Chapter 23. Neoplasms of the Prostate Gland

The prostate gland is the male organ most commonly afflicted with either benign or malignant neoplasms. McNeal et al (1988) popularized the concept of zonal anatomy of the prostate. Three distinct zones have been identified (Figure 23–1). The peripheral zone accounts for 70% of the volume of the young adult prostate, the central zone accounts for 25%, and the transition zone accounts for 5%. These anatomic zones have distinct ductal systems but, more important, are differentially afflicted with neoplastic processes. Sixty to seventy percent of carcinomas of the prostate (CaP) originate in the peripheral zone, 10–20% in the transition zone, and 5–10% in the central zone (McNeal et al, 1988). Benign prostatic hyperplasia (BPH) uniformly originates in the transition zone (Figure 23–2).

Incidence and Epidemiology

BPH is the most common benign tumor in men, and its incidence is age related. The prevalence of histologic BPH in autopsy studies rises from approximately 20% in men aged 41–50, to 50% in men aged 51–60, and to >90% in men older than 80 years. Although clinical evidence of disease occurs less commonly, symptoms of prostatic obstruction are also age related. At age 55, approximately 25% of men report obstructive voiding symptoms. At age 75, 50% of men complain of a decrease in the force and caliber of their urinary stream.

Risk factors for the development of BPH are poorly understood. Some studies have suggested a genetic predisposition, and some have noted racial differences. Approximately 50% of men younger than 60 years who undergo surgery for BPH may have a heritable form of the disease. This form is most likely an autosomal dominant trait, and first-degree male relatives of such patients carry an increased relative risk of approximately fourfold.

Etiology

The etiology of BPH is not completely understood, but it seems to be multifactorial and endocrine controlled. The prostate is composed of both stromal and epithelial elements, and each, either alone or in combination, can give rise to hyperplastic nodules and the symptoms associated with BPH. Each element may be targeted in medical management schemes.

Observations and clinical studies in men have clearly demonstrated that BPH is under endocrine control. Castration results in the regression of established BPH and improvement in urinary symptoms. Additional investigations have demonstrated a positive correlation between levels of free testosterone and estrogen and the volume of BPH. The latter may suggest that the association between aging and BPH might result from the increased estrogen levels of aging causing induction of the androgen receptor, which thereby sensitizes the prostate to free testosterone. There is evidence that estrogens acting through stromal and epithelial estrogen receptors may contribute, in part, to diseases of the prostate. Genetic or environmental factors that influence 5α-reductase appear to be important in the development of BPH as well (Alan et al, 2008; Gail et al, 2008).

Pathology

As discussed earlier, BPH develops in the transition zone. It is truly a hyperplastic process resulting from an increase in cell number. Microscopic evaluation reveals a nodular growth pattern that is composed of varying amounts of stroma and epithelium. Stroma is composed of varying amounts of collagen and smooth muscle. The differential representation of the histologic components of BPH explains, in part, the potential responsiveness to medical therapy. Thus, α-blocker therapy may result in excellent responses in patients with BPH that has a significant component of smooth muscle, while those with BPH predominantly composed of epithelium might respond better to 5α-reductase inhibitors. Patients with significant components of collagen in the stroma may not respond to either form of medical therapy. Unfortunately, one cannot reliably predict responsiveness to a specific therapy (see later).

As BPH nodules in the transition zone enlarge, they compress the outer zones of the prostate, resulting in the formation of a so-called surgical capsule. This boundary separates the transition zone from the peripheral zone and serves as a cleavage plane for open enucleation of the prostate during open simple prostatectomies performed for BPH.

Pathophysiology

One can relate the symptoms of BPH to either the obstructive component of the prostate or the secondary response of the bladder to the outlet resistance. The obstructive component can be subdivided into the mechanical and the dynamic obstruction.

As prostatic enlargement occurs, mechanical obstruction may result from intrusion into the urethral lumen or bladder neck, leading to a higher bladder outlet resistance. Prior to the zonal classification of the prostate, urologists often referred to the “three lobes” of the prostate, namely, the median and the two lateral lobes. Prostatic size on digital rectal examination (DRE) correlates poorly with symptoms, in part, because the median lobe is not readily palpable.

The dynamic component of prostatic obstruction explains the variable nature of the symptoms experienced by patients. The prostatic stroma, composed of smooth muscle and collagen, is rich in adrenergic nerve supply. The level of autonomic stimulation thus sets a tone to the prostatic urethra. Use of α-blocker therapy decreases this tone, resulting in a decrease in outlet resistance.

The irritative voiding complaints (see later) of BPH result from the secondary response of the bladder to the increased outlet resistance. Bladder outlet obstruction leads to detrusor muscle hypertrophy and hyperplasia as well as collagen deposition. Although the latter is most likely responsible for a decrease in bladder compliance, detrusor instability is also a factor. On gross inspection, thickened detrusor muscle bundles are seen as trabeculation on cystoscopic examination. If left unchecked, mucosal herniation between detrusor muscle bundles ensues, causing diverticula formation (so-called false diverticula composed of only mucosa and serosa).

Clinical Findings

Symptoms

The symptoms of BPH can be divided into obstructive and irritative complaints. Obstructive symptoms include hesitancy, decreased force and caliber of stream, sensation of incomplete bladder emptying, double voiding (urinating a second time within 2 hours of the previous void), straining to urinate, and postvoid dribbling. Irritative symptoms include urgency, frequency, and nocturia.

The self-administered questionnaire originally developed by the American Urological Association (AUA) is both valid and reliable in identifying the need to treat patients and in monitoring their response to therapy. The AUA Symptom Score Questionnaire has been extensively validated and translated, and it is now more commonly called the International Prostate Symptom Score (IPSS) (Table 23–1). The IPSS is perhaps the single most important tool used in the evaluation of patients with BPH and is recommended for all patients before the initiation of therapy. This assessment focuses on seven items that ask patients to quantify the severity of their obstructive or irritative complaints on a scale of 0–5. Thus, the score can range from 0 to 35. An IPSS of 0–7 is considered mild, 8–19 is considered moderate, and 20–35 is considered severe. The relative distribution of scores for BPH patients and control subjects is, respectively, 20% and 83% in those with mild scores, 57% and 15% in those with moderate scores, and 23% and 2% in those with severe scores (McConnell et al, 1994). As with other quality-of-life surveys, a reasonable degree of both literacy and numeracy is necessary for valid results. A multimedia version of the IPSS has been proposed which is more reliable among low-education populations (Bryant et al, 2009).

A detailed history focusing on the urinary tract excludes other possible causes of symptoms that may not result from the prostate, such as urinary tract infection, neurogenic bladder, urethral stricture, or prostate cancer.

Signs

A physical examination, DRE, and focused neurologic examination are performed on all patients. The size and consistency of the prostate is noted, even though prostate size, as determined by DRE, does not correlate with severity of symptoms or degree of obstruction. BPH usually results in a smooth, firm, elastic enlargement of the prostate. Induration, if detected, must alert the physician to the possibility of cancer and the need for further evaluation (ie, prostate-specific antigen [PSA], transrectal ultrasound [TRUS], and biopsy).

Laboratory Findings

A urinalysis to exclude infection or hematuria and serum creatinine measurement to assess renal function are required. Renal insufficiency may be observed in 10% of patients with prostatism and warrants upper-tract imaging. Patients with renal insufficiency are at an increased risk of developing postoperative complications following surgical intervention for BPH. Serum PSA is considered optional, but most physicians will include it in the initial evaluation. PSA, compared with DRE alone, certainly increases the ability to detect CaP, but because there is much overlap between levels seen in BPH and CaP, its use remains controversial (see Section “Prostate Cancer Screening and Chemoprevention”).

Imaging

Upper-tract imaging (renal ultrasound or computed tomography [CT] urogram) is recommended only in the presence of concomitant urinary tract disease or complications from BPH (eg, hematuria, urinary tract infection, renal insufficiency, history of stone disease). TRUS is useful to determine prostate size for men planning to undergo prostate surgery who are suspected to have severe prostate enlargement based on DRE.

Cystoscopy

Cystoscopy is not routinely recommended to determine the need for treatment but may assist in choosing the surgical approach in patients opting for invasive therapy. When marked obstructive symptoms exist in the setting of relative minimal prostate enlargement, cystoscopy may be useful to identify a high bladder neck, urethral stricture, or other pathology. If BPH is associated with hematuria, then cystoscopy is mandatory to rule out other bladder pathology.

Additional Tests

Measurement of flow rate, determination of postvoid residual urine, and pressure-flow studies are considered optional. Cystometrograms and urodynamic profiles are reserved for patients with suspected neurologic disease or those who have failed prostate surgery.

