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Metastatic Genitourinary Malignancies

and *.

* Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA. Corresponding Author: Przemyslaw Twardowski Email:gro.hoc@ikswodrawtp

Metastatic Cancer: Clinical and Biological Perspectives edited by Rahul Jandial.
©2013 Landes Bioscience.
Read this chapter in the Madame Curie Bioscience Database here.

Genitourinary malignancies represent a heterogeneous group of diseases linked by anatomical and physiological function but different in almost every aspect of pathophysiology, molecular biology, prognosis and treatment of metastatic disease. Prostate cancer is by far the most common of genitourinary malignancies; it is characterized by relatively indolent behavior, propensity for bone metastases and reliance on the androgen receptor pathway that is exploited therapeutically with considerable success. Kidney cancer is probably one of the most unpredictable tumors, the prototypical “internist's disease” associated with multiple paraneoplastic, metabolic and hormonal syndromes that frequently accompany metastatic process. Renal carcinoma is driven by derangements in VEGF and mTOR pathways, and compounds inhibiting signaling through these pathways bestow significant therapeutic benefit that has improved the prognosis and outcomes in patients with metastatic disease. Testicular cancer is largely curable with cisplatin-based combination chemotherapy and cures are common even in circumstances of widely disseminated disease with visceral multi-organ involvement. This represents one of the remarkable achievements of modern oncology and somewhat of a mystery since the same therapy is not nearly as effective in any other solid tumor type.

Bladder/urothelial cancers unfortunately represent the subset of neoplasms with relatively limited progress in therapeutic options for metastatic disease although rare patients can be cured with combination chemotherapy especially in the setting of low volume metastases limited to lymph nodes or lungs. In this chapter we describe the basic aspects of biology and therapy of four most common cancers of genitourinary origin: kidney, prostate, bladder/urothelium and testicular germ cell tumors focusing on unique aspects of each disease and recent therapeutic advances.

Introduction

The genitourinary (GU) malignancies comprise a heterogeneous group of cancers with different cell origins, biological behavior, and treatments. Although lymphomas and sarcomas are occasionally encountered, in this chapter we will limit the discussion to the more common histological subtypes of carcinomas of the kidney, bladder, prostate, and testis. Within this group, there is an incredible biological diversity as exemplified by the fact that the management and prognosis of metastatic GU cancers are extremely variable. For instance, surgical resection alone of the primary cancer along with metastatic foci may be curative in renal cell cancer, whereas germ cell tumors of the testis are usually curable with chemotherapy even in case of widespread metastases. Prostate cancer may be controlled for many years although not cured with hormonal treatment, and immunotherapy with IL-2 occasionally results in long-term disease remission for metastatic renal cell cancer. Crucially, these modalities are not interchangeable among the various types of GU malignancies.

Kidney Cancer

Renal cell carcinoma (RCC) denotes the subset of cancers which arise from the cells of the renal cortex and is the subject of this section; other, less common, cancers of the kidney such as oncocytoma, primary sarcoma, and Wilms tumor are not discussed here. Transitional cell carcinomas originating from the renal pelvis are classified with the urothelial carcinomas and are the topic of the next section. RCC itself includes a number of histologic subtypes of which clear-cell carcinoma is the most common, followed by papillary, chromophobe, and collecting duct cancers.1 The data presented in this chapter apply primary to the clear-cell variant as the other subsets still await better understanding of their biology and more focused drug development efforts.

