Gleason score of 8-10, seminal vesicle or lymph node invasion, immediately detectable PSA, or rapid PSA doubling time (<3 months), or those in whom a predictive nomogram suggests a high risk of recurrent disease (TAX 3501) .
Thalidomide has immunomodulatory, anti-inflammatory and anti-angiogenic properties . It is known that a metabolite of thalidomide is responsible for its anti-angiogenic activities. Thalidomide was tested in a phase II setting in men with HRPC at both a high dose (up to 1200 mg/day) and a low dose (200 mg/day) . Moderate activity was found in a small randomized phase II study where docetaxel and thalidomide was compared to docetaxel alone. At 18 months, overall survival was 68.2% as compared to 42.9% with docetaxel alone . Potentially more active and attractive analogues of thalidomide are being developed.
Of even more interest is Bevacizumab, a humanized murine monoclonal antibody to vascular endothelial growth factor (VEGF). CALGB 90006 was a trial in which patients were treated with bevacizumab in combination with docetaxel . The investigators reported a 53% partial response rate in measurable disease and a 65% biochemical response rate. A large phase III study will evaluate bevacizumab with docetaxel and prednisone versus docetaxel and prednisone alone in patients with chemotherapy naďve HRPC.
Differentiation therapy means the use of pharmatherapeutical agents to induce differentiation, cell cycle arrest and apoptosis and inhibition of tumour progression. These compounds have both cytotoxic and cytostatic activity. Moreover, their low toxicity profile permits long-term administration. Calcitriol, the active form of the steroid hormone vitamin D, has pro-apoptotic effects on cancer cells. Its receptor is also found in the epithelial cells of prostate cancer.
It has been found to potentiate the cytotoxic effect of mitoxantrone and taxanes if given at supraphysiologic concentrations, providing a rationale for combination therapy. In a phase II trial, oral calcitriol plus docetaxel were administered for 8 weeks to 37 men with HRPC, 81% had a >50% decline in PSA . Although survival was not the intended primary the ASCENT trial comparing weekly docetaxel with docetaxel plus high-dose calcitriol found an improvement in median survival (23.5 versus 16.4 months) . The ASCENT II trials seeks to randomize patients to the best arm of the ASCENT trial (using weekly docetaxel) and comparing this in approximately 900 patients to every three week docetaxel and prednisone from the TAX 327 trial.
Endothelin receptor antagonists
Prostate cancer is frequently characterized by abnormalities in a variety of growth factor signalling pathways that control the cell cycle and apoptosis. Some of these pathways are investigated as therapeutic targets.
Endothelin receptor antagonists
There is emerging evidence that endothelin-1 (ET-1) and its receptors ETa and ETb play an important role in the biology of prostate cancer, including the characteristic osteoblastic response of bone to metastases [60-62]. Acting through the ETa receptor, ET-1 appears to be central in the cancer-induced osteoblastic lesion. Osteoblasts have abundant ETa receptors. In animal models, the selective ETa receptor antagonist atrasentan significantly reduced the osteoblastic response that occurs from an ET-1 secreting tumour. ET-1 is thought to alter the balance of osteoblasts and osteoclasts to favor new bone formation that is characteristic of prostate metastases and also to mediate metastases related bone pain. The selective endothelin receptor antagonist atrasentan blocks the osteoblastic response to bone metastases and may delay androgen-refractory disease progression. In clinical trials, atrasentan (an oral agent) appears to delay androgen refractory disease progression in some men . The M00-211 study examined the role of atrasentan in HRPC with radiographic evidence of metastatic disease. There was a significant delay in time to disease progression in the evaluable subset but not in an intention-to-treat analysis. A meta-analysis including 1002 patients with metastatic and asymptomatic HRPC comparing atrasentan 10 mg and placebo showed a delay in time to progression (p=0.045), time to PSA progression (p=0.002) and an improvement in overall quality of life. Side effects were acceptable (rhinitis, headache and peripheral oedema) . A large phase III trial by the SWOG will evaluate the combination of docetaxel and prednisone with or without atrasentan.
Growth factor receptor antagonists, monoclonal antibodies
Growth factors and their receptors (e. g., epidermal growth factor receptor [EGFR], neurotrophin-specific tyrosine kinase [trk] receptor), offer new targets for anticancer therapy. The EGFR (HER-1 or c-erbB-1) belongs to a family of receptor tyrosine kinases that also includes HER-2/neu (c-erbB-2). EGFR signalling and/or autocrine loops involving neurotrophin and its receptor are thought to be an important cell survival mechanism in HRPC. Up-regulation of growth factor expression and of the receptors mediating their effects is common in HRPC . Growth factors are ubiquitous and normally active in homeostasis, wound healing, angiogenesis, and vasoconstriction, so the effects of their blockade are far less predictable than the removal of androgens through the physical or chemical elimination of Leydig cells. Many receptors and their targets are investigated in prostate cancer. Targeted therapies with small molecule trk inhibitors have the potential for inhibiting specific pathways in cancer cells while having little consequence on normal cells. Gefitinib and erlotinib are in early clinical testing in men with advanced prostate cancer. So far, gefitinib (a small-molecule EGFR tyrosine kinase inhibitor (TKI) has demonstrated minimal activity .