Differential Diagnosis

Other obstructive conditions of the lower urinary tract, such as urethral stricture, bladder neck contracture, bladder stone, or CaP, must be entertained when evaluating men with presumptive BPH. A history of previous urethral instrumentation, urethritis, or trauma should be elucidated to exclude urethral stricture or bladder neck contracture. Hematuria and pain are commonly associated with bladder stones. CaP may be detected by abnormalities on the DRE or an elevated PSA (see later).

A urinary tract infection, which can mimic the irritative symptoms of BPH, can be readily identified by urinalysis and culture; however, a urinary tract infection can also be a complication of BPH. Although irritative voiding complaints are also associated with carcinoma of the bladder, especially carcinoma in situ, the urinalysis usually shows evidence of hematuria. Likewise, patients with neurogenic bladder disorders may have many of the signs and symptoms of BPH, but a history of neurologic disease, stroke, diabetes mellitus, or back injury may be present as well. In addition, examination may show diminished perineal or lower extremity sensation or alterations in rectal sphincter tone or the bulbocavernosus reflex. Simultaneous alterations in bowel function (constipation) might also alert one to the possibility of a neurologic origin.

Treatment

After patients have been evaluated, they should be informed of the various therapeutic options for BPH. It is advisable for patients to consult with their physicians to make an educated decision on the basis of the relative efficacy and side effects of the treatment options.

Specific treatment recommendations can be offered for certain groups of patients. For those with mild symptoms (IPSS score, 0–7), watchful waiting is generally advised. On the other end of the therapeutic spectrum, absolute surgical indications include urinary retention refractory to medical management and attempts at catheter removal, recurrent urinary tract infection, recurrent gross hematuria, bladder stones, renal insufficiency, or large bladder diverticula.

Watchful Waiting

Very few studies on the natural history of BPH have been reported. The risk of progression or complications is uncertain. However, in men with symptomatic BPH, it is clear that progression is not inevitable and that some men undergo spontaneous improvement or resolution of their symptoms.

Retrospective studies on the natural history of BPH are inherently subject to bias, related to patient selection and the type and extent of follow-up. Very few prospective studies addressing the natural history of BPH have been reported. A large randomized study compared finasteride with placebo in men with moderately to severely symptomatic BPH and enlarged prostates on DRE (McConnell et al, 1998). Patients in the placebo arm of the study had a 7% risk of developing urinary retention over 4 years.

As mentioned earlier, watchful waiting is the appropriate management of men with mild symptom scores (0–7). Men with moderate or severe symptoms can also be managed in this fashion if they so choose. Neither the optimal interval for follow-up nor specific end points for intervention have been defined.

Medical Therapy

A-Blockers

The human prostate and bladder base contains α1-adrenoreceptors, and the prostate shows a contractile response to corresponding agonists. The contractile properties of the prostate and bladder neck seem to be mediated primarily by the subtype α1a-receptors. α-Blockade has been shown to result in both objective and subjective degrees of improvement in the symptoms and signs of BPH in some patients. α-Blockers can be classified according to their receptor selectivity as well as their half-life (Table 23–2).

Phenoxybenzamine and prazosin are the prototypical nonselective and selective α-blockers, but today, they are primarily of historical interest.

Long-acting α1-blockers make once-a-day dosing possible, but dose titration is still necessary. Terazosin is initiated at 1 mg daily for 3 days and increased to 2 mg daily for 11 days and then to 5 mg/d. Dosage can be escalated to 10 mg daily if necessary. Therapy with doxazosin is started at 1 mg daily for 7 days and increased to 2 mg daily for 7 days, and then to 4 mg daily. Dosage can be escalated to 8 mg daily if necessary. Possible side effects include orthostatic hypotension, dizziness, tiredness, retrograde ejaculation, rhinitis, and headache.

Selective blockade of the α1a-receptors, which are localized in the prostate and bladder neck, results in fewer systemic (particularly cardiovascular) side effects, thus obviating the need for dose titration with these agents (tamsulosin, alfuzosin, and silodosin). Other side effects such as retrograde ejaculation still can occur.

Several randomized, double-blind, placebo-controlled trials, individually comparing α-blockers with placebo, have demonstrated the safety and efficacy of all of these agents.

5α-Reductase Inhibitors

Finasteride is a 5α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (DHT). This drug affects the epithelial component of the prostate, resulting in a reduction in the size of the gland and improvement in symptoms. Six-month therapy is required to see the maximum effects on prostate size (20% reduction) and symptomatic improvement.

Several randomized, double-blind, placebo-controlled trials have compared finasteride with placebo. Efficacy, safety, and durability are well established. However, symptomatic improvement is seen only in men with enlarged prostates (>40 cm3). Side effects are uncommon and include decreased libido, decreased ejaculate volume, and impotence. Serum PSA is reduced by approximately 50% in patients being treated with finasteride, but individual values may vary.

Dutasteride differs from finasteride as it inhibits both isoenzymes of 5α-reductase. Similar to finasteride, it reduces serum PSA and total prostate volume. Randomized, placebo-controlled trials have shown the efficacy of dutasteride in symptomatic relief, symptoms scores, peak urinary flow rate, and reduced risk of acute urinary retention and the need for surgery. Side effects are relatively uncommon and include erectile dysfunction, decreased libido, gynecomastia, and ejaculation disorders. Few studies comparing finasteride and dutasteride head-to-head. One retrospective analysis of >5000 men older than 65 years treated with 5α-reductase inhibitors in the mid-2000s found small but statistically significantly differences, with rates of urinary retention of 12% and 14.7% for dutasteride and finasteride, respectively (p= 0.0042), and rates of prostate surgery of 3.9% and 5.1%, respectively (p= 0.03) (Fenter et al, 2008).

Combination Therapy

The first randomized, double-blind, placebo-controlled study investigating combination α-blocker and 5α-reductase inhibitor therapy was a four-arm Veterans Administration Cooperative Trial comparing placebo, finasteride alone, terazosin alone, and combination finasteride and terazosin (Lepor et al, 1996). More than 1200 patients participated, and significant decreases in IPSS and increases in urinary flow rates were seen only in the arms containing terazosin. However, one must note that enlarged prostates were not an entry criterion; in fact, prostate size in this study was much smaller than that in previous controlled trials using finasteride (32 vs 52 cm3). McConnell and colleagues conducted a long-term, double-blind trial involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of BPH (McConnell et al, 2003). The risk of overall clinical progression—defined as an increase above baseline of at least four points in the IPSS, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection—was significantly reduced by doxazosin (39% risk reduction) and finasteride (34% risk reduction), as compared with placebo. The reduction in risk associated with combination therapy (66% risk reduction) was significantly greater than that associated with doxazosin or finasteride alone. Patients most likely to benefit from combination therapy are those in whom baseline risk of progression is very high, generally patients with larger glands and higher PSA values.

Phytotherapy

Phytotherapy refers to the use of plants or plant extracts for medicinal purposes. The use of phytotherapy in BPH has been popular in Europe for years, and its use in the United States is growing as a result of patient-driven enthusiasm. Several plant extracts have been popularized, including the saw palmetto berry (Serenoa repens), the bark of Pygeum africanum, the roots of Echinacea purpurea and Hypoxis rooperi, pollen extract, and the leaves of the trembling poplar. S. repens has been the most well-studied agent, usually at 320 mg/day. Given the poor regulation of the nutritional supplement industry, actual tablet content may vary extremely from the dose noted on the product label (Feifer et al, 2002). A prospective, randomized clinical trial of saw palmetto showed no benefit beyond placebo for either IPSS improvement or urinary flow rate (Bent et al, 2006). An updated systematic review including this and other trials confirmed no improvement over placebo for this approach (Wilt et al, 2009).

Surgical Therapy

Transurethral Resection of the Prostate

The vast majority of subtotal prostatectomies undertaken for BPH can be completed endoscopically. Most of these procedures involve the use of a spinal or general anesthetic and usually require an overnight hospital stay. Magnitude and durability of IPSS and flow rate improvement with transurethral resection of the prostate (TURP) is superior to that of any minimally invasive therapy. However, the length of hospital stay of patients undergoing TURP is greater. Risks of TURP include retrograde ejaculation (75%), impotence (5–10%), and incontinence (<1%). Complications include bleeding; urethral stricture or bladder neck contracture; perforation of the prostate capsule with extravasation; and, if severe, transurethral resection (TUR) syndrome resulting from a hypervolemic, hyponatremic state due to absorption of the hypotonic irrigating solution.

Clinical manifestations of the TUR syndrome include nausea, vomiting, confusion, hypertension, bradycardia, and visual disturbances. The risk of the TUR syndrome increases with resection times >90 minutes and is usually seen in older men. Treatment includes diuresis and, in severe cases, hypertonic saline administration. TURP can now be performed with a bipolar electrode, allowing resection to be performed under saline irrigation. This approach eliminates the hyponatremia responsible for TUR syndrome, though significant fluid volume absorption can still occur with prolonged resection.