Approximately 20% of patients have metastatic disease at the time of diagnosis with the most common sites being lung, liver, lymph nodes, and bone,2 and a large number of patients will eventually develop metastases despite complete surgical resection. Late recurrence is also well-documented in the literature; one study cites a 6.4% chance of recurrence in patients after a disease-free interval of ten years.3 Prognosis in the setting of metastatic setting is poor with a five-year survival under 10% although long-term remissions can occasionally be obtained with immunotherapy.4 Metastatic kidney cancer is sometimes associated with paraneoplastic syndromes of hypercalcemia, polycythemia and liver function test abnormalities (Stauffer syndrome).2

Biology

In recent years RCC has been transformed from a disease with few effective treatments in the metastatic setting to one in which there are now multiple options of targeted agents. This shift has been made possible by improved understanding of the biological mechanisms underlying RCC. A key observation was that the large majority of sporadic clear cell RCC features loss of function of the tumor-suppressor gene VHL which is also lost in von Hippel-Landau disease, a genetic condition which predisposes to a variety of tumors, including clear cell RCC. As VHL expression normally leads to ubiquitination and degradation of the transcription factor hypoxia-inducible factor (HIF), VHL suppression leads to increased HIF activity which in turn results in increased expression of multiple downstream targets including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Cellular signaling pathways mediated by these ligands can be therapeutically targeted by both monoclonal antibodies as well as small molecule tyrosine-kinase inhibitors.

Signaling mediated by the protein kinase mammalian target of rapamycin (mTOR) is the other pathway which has proven to be clinically relevant as two of the approved therapeutic agents in metastatic RCC inhibit mTOR. Physiologically, mTOR is involved in regulation of HIF as well as other proteins important to cell proliferation.5 The available mTOR inhibitors function by binding to the intracellular protein FKBP12; the FKBP12-drug complex then binds to mTOR at an allosteric site which results in inhibition. Notably, while clearly possessing clinical activity, mTOR inhibitors tend to be cytostatic with low objective response rates in the phase III trials which led to their approval.

Even as many significant advances have been realized in the preceding decade, still more remains to be done. With time virtually all patients develop resistance to the available targeted agents, and long-term survival with advanced disease is still rare. A number of potential targets have already been identified, including the PI3K/Akt signaling pathway which lies upstream of mTOR, histone modification enzymes, and the MET receptor.6 Moreover, given the historical success of immunotherapy, further investigation in this area is also important. For instance, preliminary work has already identified differential effects on immune stimulation between sunitinib and sorafenib,7 and the combination of immune modulation and targeted therapy continues to be a theoretically promising albeit clinically unproven approach.

Treatment

Treatment for metastatic RCC primarily consists of systemic therapy with the caveat that removal of the primary tumor is still usually performed in light of trial data demonstrating increased survival with immunotherapy after cytoreductive nephrectomy.8 Metastasectomy of limited sites may also be an option in certain cases as discussed below. Until recently, patients had few options after disease progression with immunotherapy given the highly chemotherapy-refractory nature of RCC. However, with the advent of targeted therapy, the situation is considerably different now, and multiple agents with activity are now available. Nonetheless, durable remissions in metastatic RCC, aside from a few patients who respond exceptionally well to IL-2, remain the exception rather than the rule.

Immunotherapy

The exact interplay between RCC and the immune system is not entirely understood, but the medical literature contains multiple case reports of spontaneous regression of metastatic disease after surgical removal of the primary tumor.9 With the discovery that cytokine and interferon therapy can induce partial or even prolonged complete responses in metastatic RCC, nephrectomy followed by immunotherapy has been the standard of care in metastatic RCC for a number of years. Although largely supplanted by the targeted therapies outlined above, they remain a part of the armamentarium.

The two approved immunotherapeutic agents for RCC are interleukin-2 (IL-2) and interferon alfa (IFNα). High-dose IL-2 has been shown to result in occasional durable complete remissions lasting for many years even when administered in patients with metastatic disease. One retrospective study found a 9% complete response rate for metastatic disease, with the majority of these patients staying in durable remission up to 20 years later.10 Unfortunately, while patients with a complete response typically enter a durable remission, the complete response rate is low and was found to be under 10 percent in two observational studies.11,12 Although the overall response rate was 20 percent in both studies, the majority of patients with a partial response relapsed within a few years. Moreover, treatment is extremely toxic with frequent hemodynamic instability secondary to capillary leak syndrome.13

IFNα has long been the standard of care given the manageable side effect profile in conjunction with modest improvements in survival and response rate when given as a single agent.14 As such, it has often served as the control arm in trials featuring targeted therapeutics. However, as multiple targeted agents have consistently resulted in improved outcomes when tested against IFNα, it is now rarely used in RCC except in conjunction with bevacizumab as first-line therapy.