Combination therapy with docetaxel is now ongoing. Trastuzumab, the monoclonal antibody against HER2 was also not effective . Imatinib, a platelet derived growth factor receptor TKI (active in GIST), showed modest PSA response as a single agent but the combination with docetaxel is being explored .
Second Line Chemotherapy
The epothilones are novel microtubule inhibitors that have displayed preclinical activity in taxane-resistant tumours, with the reverse sequence also being effective .
Preclinical data suggested that molecular mechanisms of resistance to epothilone and taxanes do not totally overlap. These observations are supported by clinical trials. Hussain et al studied ixabepilone, an epothilone-B analogue, in men with HRPC as first-line therapy and reported a PSA response in 9/22 patients and an objective response in 3/10 patients .
Comparable data were reported by Galsky et al .
Rosenberg et al showed taxane response after progression on epothilone . To determine the benefit of epothilone therapy after prior chemotherapy, a randomized phase II study of ixabepilone or mitoxantrone and Prednisone in patients with taxane resistant HRPC
was undertaken. Unfortunately the results in second line after taxane failure were equivalent to mitoxantrone and prednisone .
Satraplatin is a third generation oral platinum compound that has demonstrated in vitro activity against taxane-resistant cell lines. Satraplatin has been evaluated in combination with prednisone for chemotherapy-naďve patients with HRPC in the EORTC-GU group . This study was closed prematurely, but the combination showed a better progression-free survival (5.1 versus 2.5 months) and PSA response (33.3 versus 8.7%). Based upon these results, a trial using satraplatin was conceived but the oral agent was put into second line chemotherapy. The trial known as SPARC (Satraplatin and Prednisone Against Refractory Cancer) enrolled 950 patients and was closed to accrual in December 2005. A 40% reduction in risk of disease progression was seen with satraplatin (HR 0.60; 95% CI 0.5-0.7). These results are highly statistically significant (p<0.00001) and will be fully presented at the ASCO prostate cancer meeting in February 2007. This is the first registration trial in 2° line HRPC. There are no drugs approved in this setting, it represents a major area of unmet medical need.
The antisense approach to cancer therapy involves targeting specific RNA sequences by constructing complementary oligonucleotides that bind to the native mRNA sequences and reduces their translation and subsequent protein expression. These oligonucleotides are `easily´ synthesized and can theoretically be targeted against numerous genes involved in cellular proliferation, apoptosis, metastasis and angiogenesis.
In prostate cancer, a number of genes have been identified as possible targets for this antisense approach . An important target for clinical intervention is Bcl-2, an important pro-survival regulator of apoptotic cell death. Overexpression of Bcl-2 in patients with prostate cancer is thus associated with progression to advanced or hormone independent disease. A synergistic effect has been demonstrated both in vitro and in vivo with taxanes. These data suggest a possible role of combined therapy with antisense Bcl-2 oligomers and androgen ablation/castration or taxane chemotherapy for advanced prostate cancer. In a preliminary report of a phase 2 trial for men with HRPC testing oblimersen in combination with docetaxel, a partial response was achieved in 4/15 patients with measurable disease, an a >50% reduction in PSA in 15/31 patients . Tolcher et al reported a phase I/II trial a combination treatment of docetaxel and oblimersen sodium, where PSA responses were observed in 14/27 (52%) patients and objective responses in 4/12 (33%) patients .
The EORTC-GU group has closed recruitment to a randomized phase II study comparing docetaxel and docetaxel plus oblimersen. Results will be reported at the ASCO meeting February 2007.
Gene therapy involves the transfer of DNA cells to replace, or otherwise affect the expression of a cell´s native genes. In order to perform this transfer with sufficient efficacy, a DNA transporter or vector is generally required. Methods that are used to transfer genes into cells are categorized as non-viral (naked DNA, liposomes, DNA polymer complexes) or viral based . Several major gene therapy strategies are under development for men with HRPC .
Immunotherapy, by either ex vivo tumour cell or effector cell gene transfer of immune stimulating molecules (e. g., granulocyte-macrophage colony-stimulating factor [GM-CSF], or direct administration of cytokine-transfected vectors or naked DNA into the tumour (e. g., interleukin 2 [IL-2} are being explored. The introduction of toxic or cell lytic genes, termed cytoreductive or "suicide" gene therapy and corrective gene therapy, designed to increase or abrogate aberrant expression of specific genes are also under investigation.
Immunotherapeutic approaches to HRPC are based on the premise that the immune system, if properly stimulated and/or properly mobilized, can eradicate malignant cells. Strategies to stimulate the immune system range from non-specific agents to targeted strategies, such as T-cell-based therapy against protein, a type of PSA . Also mobilization of the immune system ranges from general cellular and humoral responses to specific isolation, stimulation and expansion of a single population of immune cells, such as dendritic cells . Problems with immunotherapeutic approaches to HRPC are (1) prostate cancer cells produce large amounts of transforming growth factor-beta, a potent immunosuppressant, (2) class I major histocompatibility antigens, which are required for immune recognition, are defective in most prostate cancers and (3) defects in the T-cell receptor are noted in HRPC.