Transurethral Incision of the Prostate

Men with moderate to severe symptoms and a small prostate often have posterior commissure hyperplasia (elevated bladder neck). These patients will often benefit from an incision of the prostate. This procedure is more rapid and less morbid than TURP. Outcomes in well-selected patients are comparable, although a lower rate of retrograde ejaculation with transurethral incision has been reported (25%). The technique involves two incisions using the Collins knife at the 5- and 7-o'clock positions. The incisions are started just distal to the ureteral orifices and are extended outward to the verumontanum.

Transurethral Vaporization of the Prostate (TUVP)

Increasingly popular in recent years, ablative techniques use photo- or electroevaporation to ablate obstructing prostate tissue. The two most commonly used devices for these procedures are the neodymium-doped yttrium-aluminum-garnet (Nd:YAG) KTP “GreenLight” laser, which is preferentially absorbed by hemoglobin, and the plasma vaporization “Button” electrode. The latter works with a standard contemporary bipolar generator used for bipolar TURP.

As with modern TURP, these procedures are performed under saline irrigation. The goal of the procedure in either case is to produce a central prostate defect comparable with what would be expected after a traditional TURP, but with less bleeding and lower risk of perforation. The potential downsides are greater irritative voiding symptoms in the short term after the procedure and less durability of the result than a standard TURP. Also, as tissue is destroyed rather than resected, no specimen is sent to pathology for review.

Holmium Laser Enucleation of the Prostate (HoLEP)

Rather than progressive resection or ablation of tissue from the urethra outward as with TURP and its derivatives, HoLEP denotes an anatomic dissection in the plane between the central and peripheral zones of the prostate. This approach is felt to provide the largest defect and perhaps the longest durability, but entails a longer learning curve than TURP or TUVP.

Simple (Subtotal) Prostatectomy

When the prostate is too large to be removed endoscopically, an open enucleation is necessary. What constitutes “too large” is subjective and will vary depending upon the surgeon's experience with TURP. Glands >100 g are usually considered for open enucleation. Open prostatectomy may also be initiated when concomitant bladder diverticulum or a large bladder stone is present or if dorsal lithotomy positioning is not possible.

Open prostatectomies can be done with either a suprapubic or retropubic approach. A simple suprapubic prostatectomy is performed transvesically and is the operation of choice in dealing with concomitant bladder pathology. After the bladder is opened, a semicircular incision is made in the bladder mucosa, distal to the trigone. The dissection plane is initiated sharply, and then blunt dissection with the finger is performed to remove the adenoma. The apical dissection should be done sharply to avoid injury to the distal sphincteric mechanism. After the adenoma is removed, hemostasis is attained with suture ligatures, and both a urethral and a suprapubic catheter are inserted before closure. In a simple retropubic prostatectomy, the bladder is not entered. Rather, a transverse incision is made in the surgical capsule of the prostate, and the adenoma is enucleated as described earlier. Only a urethral catheter is needed at the end of the procedure. Robot-assisted simple prostatectomy has been reported in recent small series (Sutherland et al, 2011).

Transurethral Microwave Thermotherapy

Microwave hyperthermia is most commonly delivered with a transurethral catheter. Some devices cool the urethral mucosa to decrease the risk of injury. However, if temperatures are not >45°C, cooling is unnecessary. Improvement in IPSS and flow rate has been documented, but as these procedures are done in the office with no visual verification of tissue ablation, results have been mixed. Strong financial incentives, however, have driven frequent utilization in certain clinical contexts.

Very sparse prospective data are available to fairly compare any of the above procedures with TURP or with each other. A recent meta-analysis found few differences, but the component studies tended to be small and with limited follow-up (Ahyai et al, 2010). All of the newer procedures are more expensive than TURP, and comparative cost-effectiveness studies are sorely needed.

Incidence and Epidemiology

Prostate cancer is the most common noncutaneous cancer detected among American men. More than 200,000 cases are detected annually (Jemal et al, 2010). Approximately 30,000 men die of the disease annually—more than any other tumor type except lung cancer. However, prostate cancer mortality at the population level has declined by roughly 40% since the mid-1990s, during a time in which men have been living longer and therefore have been more likely to reach the older ages at which prostate cancer mortality would be expected to increase. There are no known dietary or other environmental trends that can explain this decline in mortality rates. The explanation is controversial but is likely multifactorial, reflecting a combination of screening programs and improvements in treatment.

These improvements in prostate cancer mortality have come at the cost of significant rates of overdiagnosis and overtreatment. The number of prostate cancer deaths annually is far outweighed by the number of diagnoses, and most men diagnosed ultimately die of other causes, most often cardiovascular disease. Of all cancers, the prevalence of CaP increases the most rapidly with age. However, unlike most cancers, which have a peak age of incidence, the incidence of CaP continues to increase with advancing age. The lifetime risk of a 50-year-old man for latent CaP (ie, detected as an incidental finding at autopsy, not related to the cause of death) is 40%; for lifetime diagnosis of CaP, 15%; and for death from CaP, 2.9%. Thus, many prostate cancers are indolent and inconsequential to the patient while others are virulent, and if detected too late or left untreated, they result in a patient's death. This broad spectrum of biological activity can make decision making for individual patients difficult, and highlight the critical need for risk stratification of prostate cancers, which will be discussed in further detail later.

Several risk factors for prostate cancer have been identified. As discussed earlier, increasing age heightens the risk for CaP. Which of the factors associated with the aging process are responsible for this observation is unknown. The probability of CaP diagnosis in a man younger than 40 years is 1 in 10,000; for men 40–59 years old, it is 1 in 103; and for men 60–79 years old, it is 1 in 8. African Americans are at a higher risk for CaP than whites. In addition, African American men tend to present with higher disease risk than whites. Controversial data have been reported suggesting that mortality from this disease may also be higher for African Americans. A positive family history of CaP also increases the relative risk for CaP. The age of disease onset in the family member with the diagnosis of CaP affects a patient's relative risk. If the age of onset is 70, the relative risk is increased fourfold; if the age of onset is 60, the relative risk is increased fivefold; and if the age of onset is 50, the relative risk is increased sevenfold.

Although diagnostic biases due to varying penetrance of PSA screening exist across countries, differences in the incidence of prostate cancer are real. These differences may be related, in part, to differences in diet (Chan et al, 2005). Epidemiologic studies have shown that the incidence of clinically significant prostate cancer is much lower in parts of the world where people eat a predominantly low fat, plant-based diet. In addition, migrant studies demonstrate that when men from a low-risk country move to the United States and begin eating a westernized diet, their rates of prostate cancer increase severalfold and approach that of the host country. Total fat intake, animal fat intake, and red meat intake are associated with an increased risk of prostate cancer, whereas intake of fish is associated with a decreased risk. There is considerable controversy on the impact of obesity on prostate cancer. Some studies suggest that obesity is associated with an increased risk of more advanced disease and a higher recurrence rate after treatment. In addition, lycopene, selenium, omega-3 fatty acids (fish), and vitamin E intake have been shown to be protective, whereas vitamin D and calcium increase risk. No dietary supplementation study has yet shown a tangible benefit in terms of reducing risk of diagnosis or mortality. Previous vasectomy has been suggested as a factor that heightens the risk for CaP, but this association has not been validated in larger studies (Cox et al, 2002).

Pathology

More than 95% of the prostate cancers are adenocarcinomas. The histology of the remaining 5% of prostate cancer is heterogeneous, arising from stromal, epithelial, or ectopic cells. Nonadenocarcinoma variants can be categorized into two groups based on the cellular origin: epithelial and nonepithelial. Epithelial variants consist of endometrioid, mucinous, signet-ring, adenoid cystic, adenosquamous, squamous cell, transitional cell, neuroendocrine, and comedocarcinoma. Nonepithelial variants include rhabdomyosarcoma, leiomyosarcoma, osteosarcoma, angiosarcoma, carcinosarcoma, malignant lymphoma, and metastatic neoplasms among others.

The remainder of this discussion will focus on adenocarcinoma. However, it is increasingly evident that neuroendocrine (“small cell”) differentiation may occur in response to prolonged androgen deprivation. This can be recognized by staining such tissue for neuroendocrine markers (chromogranin A, neuron-specific enolase) and/or by measuring such markers in serum.