Targeted Therapy

At the time of writing there are seven FDA-approved targeted agents for the treatment of advanced RCC: sunitinib, sorafenib, pazopanib, axitinib, bevacizumab (in conjunction with IFNα), temsirolimus, everolimus. The first four are tyrosine kinase inhibitors (TKI) with multiple targets including vascular endothelial growth factor receptor (VEGFR). Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), and the latter two agents are small molecular inhibitors of mammalian target of rapamycin (mTOR) kinase. Table 1 lists the currently approved therapies for advanced RCC.

Table 1.. Currently approved therapies for advanced RCC.

Table 1.

Currently approved therapies for advanced RCC.

TKI

Sunitinib and pazopanib are approved for first-line treatment of advanced RCC on the basis of phase III trials demonstrating increased progression-free survival and response rate against interferon alfa although neither reached the threshold for statistical significant for overall survival.15,16 Sorafenib was tested in patients who had failed prior cytokine therapy and showed an increased progression-free survival compared with placebo in a phase III trial.17 Axitinib is the most recent of the VEGFR TKI to obtain FDA approval which was granted in January 2012. It was tested in a phase III trial against sorafenib in patients who had failed first-line therapy with either sunitinib, bevazicumab plus interferon-alfa, temsirolimus, or cytokines and found to have an increased response rate as well as prolong progression-free survival.18

As a class, the side effects of the VEGFR TKI are all fairly similar although most of the available data have been gathered from experience with sunitinib and sorafenib. Hypertension is very commonly seen and may be a marker of efficacy.19 Thyroid dysfunction (usually hypothyroidism although transient hyperthyroidism can also be seen) has been reported with all four agents as well. Hand-foot syndrome and other cutaneous side effects are also common.

Bevacizumab

A monoclonal antibody targeted against VEGF-A, bevacizumab has been shown clinical activity in many solid malignancies. In metastatic RCC, it was tested in conjunction with IFNα vs. IFNα alone in previously untreated patients in two phase III trials and found to increase progression-free survival in both,20,21 leading to FDA approval in the first-line setting.

mTOR inhibitors

Two mTOR inhibitors have received FDA approval in advanced RCC. Everolimus is approved for second-line therapy after disease progression with a VEGFR TKI,22 and temsirolimus is approved for first-line therapy after being shown superior to IFN in patients with poor-risk disease.23

With the increasingly large number of targeted agents approved for the treatment of advanced RCC, the optimal way to use them has become gradually more complex. ie. sunitinib, pazopanib, bevacizumab with interferon-alfa, and temsirolimus are all approved in the first line setting although the latter is generally used with poor-risk patients. In the second-line situation everolimus and axitinib are both approved although there is no trial directly comparing the two. Complicating matters further is the fact that multiple new agents are in development, including the small-molecular VEGFR inhibitor tivozanib which has recently bested sorafenib in the first-line setting in a phase III trial.

Surgery

As mentioned above, surgical removal of the primary tumor in metastatic RCC has been shown to improve survival when followed by immunotherapy. There are no mature trial data specifically evaluating the efficacy of cytoreductive nephrectomy with targeted therapy, but the general recommendation is that cytoreductive nephrectomy should be performed whenever medically and surgical feasible.24

Metastasectomy also has a role in the management of advanced RCC. Although randomized data are scarce, multiple case series have noted that long-term remission is possible even with metastatic disease. One case series of 278 patients noted a 44% 5-y survival in patients undergoing metastasectomy with curative intent. Disease-free interval to recurrence greater than 12 mo, solitary metastasis at recurrence, curative metastasectomy, and male gender were all predictive of increased survival on multivariate analysis.25 Another retrospective study specifically examining the role of surgical removal of multiple metastases including both synchronous and asynchronous disease found that complete surgical resection was associated with a greatly increased overall survival (4.0 y vs. 1.3 y). Patients with lung-only metastases had the highest survival rate, but patients with other sites of disease also had improved survival when complete metastasectomy was possible.26 Both studies found brain metastases to be associated with worse overall survival compared with other sites of metastases even if complete resection were possible.