A meta-analysis of 2 phase II trials with APC 8015 (Provenge), in which dendritic cell precursors are harvested by leukopheresis and pulsed with PAP-GM-CSF fusion protein showed a 4.3 month improvement in median survival and was reported at the ECCO meeting in 2005 .
Other approaches to immunotherapy include the use of a cellular vaccine comprised of 2 allogeneic cell lines, LNCaP (lymph node metastasis) and PC-3 (bone metastasis). The cell lines are modified to secrete GM-CSF and then lethally irradiated to prevent further cell division. GVAX vaccine demonstrates immunogenicity and clinical activity in metastatic HRPC patients which appears to be dose-dependent in phase II trials . Two large phase III international randomized trials, Vital I and Vital II are evaluating this approach to immunotherapy as compared to docetaxel or in combination with docetaxel.
Osteoclast-targeted therapies: Bisphosphonates
Skeletal complications are a major cause of morbidity for men with metastatic prostate cancer. In addition, androgen deprivation therapy induces bone mineral density loss and increases the risk of bone fracture. Pathologic osteoclast activation plays a central role in disease-related skeletal morbidity. Markers of osteoclast activity predict independently the risk for subsequent skeletal complications, suggesting that cancer-mediated osteoclast activation not only accompanies bone metastases but also contributes to the clinical complications of metastatic disease . Bisphosphonates inhibit osteoclast activity by cellular mechanisms that affect osteoclast attachment, differentiation and survival and they also reduce osteoclast activity indirectly through effects on osteoblasts.
In the ZOMETA 039 study (a multicenter randomized placebo controlled trial), men with HRPC and asymptomatic or minimally symptomatic bone metastases received randomly intravenous zoledronic acid (4 or 8 mg every 3 weeks) or placebo . Zoledronic acid significantly diminished the number of skeletal related events compared with the placebo group (p=0.021) and extended the time to the first skeletal complication (p=0.011). The study was not designed to evaluate the effect of zoledronic acid on survival. Pamidronate and clodronate are 2 other bisphosphonates, which have been investigated in randomized controlled trials. Inadequate sample size, use of less potent bisphosphonates and end point definition may account for the lack of statistically significant benefit in these studies [86,87]. Patients on bisphosphonates should be informed about potential myalgias and fever in up to 25% of patients, also the renal function should be assessed. With zoledronic acid osteonecrosis of the jaw has been rarely reported .
Proteasome inhibitioProteasome inhibition
Cellular homeostasis requires an efficient and regulated mechanism for the degradation of proteins. The actual destruction takes place in the proteasome, a large protein complex with proteases on the inner walls that degrade the protein into small peptides . The activity of certain proteins requires proteasome-mediated degradation of other inhibitory proteins. Inhibition of the proteasome results in cell cycle arrest and induction of apoptosis; cancer cells appear to be particularly vulnerable to loss of proteasome activity. Bortezomib, a specific inhibitor of the chymotryptic-like activity of the proteasome has been studied in a phase 1 study in men with HRPC. Papandreou et al showed that 2/47 patients (4%) had a decrease in serum PSA of >50%, and 2 patients had a partial response in lymphnodes . Adverse effects were fatigue, diarrhoea, hypotension and hypertension. The combination of bortezomib with docetaxel is also investigated.
New agents are usually tested in HRPC patients. The question remains if this is the best target group for all new agents. Fortunately, active chemotherapeutic agents are now available, although the survival benefit is only moderate. The focus of many pharmaceutical companies is now on the development of new agents for the treatment of (prostate) cancer and many agents are now in the pipeline. The challenge is how to select from the abundance of new agents to be tested in formal phase II/III trials. New markers and endpoints should be developed, because the traditional endpoint (overall survival) takes too long and may not be relevant in terms of targeted cytostatic therapies.
Patient selection for adjuvant treatment is also very important. Given the long time frame of high-risk and recurrent prostate cancer, there is a need for better identification of those with slow progression versus those more likely to die from their disease and who would be candidates for early intervention or recruitment to ongoing clinical trials. Once new active agents have been identified in patients with HRPC, the possibility of administration of the drug at an earlier phase should be investigated.
Postoperative nomograms to predict recurrence are imprecise in many cases, and genetic profiling is still at this time an investigational strategy.
Given the interest in advanced profiling technologies (i. e., genomics and proteomics), more accurate predictions of recurrence risk are likely to be available in the near future [91-93]. These trials all aim to identify treatments that may be capable of converting aggressive prostate cancer to a more latent and chronic phenotype. Then these high-risk individuals are more likely to die with prostate cancer, rather than due to the cancer.
The goal is to convert prostate cancer from a proliferative process to a chronic disease. However, if given chronically or at an early phase the side effect profile of the drug is also of major importance in these circumstances.
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Theo M. de Reijke
Department of Urology
Academic Medical Center
1105 AZ AMSTERDAM
tel. +31 20 5666004