The cytologic characteristics of CaP include hyperchromatic, enlarged nuclei with prominent nucleoli (Figure 23–3). Cytoplasm is often abundant; thus, nuclear-to-cytoplasmic ratios are not often helpful in making a diagnosis of CaP, unlike their usefulness in diagnosing many other neoplasms. Cytoplasm is often slightly blue tinged or basophilic, which may assist in the diagnosis. The diagnosis of CaP is truly an architectural one. The basal cell layer is absent in CaP, whereas it is present in normal glands, BPH glands, and the precursor lesions of CaP. If the diagnosis of CaP is in question, high-molecular-weight keratin immunohistochemical staining is useful, as it preferentially stains basal cells. Absence of staining is thus consistent with CaP. Those biopsies that remain equivocal could be stained with new markers such as AMACR or EPCA, which appear to identify those with the disease, but who have equivocal or negative biopsies based on standard tissue staining.

Prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP) are thought to be precursor lesions. However, the risk of prostate cancer appears to be higher in those with the latter histology. Men found to have either lesion may be at an increased risk of prostate cancer and warrant repeat biopsy, particularly if an extended-core biopsy was not performed initially. High-grade PIN (HGPIN) is characterized by cellular proliferations within preexisting ducts and glands, with nuclear and nucleolar enlargement similar to prostate cancer. However, unlike cancer, HGPIN retains a basal cell layer identifiable by immunohistochemistry.

Approximately 60–70% of cases of CaP originate in the peripheral zone, 10–20% originate in the transition zone, and 5–10% in the central zone. Although prostate cancer is frequently multifocal, the use of widespread screening and extended biopsy techniques has resulted in the increasing detection of unifocal and smaller cancers.

Penetration of the prostatic capsule by cancer is a common event and often occurs along perineural spaces. Seminal vesicle invasion is associated with a high likelihood of regional or distant disease. Locally advanced CaP may invade the bladder trigone, resulting in ureteral obstruction. Rectal involvement is rare as Denonvilliers' fascia represents a strong barrier. (Of note, this barrier is largely one way, as rectal cancer may invade the prostate relatively commonly.) Lymphatic metastases are most often identified in the obturator, external iliac, and internal lymph node chains. Other sites of nodal involvement include the common iliac, presacral, and periaortic lymph nodes.

The axial skeleton is the most usual site of distant metastases, with the lumbar spine being most frequently implicated (Figure 23–4). The next most common sites in decreasing order are proximal femur, pelvis, thoracic spine, ribs, sternum, skull, and humerus. The bone lesions of metastatic CaP are typically osteoblastic. Involvement of long bones can lead to pathologic fractures. Vertebral body involvement with significant tumor masses extending into the epidural space can result in cord compression. Visceral metastases most commonly involve the lung, liver, and adrenal gland. Central nervous system involvement is usually a result of direct extension from skull metastasis.

Molecular Genetics and Pathobiology

Molecular profiling of human tissues has identified differential expression of specific genes and proteins in the progression from normal precursor tissue to preneoplastic lesions to cancer (both androgen dependent and independent). In doing so, diagnostic, prognostic, and therapeutic markers have been discovered.

Chromosomal rearrangements or copy number abnormalities at 8p, 10q, 11q, 13q, 16q, 17p, and 18q have been described in prostate cancers. Some of these such as specific loss at 8p23.2 and/or gain at 11q13.1 are predictive of prostate cancer progression.

The entire prostate microenvironment, not just the epithelial compartment, is important for both normal and neoplastic growth as significant epithelial–mesenchymal/stromal interactions occur (Chung et al, 2005). Molecular events may not always be spontaneous, but the product of environmental influences. For instance, both epidemiologic and molecular data suggest that inflammation may be related to prostate cancer development (Nelson et al, 2004). RNASEL, encoding an interferon-inducible ribonuclease, and MSR1, encoding subunits of the macrophage scavenger receptor, are candidate-inherited susceptibility genes for prostate cancer, including familial cancer. Proliferative inflammatory atrophy lesions containing activated inflammatory cells and proliferating epithelial cells appear likely to be precursors to PIN lesions and prostatic carcinomas.

Using a novel bioinformatics approach, Tomlins and colleagues identified two transcription factors ERG and EtV1 that were overexpressed in prostate cancer tissue. Furthermore, TMPRSS2 was fused to these genes suggesting that fusion accounted for overexpression. This genetic rearrangement appears to be the most common identified in prostate cancer. The TMPRSS2:ERG fusion has been identified in approximately 50% of prostate tumors and likely represents an early molecular event in carcinogenesis. Furthermore, this fusion may yield a distinct phenotype with a more aggressive natural history, independent of Gleason grade (Narod et al, 2008).

Some overexpressed genes or combinations of genes may be important biomarkers capable of not only identifying cancer in equivocal biopsy samples (alpha-methylacyl coenzyme A racemase [AMACR] and early prostate cancer antigen [EPCA]) but also in predicting response to treatment and progression (Rubin, 2004). Multiple research efforts have identified other promising multiparametric models to improve risk stratification and prediction (Cuzick et al, 2011; Mucci et al, 2008; Paris et al, 2010; Penney et al, 2011), though none of these has yet been well validated or reached clinical practice. Beyond genetic analyses, parallel advances in proteomics and metabolomics likewise are yielding novel insights into both the pathophysiology of prostate cancer and improved risk stratification of the disease (Sreekumar et al, 2009).

The number of prostate cancers attributable to heritable factors may be greater than once thought (Lichtenstein et al, 2000). Although the loci 8q, 3p, 7p/q, 9q, 10q, 11q, 17q, and 22q have been identified as harboring potential predisposition genes in those with a family history of prostate cancer, a multigene model may best explain familial clustering of this disease. In addition, men with a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutations as they are at increased risk of breast and prostate cancers.

Clinical Findings

Symptoms

The large majority of patients with early-stage CaP are asymptomatic. The presence of symptoms often suggests locally advanced or metastatic disease. Obstructive or irritative voiding complaints can result from local growth of the tumor into the urethra or bladder neck or from its direct extension into the trigone of the bladder. Much more commonly, however, such symptoms are attributable to coexisting BPH. Metastatic disease to the bones may cause bone pain. Metastatic disease to the vertebral column with impingement on the spinal cord may be associated with symptoms of cord compression, including paresthesias and weakness of the lower extremities and urinary or fecal incontinence.

Signs

A physical examination, including a DRE, is needed. Induration or nodularity, if detected, must alert the physician to the possibility of cancer and the need for further evaluation (ie, PSA, TRUS, and biopsy). Locally advanced disease with bulky regional lymphadenopathy may lead to lymphedema of the lower extremities. Specific signs of cord compression relate to the level of the compression and may include weakness or spasticity of the lower extremities and a hyperreflexic bulbocavernosus reflex.

General Laboratory Findings

Azotemia can result from bilateral ureteral obstruction either from direct extension into the trigone or from retroperitoneal adenopathy. Anemia may be present in metastatic disease. Alkaline phosphatase may be elevated in the presence of bone metastases. Serum acid phosphatase may be elevated with disease outside the confines of the prostate.

Prostate-Specific Antigen and Other Tumor Markers

PSA is a serine protease in the human kallikrein (hK) family produced by benign and malignant prostate tissues. It circulates in the serum as uncomplexed (free or unbound) or complexed (bound) forms. PSA is used both as a diagnostic (screening) tool and as a means of risk-stratifying known prostate cancers. In both contexts, its use is complicated by the fact that PSA is prostate specific, not prostate cancer specific. Other prevalent conditions such as BPH and prostatitis—as well as urethral instrumentation and perineal insults such as prolonged bike ride—can elevate the PSA, producing false-positive results.

A “normal” PSA has traditionally been defined as ≤4 ng/mL, and the positive predictive value of a serum PSA between 4 and 10 ng/mL is approximately 20–30%. For levels in excess of 10 ng/mL, the positive predictive value increases from 42% to 71.4%. In light of variation with age and ethnicity, age- and race-specific reference ranges have been proposed (Oesterling et al, 1993). More importantly, the results of the Prostate Cancer Prevention Trial (PCPT) study, which included biopsy regardless of PSA level—thus avoiding the ascertainment bias otherwise confounding virtually all other studies of PSA—demonstrated that there is no level of PSA below which prostate cancer risk falls to zero. PSA is rather indicative of a continuum of risk—the higher the level, the higher the risk (Thompson et al, 2004).

Current prostate cancer screening and detection strategies therefore include with PSA other risk factors such as family history, race, age, and others (Greene et al, 2009). Online risk calculators integrating these variables have been made generated to determine risk of prostate cancer and risk of high-grade prostate cancer. A calculator based on the PCPT data, for example, is available at http://tinyurl.com/caprisk.

Use of medications such as 5α-reductase inhibitors (including the 1 mg finasteride formulation marked for alopecia as Propecia) must be ascertained, as these medications can artificially lower the PSA by approximately 50%. Interestingly, serum PSA levels have also been noted to be decreased in men with high body mass indexes compared with normal weight men, likely as a result of hemodilution (Banez et al, 2007).