Urothelial Cancer

The term urothelial cancer (UC) refers to a heterogenous array of neoplasms arising from the urinary tract between the renal pelvis to the proximal urethra. The most common histological subtype is transitional cell carcinoma, derived from the transitional epithelium which lines the inner surface of the urinary tract, and the most common site of origin is the bladder. In 2011 there were projected to be approximately 69,000 new cases of bladder cancer with 15,000 deaths; additionally, there were an additional 3,000 estimated new cases of cancer arising from the ureter and other urinary organs.27 While most patients present initially with low-grade, non-muscle-invasive disease, 4% of patients have metastatic disease at diagnosis and an additional 8% of patients have locally advanced disease.1

The most common site of metastasis outside of the pelvis is bone, followed by lymph nodes and lung.28 Although long-term survival is occasionally seen, the prognosis remains poor for metastatic UC with a median survival of approximately 14 mo.29 Despite this sobering statistic, the standard first-line therapy for UC has not changed appreciably in many years and remains platinum-based cytotoxic chemotherapy. Therefore, new treatments grounded in an improved understanding of the biology of UC are urgently needed.

Biology

Much progress has been made in recent years in elucidating the biological processes underlying the pathogenesis of UC. Unfortunately, these scientific advances have not yet been translated into clinical application, as no clear breakthrough has been realized despite a number of small early phase trials evaluating targeted therapy. The epidermal growth factor receptor (EGFR) family and vascular endothelial growth factor (VEGF)-mediated signaling have both been implicated in the pathogenesis of bladder cancer, and much attention has been given to targeting these pathways in bladder cancer. We will briefly summarize the existing knowledge in that area.

Epidermal Growth Factor Receptor Family

Members of the epidermal growth factor receptor (EGFR) family, consisting of the four cell-surface receptors tyrosine kinases EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her3 (ErbB-3), Her4 (ErbB-4), are frequently overexpressed in UC. Under normal conditions, ligand binding stimulates homo- and heterodimerization with activation of downstream signaling cascades via the MAPK and Akt pathways. Overexpression in cancer can be associated with constitutive activity with resultant aberrant cell signal transduction. EGFR and HER2/c-neu are often linked to muscle-invasive bladder cancer30 and appear to portend a worse prognosis in bladder cancer31 while ErbB-3 and ErbB-4 are associated with non-invasive papillary tumors; notably, HER2/c-neu has no ligand and instead depends on heterodimerization with another EGFR to effect downstream signaling. Other growth factor receptors which are overexpressed in UC include fibroblast growth factor-3 and insulin-like growth factor 1 receptor.

While multiple EGFR-directed targeted therapies are already in clinical use in other tumor types, data in bladder cancer remain scarce. Gefitinib, a small-molecule EGFR inhibitor, has been tested in both the first and second-line settings without showing significant clinical activity.32

Trastuzumab, a monoclonal antibody against HER2/c-neu, was tested in conjunction with paclitaxel, carboplatin, and gemcitabine in a phase II study and did not appear to offer any benefit beyond what would have been expected by chemotherapy alone.33 Lapatinib, a small-molecule inhibitor of both HER2/c-neu and EGFR, has been tested as a single-agent as second-line treatment for UC and found to have low clinical activity although subgroup analysis showed an improvement in survival in patients tumors overexpressing HER2/c-neu and/or EGFR; further studies are in progress.34 Finally, there is an ongoing trial evaluating cetuximab, a monoclonal antibody against EGFR, in conjunction with gemcitabine plus cisplatin in advanced UC.

Vascular Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) and angiogenesis have been implicated in the pathogenesis of bladder cancer, and increased microvessel density has specifically been shown to be an independent poor prognostic indicator in muscle-invasive bladder cancer.35 Multiple agents targeting VEGF signaling have already demonstrated activity both as monotherapy as well as in combination with cytotoxic therapy in other solid tumors, but only scant data exist regarding their use in bladder cancer and multiple studies are underway.

Bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, was studied in conjunction with cisplatin and gemcitabine as first-line treatment for metastatic UC with results which compare favorably with historical controls,36 and this regimen is being evaluated in a phase III trial. Aflibercept (a soluble recombinant receptor of VEGF) was tested as a single-agent in a phase II trial in the second-line setting and found to have limited activity.37 Similarly, multiple tyrosine kinase inhibitors of VEGF receptor, including sunitinib, sorafenib, and pazopanib, have been found to have very modest activity as well.38,39,40,41 Vandetanib, a tyrosine kinase inhibitor with activity both against VEGF receptor 2 as well as EGFR was recently tested with docetaxel as second-line treatment for UC and found to have minimal activity.42

Treatment

Bladder cancer is a chemosensitive tumor, and response rates with chemotherapy alone are around 50%. Nonetheless, although there are a few long-term survivors with metastatic bladder cancer treated with chemotherapy, the prognosis remains very poor and remissions tend to be short-lived. For a number of years, first-line treatment has consisted of combination chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) which, although toxic, resulted in a high response rate and improved overall survival compared with single-agent cisplatin43 or a combination regimen of cisplatin, cyclophosphamide, and doxorubicin.44 This regimen has since been largely supplanted by doublet chemotherapy with gemcitabine and cisplatin (GC) which was found to be non-inferior and less toxic than MVAC.45 Dose-dense GC was also found to have similar efficacy to dose-dense MVAC in a recent trial.46

Unfortunately, response to second-line chemotherapy in metastatic urothelial cancer is poor with no agent or combination of agents established as standard of care.47 Multiple cytotoxic drugs have demonstrated clinical activity in this setting, but none have been clearly demonstrated to prolong survival above best supportive care. The highest response rate reported has been with single-agent nab-paclitaxel which showed a response rate of 33% in a recent phase II trial.48 Eribulin (halichondrin b analog) is currently being evaluated in the multicenter phase II trial and is demonstrating promising activity.

Surgery

Although metastasectomy or cystectomy in the setting of metastatic disease is often thought to be palliative, selected patients may benefit from aggressive surgical resection of sites of metastases. Multiple non-controlled case series have suggested possible benefit of surgery in well-selected patients,49,50 with a sizable five-year survival which far exceeds historical controls including one Japanese cohort with an overall five-year survival rate of 50% after pulmonary metastasectomy.51 Typically these patients have chemotherapy-responsive disease; metastases to the retroperitoneum and lung are associated with better prognoses, and brain metastases predict significantly shortened survival.

Prostate Cancer

Prostate cancer is overwhelmingly the most common non-cutaneous cancer in men, with over 240,000 estimated new cases occurring in 2011 alone in the US52 Over 33,000 men died of prostate cancer in 2011 making it a significant cause of cancer mortality in the US; in fact, lung cancer is the only malignancy that claims more lives among American men. At the same time, however, it is one of the more treatable solid tumors, and even metastatic disease can often be kept under control for years.

Biology

The biology of prostate cancer is unique for a number of reasons. For one, the behavior of prostate cancer can be highly unpredictable; it can remain an indolent disease for years or even decades, or it can metastasize rapidly. Another is that prostate cancer has an extremely strong predilection to form bone metastases. Finally, prostate cancer is strongly hormonally driven, and androgen deprivation either through medical or surgical means is associated with extremely high response rates in the setting of advanced disease.