Numerous strategies to refine PSA for cancer detection have been explored. Their common goal in general has been to decrease the number of false-positive test results, thus increasing the specificity and positive predictive value of the test and lead to fewer unnecessary biopsies, lower costs, and reduced morbidity of cancer detection. Attempts at refining PSA have included PSA velocity (PSAV) (change of PSA over time), PSA kinetics (standardizing levels in relation to the size of the prostate), and PSA isoforms (free vs protein-bound molecular forms of PSA).

PSA Kinetics

PSAV refers to the rate of change of serum PSA; its inverse, PSA doubling time (PSADT) indicates the amount of time required for the PSA to double. A retrospective study has shown that men with prostate cancer have a more rapidly rising serum PSA in the years before diagnosis than do men without prostate cancer. Patients whose serum PSA increases by 0.75 ng/mL per year appear to be at an increased risk of harboring cancer. However, PSAV must be interpreted with caution. An elevated PSAV should be considered significant only when several serum PSA assays are carried out by the same laboratory over a period of at least 18 months. Very rapid PSA increases may be indicative of prostatitis (symptomatic or otherwise) rather than cancer. Recent studies have questioned whether PSA kinetics in fact add significantly to the absolute PSA level in the prediagnosis setting (Vickers et al, 2011), and the optimal use of PSA kinetics remains controversial.

PSA Density

PSA levels are elevated on average approximately 0.12 ng/mL per gram of BPH tissue. Thus, patients with enlarged glands due to BPH may have elevated PSA levels. The ratio of PSA to gland volume is termed the PSA density. Some investigators advocate prostate biopsy only if the PSA density exceeds 0.1 or 0.15, while others have not found PSA density to be useful. Problems with this approach include the facts that (1) epithelial–stromal ratios vary from gland to gland and only the epithelium produces PSA and (2) errors in calculating prostatic volume based on TRUS may approach 25%. The positive predictive value of PSA density is slightly higher than the use of a PSA level >4 ng/mL in several series (30–40% vs 20–30%). The other major problem with PSA doubling (PSAD) is that it still requires TRUS, which, while a lower risk procedure than biopsy, is still invasive and uncomfortable. Thus, PSAD may be most useful in settings in which the prostate volume is already known (ie, PSA rising after a negative prior biopsy).

Instead of adjusting the PSA to total prostate volume, some have advocated adjusting it to transition zone volume (PSA transition zone density, PSAT [Djavan et al, 2002]). However, like PSA density, such calculations are subject to error, require TRUS, and do not seem to be superior to the use of PSA in most patients.

Molecular Forms of PSA

Various molecular isoforms of PSA have been identified and studied. Approximately 90% of the serum PSA is bound to α1-antichymotrypsin (ACT), and lesser amounts are free or are bound to α2-macroglobulins. In the latter form, no epitopes to the antibodies used in the current assays are available, while PSA bound ACT may have three of its five epitopes masked. Early studies suggest that prostate cancer patients demonstrate a lower percentage of free PSA than do patients with benign disease. A large multicenter study has reported that in men with a normal DRE and a total PSA level between 4 and 10 ng/mL, a 25% free PSA cutoff would detect 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with >25% free PSA were more prevalent in older patients and generally were less threatening in terms of tumor grade and volume (Catalona et al, 1998). The predictive utility of percentage of free PSA in subsequent studies, however, has been mixed.

More recent studies have focused on other PSA subtypes. A serum panel adding free PSA, intact PSA, and hK2 to total PSA has been shown to improve predictive accuracy for prostate cancer diagnosis among men with a PSA >3 (Vickers et al, JCO 2010) and is currently undergoing validation studies. A truncated form of PSA designated −2proPSA has also shown promise in this setting and is likewise undergoing validation studies (Catalona et al, 2011; Mikolajczyk et al, 2004).

PCA3

Prostate cancer antigen 3 (PCA3) is a noncoding, prostate-specific mRNA, which is overexpressed in the majority of prostate cancers, with a median 66-fold upregulation compared with adjacent noncancer tissue (Hessels et al, 2007). PCA3 predicts the presence of cancer in a biopsy setting with an accuracy of 74.6% (Groskopf et al, 2006). PCA3 may be particularly useful in the evaluation of men with a negative prior biopsy and a rising PSA (Haese et al, 2008).

Diagnosis and Evaluation

Prostate Biopsy

Prostate biopsy should be considered in men with an elevated serum PSA, abnormal DRE, or a combination of the two, depending additionally on the patient's overall health, comorbidities, life expectancy, levels of anxiety and of risk aversion, and information preferences. Prostate biopsy is performed under TRUS guidance using a spring-loaded biopsy device coupled to the imaging probe. Biopsies are taken throughout the peripheral zone of the prostate, with optional additional sampling of any abnormal areas on DRE and/or TRUS. Traditionally, six (sextant) biopsies were taken along a parasagittal line between the lateral edge and the midline of the prostate at the apex, midgland, and base bilaterally. However, several investigators have shown that increasing the number (≥10) and performing more laterally directed biopsies of the peripheral zone will increase detection rates 14–20% over the more traditional sextant technique. Although a small number of prostate cancers will originate in the transition zone, specific transition zone biopsies add little to overall cancer detection rates when an extended-pattern biopsy is performed. Some practitioners do add biopsies of the anterior commissure, a relatively frequent site of initially missed cancers found on second or subsequent biopsy. There is ongoing interest in the use of even more extended biopsy schemes (“saturation biopsy”) or use of a transperineal approach to improve cancer detection, usually in those who have had a negative biopsy, but are thought to be at an increased risk of prostate cancer based on a persistently abnormal serum PSA.

Prostate biopsy is usually performed using local anesthesia and preprocedure antibiotic prophylaxis (usually a fluoroquinolone). The use of local anesthesia, either applied topically along the anterior rectal wall, injected into or adjacent to the prostate, or a combination of the two, decreases pain associated with the procedure. Hematospermia, hematochezia, and hematuria are common occurring in approximately 40–50% of patients. With rising prevalence of antibiotic-resistant bacteria, rates of sepsis despite standard prophylaxis have been growing (Lange et al, 2009). These can be life threatening even in otherwise-healthy men, and patients are counseled to return immediately to the emergency department for any high fevers after the procedure.

Saturation schemes consist of 20 or more cores that emphasize sampling of the peripheral zone. One of the more common saturation schemes involves taking two cores from the lateral base, three cores from the lateral mid, three cores from the apex (including anterior apex), and one core from the parasagittal mid and one core from the parasagittal base. While initial saturation schemes included two cores at both the parasagittal mid and parasagittal base, unique identification of cancer in these areas is rare and thus it has been recommended to only obtain one care for each of these areas. Investigators have demonstrated that saturation biopsies can be performed in the office using a periprostatic block. They observed no improved yield by using a saturation biopsy as the initial biopsy scheme or the first repeat biopsy scheme but rather advocate it as a second repeat biopsy strategy (Jones et al, 2002).

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial allows us to prospectively look at both cancer detection rates and quality of cancers in a repeat biopsy situation. Recall that entry criteria for this trial mandated a prior negative biopsy (minimum of a negative sextant biopsy) within 6 months of enrollment. In the placebo arm, 3346 patients underwent a repeat biopsy within 1–2 years of enrollment and 17.2% were found to have cancer of which 30% were high grade (Gleason score >7). At the repeat biopsy between years 3 and 4, 11.7% of 2343 patients were found to have cancer of which 21% were high grade. Considering only patients with primary Gleason pattern 4 or 5, 8.7% and 2.6% of the cancers were high grade at the 2- and 4-year biopsy, respectively. This study also compared the relative merit of PCA3 and F/T PSA in the repeat biopsy population. No significant difference was seen between these two markers for predicting cancer (Andriole et al, 2010).

Grading and Staging

The Gleason system is the most commonly employed grading system. The system relies on the low-power appearance of the glandular architecture under the microscope. In assigning a grade to a given tumor, pathologists assign a primary grade to the pattern of cancer that is most commonly observed and a secondary grade to the second most commonly observed pattern in the specimen. Grades range from 1 to 5 (Figure 23–3). If the entire specimen has only one pattern present, then both the primary and secondary grade are reported as the same grade (eg, 3 + 3). The Gleason score or Gleason sum is obtained by adding the primary and secondary grades together.

Traditionally, Gleason grades ranged from 1 to 5, and Gleason scores thus ranged from 2 to 10. Gleason scores of 2–4, 5–7, and 8–10 corresponded to well-, moderately, and poorly differentiated tumors, respectively. However, pathology grading practices have changed over time, and this grouping is largely outdated (though it is still sometimes reported in the literature). In contemporary pathology practice, Gleason patterns 1 and 2 are rarely assigned, so Gleason pattern 3 corresponds with low-grade disease (variable-sized glands that percolate through normal stroma and between normal glands), Gleason pattern 4 corresponds with intermediate-grade disease (incompletely formed glands with variable amounts of fusion and more infiltrative growth pattern), and Gleason pattern 5 corresponds with high-grade disease (single infiltrating cells with no gland formation). Variations in growth such as cribriform patterns and comedocarcinoma are also observed.