Prognostic Factors

Unlike most solid tumor malignancies which usually demand prompt treatment as soon as the diagnosis is made, observation may be acceptable in some instances of prostate cancer. Nonetheless, low-risk prostate cancer can relapse even after definitive treatment, and as a result many predictive models have been constructed to aid with clinical decision-making including nomograms and probability tables.53 These typically take into account multiple factors including the Gleason score, prostate specific antigen (PSA), PSA doubling time, and clinical stage. However, these methods can only offer probabilities; they cannot anticipate with certainty for any given patient the future disease course. More recent data indicate that the preoperative presence of circulating tumor cells may be a promising biomarker in this arena as it is an independent risk factor for tumor recurrence.54

Bone Metastases

By far the most common site of distant metastases in prostate cancer is bone. One autopsy study indicated that 90% of patients with advanced prostate cancer had bony metastases.55 Bone metastases are an important cause of morbidity in patients with metastatic prostate cancer. Consequences can include pain, which can be extremely severe, pathological fractures, and spinal-cord compression. An increasing number of therapies directed specifically against metastatic bone disease are available in prostate cancer. The importance of bone disease in prostate cancer is highlighted by the growing evidence that bone-directed therapy not only palliates symptoms from bony disease but may also delay the onset of bone metastases or even prolong survival.

Normal bone physiology is a complex process marked by the tightly regulated activity of osteoblasts, which form bone, and osteoclasts, which break down bone. Metastatic bone disease is marked by a disruption in this homeostasis resulting in lesions which can either be osteolytic (marked by bone breakdown), osteosclerotic (marked by enhanced bone growth), or mixed. Prostate cancer is relatively unusual among cancers not just for its extreme predilection for bone, but also because it is marked by a high incidence of osteosclerotic lesions.56 While the precise mechanisms underlying metastatic bone disease are complicated and incompletely understood, there is an increasing appreciation for the various signaling pathways involved.

The presence of metastatic bone disease is associated with derangement in a number of factors in the microenvironment. One of the most important ones is the receptor activator of nuclear factor kappa-B ligand (RANKL), a protein released by osteoblast precursors and which activates osteoclasts. This finding has been clinically significant as inhibition of RANKL via the monoclonal antibody denosumab has demonstrated slowing both onset of metastatic bone disease as well as skeletal events in patients already known to have bone metastases. Other growth factors and proteins which appear to have a role in the development of bone metastatic disease include endothelin-1 (ET-1), transforming growth factor β (TGF-β), urokinase-type plasminogen activator (uPA), and Wnt-1.

Androgen Receptor

The critical dependence of prostate cancer on androgen-mediated signaling has been known for decades, as surgical castration was observed to result in dramatic improvement in a number of patients with advanced prostate cancer as early as the 1940s. Since then, depletion of circulating testosterone, whether in the form of medical or surgical castration, has become the standard of care in the initial management of advanced prostate cancer and is associated with very high response rates. Nonetheless, despite depleted levels of circulating testosterone, patients nearly always develop progressive disease eventually. At this point they are deemed to have castrate-resistant prostate cancer (CRPC) although they should not be considered as having androgen-independent disease since further hormonal manipulation can often result in clinical responses.

The discovery that de novo testosterone synthesis occurs within the tumor57 and that androgen-receptor signaling remains active in CRPC58 have led to further efforts targeting this pathway both at the level of androgen synthesis as well as at the level of the androgen receptor. The latter is particularly important as a splice variant androgen receptor may be able to mediate signal transduction in the absence of ligand binding.59 More recent research implicates that synthesis of the principal androgen receptor agonist 5a-dihydrotestosterone, which physiologically usually occurs via testosterone, may occur via various escape pathways in CRPC which bypass testosterone altogether.60,61

Given the preponderance of evidence suggesting that CRPC is still very much dependent on the androgen receptor signaling, further research in this area is needed. Optimizing blockade of the androgen receptor and its splice variants, interruption of alternative pathways of 5a-dihydrotestosterone synthesis, and characterization of the mechanisms underlying resistance to androgen biosynthesis inhibitors are important topics which are still being studied.

Therapy

Androgen-Deprivation Therapy

As mentioned above, prostate cancer growth is strongly driven by androgens, and the mainstay of therapy of advanced disease has long been androgen deprivation therapy (ADT). Although other combinations are possible, initial treatment normally consists of a gonadotropin releasing hormone (GnRH) agonist with or without concomitant blockade of the androgen receptor. The former results in medical castration as it causes testosterone levels to drop precipitously, and the addition of the latter results in combined androgen blockade. Three GnRH agonists have obtained FDA approval for treatment of advanced prostate cancer: leuprolide, goserelin, and triptorelin, and the nonsteroidal antiandrogens in the US are flutamide, bicalutamide, and nilutamide. Of note, upfront androgen receptor blockade by itself is rarely used; in a large meta-analysis a single non-steroidal agent was associated with slightly worse outcomes than castration monotherapy although the confidence interval crossed unity.62

Initial response rates to ADT as marked by improvement of existing lesions and normalization of PSA are overwhelmingly high. Unfortunately, nearly all patients will eventually progress in spite of depletion of circulating testosterone. Moreover, ADT itself is associated with a number of significant side effects ranging from hot flashes and impotence to osteoporosis. Whether or not it increases cardiovascular risk remains controversial.63 A number of secondary hormonal manipulations can be attempted, ranging from withdrawal of anti-androgen therapy to suppression of adrenal steroid synthesis with high-dose ketoconazole or estrogen administration. However, response rates are significantly lower with this approach, and any clinical responses tend to be short-lived.

The newest FDA-approved agent targeting androgen receptor signaling is abiraterone, a CYP17 enzyme inhibitor which blocks production of testosterone. It demonstrated overall survival benefit when tested against placebo in a phase III randomized-control trial in patients with CRPC who have previously received docetaxel chemotherapy.64 TAK-700, a drug with a similar mechanism, is undergoing phase III testing currently, and MDV-3100, a novel androgen receptor antagonist which blocks nuclear translocation demonstrated survival benefit in patients with chemotherapy pre-treated CRPC and is being considered for FDA approval.

Chemotherapy

Because of the prolonged periods of disease control afforded by hormonal therapy in prostate cancer, cytotoxic chemotherapy has typically been reserved for patients whose disease becomes refractory to all hormone manipulation. Mitoxantrone was the first chemotherapeutic agent to be approved in prostate cancer; although it did not show any overall survival advantage compared with steroid therapy, quality of life was improved.65 Docetaxel given every three weeks was shown to prolong overall survival as compared with mitoxantrone in a phase III trial. PSA response rate and pain response rates were also improved.66 Accordingly, docetaxel has become approved in patients with metastatic castrate-resistant prostate cancer. Cabazitaxel, a novel taxane, has recently been shown to prolong survival compared with mitoxantrone in patients who had previously progressed on docetaxel67 and has since received FDA approval for treatment of metastatic castrate-resistant prostate cancer after progression on docetaxel.

Immunotherapy

Sipuleucel-T (Provenge) was approved by the FDA for use in April 2010 in metastatic castrate-resistant prostate cancer, marking the true advent of immunotherapy in prostate cancer. It is essentially a personalized tumor vaccine in which dendritic cells from a patient are extracted via leukapheresis, incubated with a fusion protein consisting of prostatic acid phosphatase and GM-CSF, and reinfused into the patient. An initial phase III trial demonstrated overall survival benefit but did not meet its primary endpoint of time to disease progression68 and did not result in approval. However, another phase III trial was conducted with overall survival as the primary endpoint with the finding of prolongation of median overall survival by 4 mo.69

Bone-Directed Therapy

Although the most important treatment for patients with bony disease remains systemic therapy, the high prevalence of bone metastases in prostate cancer has led to an interest in specific bone-directed therapies. Bisphosphonates, which inhibit osteoclast activity, have been extensively studied in bone metastases arising from a variety of solid tumors. The only bisphosphonate approved in advanced prostate cancer is zoledronic acid which has been shown in a phase III trial to reduce skeletal-related events compared with placebo.70 With the discovery of the role of RANKL in metastatic bone disease, denosumab, a monoclonal antibody against RANKL, was tested in prostate cancer and found to be superior to zoledronic acid for prevention of skeletal events;71 more recently, it has been shown to delay the onset of skeletal metastases in patients with high-risk, non-metastatic CRPC.72 Both agents can cause osteonecrosis of the jaw, and the rate of this complication appears to be fairly similar between them.