A Gleason score 6 (3 + 3) tumor is uniformly low grade. In differentiating intermediate- and high-grade tumors, the primary Gleason pattern is the most important determinant of biologic risk. Thus, among Gleason score 7 tumors, those assigned 4 + 3 are more aggressive than those read as 3 + 4. Many clinical series have failed to distinguish between these two populations and, therefore, caution must be exercised in reviewing these series.

The 2010 AJCC TNM staging system for CaP is presented in Table 23–3. Note that with respect to the primary tumor categorization (T stage), the clinical staging system uses results of the DRE and TRUS, but not the results of the biopsy. Some examples to illustrate this staging system are as follows. If a patient has a palpable abnormality on one side of the prostate, even though biopsies demonstrate bilateral disease, his clinical stage remains T2a. If a patient has a normal DRE, with TRUS demonstrating a lesion on one side and a biopsy confirming cancer, his clinical stage is also T2a (using results of DRE and TRUS). A T1c cancer must have both a normal DRE and a normal TRUS. It should be noted that compared with risk factors such as Gleason score and PSA levels, clinical T stage in prostate cancer is a relatively weak prognostic factor. Partly due to the subjectivity of DRE and TRUS interpretation, and given adjustment for more objective measures of tumor volume such as percent of biopsy cores involved, T stage often drops out of multivariable models of prostate cancer prognosis, at least among T1 and T2 tumors which account for the vast majority of tumors diagnosed in contemporary practice (Reese et al, 2011)

Imaging

TRUS

As described earlier, TRUS is useful in helping guide prostatic biopsies and other prostate-directed interventions. TRUS also provides useful local staging information if cancer is detected, usually with greater accuracy than DRE. If visible, CaP tends to appear as a hypoechoic lesion in the peripheral zone and/or hypervascularity seen on power Doppler examination. The sonographic criteria for extracapsular extension are bulging of the prostate contour or angulated appearance of the lateral margin. The criteria for seminal vesicle invasion are a posterior bulge at the base of the seminal vesicle or asymmetry in echogenicity of the seminal vesicle associated with hypoechoic areas at the base of the prostate. In some protocols under development, 3D TRUS permits a three-dimensional image to be constructed from a series of 2D images by a computer algorithm. Use of an intravenous microbubbles may also improve visualization of tumor microvasculature, and targeted microbubbles under development may further improve this emerging modality (Sanna et al, 2011). Elastography—an imaging modality based on differential compressibility of benign and malignant tissue—may also emerge as a useful adjunct to standard TRUS (Mahdavi et al, 2011).

Endorectal Magnetic Resonance Imaging (MRI)

Use of an endorectal coil improves cancer detection and staging compared with the use of a standard body coil. While rendering high image quality, the use of an endorectal coil appears to be operator dependent, requiring education and expertise. Routine use of this technology may not alter treatment decisions compared with the information gained by assessment of more standard clinicopathologic information. Use of magnetic resonance spectroscopy (MRS) in conjunction with MRI may improve the accuracy of imaging. Prostate cancer is associated with proportionately lower levels of citrate and higher levels of choline and creatine compared with BPH or normal prostate tissue. The combined metabolic and anatomic information provided by a multiparametric MRI exam and MRS may allow for a more accurate assessment of cancer location and stage. The reported staging accuracy of endorectal MRI varies from 51% to 92%. It appears to add novel information to the assessment of some patients over the use of nomograms alone, but it may be best utilized in high-risk patients where it is most accurate and helpful (Afnan et al, 2010; Verma et al, 2010).

Axial Imaging (CT, MRI)

Cross-sectional imaging of the pelvis in patients with CaP is selectively performed to exclude lymph node metastases in high-risk patients who are thought to be candidates for definitive local therapy, whether it be surgery or irradiation. Both CT and body coil-based MRI are used for this purpose. Neither modality is particularly accurate for local T staging. Patients identified as having lymphadenopathy on imaging may occasionally undergo CT-guided fine-needle aspiration if the diagnosis is equivocal. If lymph node metastases are confirmed, such patients may be candidates for alternative treatment regimens. However, the incidence of lymph node metastases in contemporary radical prostatectomy (RP) series is low (<10%). In addition, imaging is costly and its sensitivity is limited (30–40%). Various criteria can be used to identify patients for axial imaging, including negative bone scans and either T3 cancers or a PSA >20 ng/mL and primary Gleason grade 4 or 5 cancers. Like bone scan, cross-sectional imaging—CT in particular—is widely overused for staging of low-risk tumors which are very unlikely to be associated with lymph node metastases.

Intravenous administration of superparamagnetic nanoparticles, which gain access to lymph nodes by means of interstitial-lymphatic fluid transport, at the time of high-resolution MRI, appears to improve visualization of small nodal metastases, but this agent is not yet approved for use in the United States.

Bone Scan

When prostate cancer metastasizes, it most commonly does so to the bone (Figure 23–4). Soft tissue metastases (eg, lung and liver) are rare at the time of initial presentation. Although a bone scan has been considered a standard part of the initial evaluation of men with newly diagnosed prostate cancer, good evidence has been accumulated that it can be excluded in most of these men on the basis of serum PSA. Several investigators have shown that bone scans can be omitted in patients with newly diagnosed, untreated prostate cancer who are asymptomatic, have T1 and T2 disease, and have serum PSA concentrations <20 ng/mL. These recommendations in fact are incorporated into clinical guidelines for the management of clinically localized prostate cancer, but bone scan remains widely overused among men with low-risk disease, as confirmed in a number of recent studies (Palvolgi et al, 2011).

Antibody Imaging

ProstaScint is a murine monoclonal antibody to prostate-specific membrane antigen (PSMA), which is conjugated to 111indium. After infusion of the antibody, single photon emission computed tomography (SPECT) images are usually obtained at 30 minutes to access vasculature and at 72–120 hours. It has been studied—and is Food and Drug Administration (FDA) approved—for initial staging and workup of recurrent disease. However, the antibody recognizes an intracellular epitope of PSMA; only soft tissues are imaged and the test may suffer from both false-positive and -negative results in both clinical situations described earlier. Use of new antibodies, which recognize the extracellular domain of PSMA, appear to allow for recognition of both bone and soft tissue metastases and could be used as agents for therapy, not only improved imaging (Bander et al, 2006).

Multivariable Risk Assessment

As discussed elsewhere in this chapter, contemporary treatment patterns for prostate cancer are marked by both overtreatment of low-risk disease and undertreatment of high-risk disease. A key approach to mitigating this problem is better and more consistent risk stratification intended to help identify the best timing and intensity of treatment for a given patient. The critical variables for optimal risk stratification have been detailed earlier: the PSA level, the Gleason score, and some measure of tumor volume—clinical T stage and/or extent of biopsy core involvement (eg, percent of cores positive or percent of all biopsy tissue positive). More than 100 risk formulae, lookup tables, nomograms, and other instruments have been published to help with this task (Cooperberg, 2008; Shariat et al, 2008). Some key instruments are described as follows.

Risk Groups

One of the first widely adopted approaches to risk stratification is a three-level risk group classification published by D'Amico et al and formally adopted by the AUA's practice guideline for localized prostate cancer treatment (D'Amico et al, 1998; Thompson, 2007). In this classification, men are assigned to one of three groups as follows:

• Low risk: PSA ≤10, Gleason ≤6, and clinical stage T1 or T2a.
• Intermediate risk: PSA 10–20, Gleason 7, or clinical stage T2b.
• High risk: PSA >20, Gleason 8–10, or clinical stage T2c or T3a.

The major advantage to this system is its simplicity, and it is used very commonly. However, it has significant drawbacks. First, it overweights T stage which, as noted earlier, is not an accurate measure of tumor extent within the T2 category. Second, it does not distinguish between Gleason 3 + 4 and 4 + 3 tumors, which (again, as noted earlier) behave very differently within the Gleason 7 category. Finally, and most importantly, it is not a true multivariable instrument in that it does not account for information from the various risk variables. Both a PSA 19.8, Gleason 4 + 3, stage T2b tumor and a PSA 4.2, Gleason 3 + 4, stage T1c tumor are “intermediate risk” in this classification, but would be expected to behave quite differently.

Lookup Tables and Nomograms

Most risk instruments are based on multivariable logistic regression or Cox proportional hazards models depending on the outcome of interest. For example, the well-validated lookup tables first published by Partin et al predict pathologic outcomes such as extracapsular extension and seminal vesicle invasion (Makarov et al, 2007).

A nomogram is a graphical representation of a regression model. First popularized in urology by Kattan et al (2003), nomograms are alternatives to lookup tables (see Figure 23–5). To use a nomogram, a patient is assigned a number of points for each risk factor; these are then summed to yield a prediction for the outcome (eg, 5-year biochemical recurrence-free survival), usually with a ±10% margin of error.

Many other nomograms have been published since, intended to predict pathologic outcomes, biochemical outcomes after surgery or radiation therapy, or longer-term outcomes such as metastasis or mortality. Two important caveats should be noted. First, a given nomogram is developed based on data from a specific cohort of men, usually treated in one or a few academic centers in which a small number of highly trained surgeons or radiation oncologists treat large volumes of patients. A great deal of caution must be exercised in calculating specific risks of recurrence for patients treated in other settings by different clinicians, and ideally nomograms should be formally validated in a given setting before they are used routinely in that setting (Greene, 2004).

Second, with computer software, it is very easy to calculate multiple nomogram scores simultaneously, creating a temptation to use the nomogram scores to compare treatment options such as surgery or radiation. Nomograms cannot be used this way—the cohorts of patients used to develop each are very different, as are the definitions of the outcomes reported. In particular, with few exceptions, nomograms predict likelihood of PSA recurrence after treatment, which is defined very differently after radiation than after surgery. Thus, nomograms may be useful to give a patient undergoing a specific treatment a sense of the likely outcomes, but should not help guide treatment decisions.

Capra Score

Because of these limitations—and the fact that nomograms are difficult to calculate for hundreds or thousands of patients in research settings and cannot be used to consistently identify low- or high-risk cohorts—the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score was developed, intended to combine the accuracy of nomograms with the ease of calculation of a risk grouping system (Cooperberg et al, 2005). To calculate the CAPRA score, points are assigned based primarily on the PSA and Gleason score, with lesser weights given to T stage, percent of biopsy cores positive, and patient age (Figure 23–6):

Points are added to yield a 0–10 score. Overall, every 2-point increase in score (eg, from 2 to 4 or from 5 to 7) indicates roughly a doubling of risk. CAPRA scores in the 0–2 range indicate relatively low-risk disease, CAPRA 3–5 tumors are intermediate risk, and CAPRA 6–10 tumors are high risk. The CAPRA score has been widely validated in the United States and Europe in multiple contexts. It was recently found to offer better accuracy than competing instruments in an independent head-to-head comparison study (Lugghezani, Eur Urol 2009). Moreover, it has been shown to predict metastasis and mortality as well as biochemical outcomes—after surgery, radiation therapy, and hormonal therapy (Cooperberg et al, 2009). A postoperative version incorporating pathologic data has also been published recently, but it has not yet been externally validated (Cooperberg et al, Cancer 2011).

It is important to note that the CAPRA score is primarily meant to indicate relative rather than absolute risk. Thus, a tumor with a CAPRA score of 4 has an intermediate risk of recurrence or progression after surgery or radiation. This tumor will be more likely to progress than one with a score of 2, and less likely than one with a score of 6, regardless of treatment approach or setting. The specific risk (eg, likelihood of being free of disease at 5 years after treatment), while roughly consistent across different cohorts, will depend at least in part on factors such as surgeon skill and experience, pathology grading practices, etc.

Prostate Cancer Screening and Chemoprevention

Prostate cancer screening is a subject of substantial ongoing controversy in the United States and elsewhere. Some organizations, such as the AUA, generally support at least offering screening to men with good life expectancy (at least 10 years), whereas others are neutral and some, such as the US Preventive Services Task Force (2008), are relatively hostile to screening (Greene et al, 2009).

The case for CaP screening is supported by the following: the disease is burdensome in this country; PSA improves detection of clinically important tumors without significantly increasing the detection of unimportant tumors; most PSA-detected tumors are curable; prostate cancer mortality is declining in regions where screening occurs; and curative treatments are available. If screening is undertaken, it appears that the use of both DRE and serum PSA is preferable to either one used alone. Although most guidelines recommend that screening be undertaken at age 50, some have advocated for earlier screening starting at age 40, based on (1) less confounding of PSA assessment by BPH at earlier ages and (2) the fact that a small but significant number of men already have high-risk or advanced prostate cancer by the age of 50. There is broader consensus that screening should start earlier for men with risk factors such as family history and/or African American ethnicity. Although annual screening is most often recommend in the United States, some feel that men with very low serum PSA level (eg, ≤1 ng/mL) may be able to be screened at less frequent intervals (every 2 or 3 years). Determining an optimal interval for screening is another rationale for establishing a baseline PSA level at age 40. Similarly, if the PSA level remains <1 ng/mL by the age of 60, then the likelihood of death from prostate cancer by the age of 85 falls to <1% (Vickers et al, BMJ 2010).

Two large randomized screening trials were reported in 2009, which, if anything, only fueled the controversy surrounding screening. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial randomized 76,693 men in the United States to annual PSA screening or usual care. The risk of prostate cancer death with 7 to 10 years follow-up was very low both in screened and unscreened men and did not differ significantly between them. However, the duration of follow-up was too short to observe a difference given the long natural of prostate cancer. Moreover, a very high proportion of men in the “control” arm of the study, in fact, were screened with PSA before the start of the study and/or during the study. Finally, the rate of prostate biopsy among men who crossed the predefined PSA threshold of 4.0 ng/mL was quite low. These limitations limit the ability of this study to fairly test the hypothesis, even as longer follow-up accumulates in the future (Andriole et al, 2009). Despite these limitations, a recent subset analysis found a substantial decrease in prostate cancer–specific mortality for men undergoing screening with no major comorbidity, while those with comorbid disease demonstrated a trend toward increased mortality in the screening arm (Crawford et al, 2011).

The European Randomized Study of Screening for Prostate Cancer (ERSPC) randomized 162,387 men in seven countries to PSA screening at 2- or 4-year intervals, with biopsy thresholds ranging from 2.5 to 4.0 ng/mL. This was a larger study than PLCO, with longer follow-up and much less contamination among control patients. The study demonstrated that screening was associated with a 20% relative reduction in prostate cancer–specific mortality at 9 years median follow-up. A follow-up analysis found that with adjustment for compliance with screening, the reduction in mortality rose to 31%. The hazard curves in the ERSPC study only began to diverge approximately 7 years into the trial; thus, with longer follow-up, the observed benefit to screening will likely be further magnified (Schroder, 2009). In a subanalysis of patients from one of the ERSPC study centers with particularly high compliance and long (14 years) follow-up, the mortality reduction was nearly 50% (Hugosson, 2010).

The primary argument against screening is that many cancers identified through screening efforts would never result in clinically significant disease in the patient if left untreated, a phenomenon called overdetection. Some have estimated that between 29% and 48% of cancers detected by an aggressive screening program are such cancers (Draisma et al, 2003; Etzioni et al, 2002). This underscores the importance of informed consent before screening is undertaken and the need to discuss all treatment options, including active surveillance, in those found to have the disease. Indeed, overdetection is primarily a problem to the extent that it leads to overtreatment, which in fact is a pervasive problem in the United States and elsewhere (Cooperberg, JCO 2010). It is hoped that properly risk-adapted management strategies, including greater use of active surveillance for men with lower risk disease, may ultimately ameliorate the controversy surrounding screening, at least to an extent.

Chemoprevention

There is much interest in prostate cancer prevention due to the disease's high prevalence, slowly progressive nature, long latency period, and high absolute mortality. The ideal therapeutic intervention would arrest disease progression during the latency period and decrease the incidence of clinical disease. The ideal agent should be nontoxic and of low cost and the ideal patient would be one at high risk of the disease. To date, several promising chemopreventive agents have been identified and are under laboratory and clinical investigation.

In the PCPT, 18,882 men aged 55 or older with normal DRE and PSA level <3 ng/mL were randomized to either placebo or the 5α-reductase inhibitor, finasteride (5 mg/day) (Thompson et al, 2003). Prostate cancer was detected in 18.4% of those on finasteride and 24.4% on placebo, for a 24.8% reduction in prevalence. Cancers of Gleason grades 7, 8, 9, or 10 were more common in the finasteride group than in the placebo group (37.0% vs 22.2%). This apparent increase in the risk of high-grade cancers may be artifactual for several reasons, related most importantly to downsizing of benign prostate tissue by the medication and resulting improvement in the receiver operating characteristic curve of prostate biopsy for the detection of high-grade cancer (by analogy, one is more likely to find a given needle in a smaller haystack than in a larger haystack). However, this question—whether the higher incidence of high-grade disease is attributable to detection bias—remains controversial, and the FDA decided recently not only to decline an expanded label for chemoprevention for 5α-reductase inhibitors but also to add an explicit warning to the labels regarding risk of high-grade prostate cancer (Theoret et al, 2011). Sexual side effects were more common in those receiving finasteride, whereas urinary symptoms were more common in those receiving placebo.