Radiopharmaceuticals

Multiple radioisotopes have been studied in prostate cancer, and there is evidence suggesting palliation of symptomatic bony disease when other modalities such as hormonal therapy, narcotic analgesia, and external-beam radiation therapy have either been exhausted or are poorly tolerated. These agents localize to areas of osteoblastic activity and are not suitable for use in patients with predominantly osteolytic lesions; as such, patients with bony metastases in the setting of most other malignancies will not derive benefit.

The most extensive data and experience are with strontium-89 chloride and samarium-153. A phase III trial comparing strontium-89 to placebo after local external beam radiation therapy was performed in patients with metastatic castrate-resistant prostate cancer and demonstrated no difference in survival or pain relief at the original index site but showed less development of new sites of pain and improved physical activity.73 Samarium-153 has been evaluated in two placebo-controlled trials demonstrating decreased analgesic consumption and improved pain control.74,75 Marrow toxicity is a significant concern with the use of both of these agents.

Radium-223 chloride was recently shown in a placebo-controlled phase III trial to provide an overall survival advantage as well as delay the time to multiple skeletal-related events including pathologic fracture, spinal cord compression, and external beam radiotherapy although not surgery.

It is the only radiopharmaceutical to date which has demonstrated a survival advantage and is being considered for approval by the FDA.

Testicular Germ Cell Tumors

Treatment of metastatic testicular cancer is regarded as the prototype success story of modern oncology since becoming the first major solid tumor type that was rendered highly curable with the application of cisplatin-based combination chemotherapy developed in the 1970s.

The most commonly used regimen consists of cisplatin, etoposide and bleomycin (PEB) administered over 3-4 cycles depending on the estimated risk of recurrence.76 The exquisite sensitivity to chemotherapy and curability of germ cell malignancies are poorly understood. One hypothesis postulates that malignant germ cells demonstrate intrinsic state of susceptibility to proapoptotic stresses, possess impaired DNA repair mechanisms and wild type p-53 making them uniquely sensitive to DNA-damaging chemotherapy.77 Another theory suggests that metastatic germ cells reside in relatively hyperthermic environment (as compared with natural location in the scrotum) and are more susceptible to chemotherapy on the basis of temperature-mediated disruption of nuclear matrix scaffolding.78

Following completion of chemotherapy approximately 70% of patients demonstrate persistent masses that typically contain fibrosis, but in a minority of cases can harbor teratoma or viable cancer cells.79 In the case of nonseminomatous tumors these masses are surgically resected. Additional chemotherapy is administered if viable cancer cells persist; otherwise no further therapy is given. Residual masses after treatment of seminoma are typically evaluated with PET scan and in the presence of PET activity confirmatory biopsy is performed and more chemotherapy is recommended in case viable cancer cells are present. Radiation therapy can also be considered in view of radiosensitivity of this tumor type. Resection of post-chemotherapy seminoma masses is typically not performed due to extensive fibrosis which may be associated with significant surgical complications. Overall 80-90% of patients with testicular germ cell tumors are cured of their metastatic disease utilizing modern combination chemotherapy. Even very extensive disease with brain and visceral organ involvement can be eradicated in approximately 40% of cases and relapsed cancers can be frequently salvaged utilizing second line chemotherapy and /or high-dose chemotherapy and peripheral stem cell rescue.80

Conclusion

Even though the genitourinary malignancies are an widely varied group of cancers which differ with respect to epidemiology, treatment, and prognosis, with the exception of germ cell tumors they generally remain incurable in the metastatic setting. Much progress has been realized recently in understanding the pathophysiology behind advanced disease, some of which has been elegantly translated into new therapies, but more work is sorely needed, as progression to disease which is refractory to all available treatments still occurs far too often.

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