Another recently reported placebo-controlled, randomized trial (the REDUCE study) found a similar 22.8% reduction in incidence of prostate cancer among men 50–75 years of age, with PSA levels 2.5–10 ng/mL and a prior negative biopsy, who were treated with dutasteride rather than placebo. As in the PCPT, urinary symptoms were significantly ameliorated on the treatment arm, at the expense of sexual side effects among some participants (Andriole et al, 2010).

Uptake of prostate cancer chemoprevention with 5α-reductase inhibitors has been slow since the PCPT was first reported, but a guideline from the AUA and American Society of Clinical Oncology advises that men at risk be informed of chemoprevention as an option (Kramer et al, 2009). Other chemoprevention studies are ongoing, but no other agents have yet been found to be as promising as finasteride and dutasteride. In one notable negative study (the SELECT study), a randomized, placebo-controlled trial of >35,000 men, selenium and vitamin E were shown to be of no benefit for prostate cancer chemoprevention (Lippman et al, 2009).

Treatment

Localized Disease

General Considerations

The optimal form of therapy for all stages of CaP remains a subject of great debate. Treatment dilemmas persist in the management of localized disease (T1 and T2) because of the uncertainty surrounding the relative efficacy of various modalities, including RP, radiation therapy, and surveillance. Currently, treatment decisions are based on the grade and stage of the tumor, the life expectancy of the patient, the ability of each therapy to ensure disease-free survival, its associated morbidity, and patient and physician preferences. Until recently, there was little information to be sure that treatment of early stage disease had an important impact on overall and cancer-specific survival. A well-conducted randomized trial of RP versus surveillance in men with early stage prostate cancer generally diagnosed before the PSA era was conducted in Scandinavia (Bill-Axelson et al, 2011). With 13 years follow-up, men who underwent RP were less likely to die of prostate cancer (relative risk, 0.62). The advantage to surgery was most apparent in younger patients (<65 years old at diagnosis).

No randomized controlled trials comparing active local therapies (eg, surgery and radiation therapy) have been published. Studies of nonrandomized but prospectively accrued cohorts with high quality data have recently shown, after extensive risk adjustment and various controls for confounding, a consistent mortality benefit for surgery relative to external beam radiation therapy or hormonal therapy, and for any local therapy (surgery or radiation) relative to hormonal therapy alone (Cooperberg, Cancer 2010; Zelefsky, 2010). The differences seem to be greatest for men with relatively high-risk tumors. Other similar studies are ongoing. Despite the ongoing controversies, what is clear is that many men with low-risk disease are candidates for active surveillance; those with low- to intermediate-risk disease should receive local monotherapy (surgery or radiation), and those with higher-risk disease usually need multimodal therapy, either radiation with hormonal therapy or surgery followed selectively by radiation depending on the pathology and early PSA outcomes. These strategies are described in further detail later.

Watchful Waiting and Active Surveillance

Although local cancer progression may occur, with watchful waiting for early stage prostate cancer, disease-specific mortality at 10 years is low varying generally between 4% and 15%. However, in further follow-up from 15 to 20 years, a substantial increase in the risk of local and systemic progression and death from prostate cancer may be seen (Johansson, Andren et al, 2004). The risk of progression is related significantly to cancer grade. The risk of progression is low in those with Gleason grades 2–6 (no pattern 4 or 5), but increases significantly for those with high-grade disease, even among men diagnosed at relatively advanced age (Lu-Yao, 2009). Most of the men, in these previously reported series of men managed with watchful waiting, had palpable disease and, therefore, larger, more significant cancer than most of those detected currently based on serum PSA. In addition, most men were not followed carefully with periodic clinical, radiographic, and laboratory (PSA) reevaluation. They were treated, usually with androgen deprivation, when symptomatic metastatic disease was detected.

A more modern concept of watchful waiting is better termed “active surveillance.” In surveillance, men with very well-characterized, early-stage, and low- to intermediate-grade cancer are followed very carefully with serial DRE and PSA assessments, and follow-up TRUS-guided biopsies to ensure stability of the tumor. Cancers are usually treated at the first sign of subclinical progression (Cooperberg et al, 2011a, 2011b; Dall'Era, Cancer 2008; Klotz, 2010). Although between 20% and 41% of men on such regimens may require treatment at 3–5 years of follow-up, treatment at progression appears to be as effective as it would have been if delivered at the time of diagnosis for most men. Optimal surveillance strategies, end points for intervention, and exact risks of surveillance have not been well defined, as yet. There is little question, however, that given the trends toward diagnosis of low-risk, often indolent tumors, active surveillance remains underused as an initial management strategy and likely will play a greater role in the coming years.

Radical Prostatectomy

The first radical perineal prostatectomy was performed by Hugh Hampton Young in 1904, and Terence Millin first described the radical retropubic approach in 1945. However, the procedure remained unpopular because of frequent complications of incontinence and impotence. The rebirth of RP has resulted from a better understanding of the surgical anatomy of the pelvis. Description of the anatomy of the dorsal vein complex and prostate apex anatomy resulted in modifications in the surgical technique leading to reduced operative blood loss. In addition, improved visualization made possible a more precise apical dissection, allowing better sparing of the external urethral sphincter and resulting improved continence. Description of the course of the cavernous nerves enabled further modifications of the surgical technique—so-called nerve-sparing techniques—in appropriate cases, resulting in better long-term preservation of erection function.

Lymph node dissection, once done routinely, may be performed only in those at significant risk of lymph node metastases. Such men can be identified with use of probability tables and nomograms as described earlier. Previously, only limited node dissections were performed harvesting lymph nodes from the obturator fossa. However, results from extended dissections showed that more than half of lymph node metastases are found outside this region. Therefore, a more extended and meticulous dissection is advised. Some feel that this may not only have diagnostic value but also could have a therapeutic impact in those with limited nodal disease (Allaf et al, 2004; Bader et al, 2003).

Considerable experience has been gained recently using a laparoscopic approach to RP. This can be performed through an extra- or transperitoneal approach. The advent of the DaVinci surgical robot has transformed laparoscopic prostatectomy and has been adopted very rapidly in the United States. Laparoscopy reduces blood loss substantially, shortens the overall recovery time, and in some series reduces hospitalization time. Whether robot-assisted or unassisted laparoscopic surgery results in better or worse results in terms of the critical outcomes of cancer control, preservation of continence, and preservation of erectile function, however, remains unclear (Ficcara, Eur Urol 2009). Randomized trails were not performed, and even high-quality comparative cohort data remain fairly sparse, though this situation is gradually starting to change. The best evidence to date suggests that outcomes after robot-assisted surgery are probably comparable with—and are certainly not worse than—those obtained with the open approach (Barocas, 2010). However, the robot and associated disposable equipment are expensive, so the cost–benefit relationships remain unclear. It should be noted, however, that unlike some other novel technologies in prostate cancer care, Medicare and other payors do not offer any additional reimbursement for robot-assisted surgery. These costs in most cases are absorbed by the hospitals.

The prognosis of patients treated by RP correlates with the pathologic grade and stage of the specimen, and by the PSA response. PSA should fall to undetectable levels within 6 weeks of surgery in most cases. Distant metastases occur in about 85% of patients with positive lymph nodes; some men with limited micrometastatic nodal involvement may be cured by RP and lymphadenectomy, but all men with node involvement should be offered adjuvant androgen deprivation therapy. A high percentage of patients with seminal vesical involvement at RP, and a smaller proportion of those with extracapsular extension, are likewise destined to distant failure. There are several nomograms and other scoring systems available to help determine prognosis after surgery, similar to those discussed earlier for risk assessment prior to treatment (Cooperberg et al, Cancer 2011; Stephenson et al, 2005).

Patients with organ-confined cancer have 10-year disease-free survival ranging from 70% to 85% in several series. Those with focal extracapsular extension demonstrate 85% and 75% disease-free survival at 5 and 10 years, respectively. Patients with more extensive extracapsular extension demonstrate 70% and 40% disease-free survival at 5 and 10 years, respectively. High-grade tumors (Gleason sum >7) have a higher risk of progression than do low-grade tumors. Disease-free survival at 10 years for patients with Gleason sum 2–6 tumors is in excess of 70%; for Gleason sum 7, 50%; and for Gleason sum >8, 15%. The impact of positive surgical margins is controversial, and may relate to the extent, location, and grade of tumor at the margin. Neoadjuvant androgen deprivation, studied by several investigators, reduces the risk of positive surgical margins, but it does not appear to impact long-term biochemical relapse-free survival.

The management of patients with adverse pathologic features (positive surgical margins, extracapsular extension, and/or seminal vesicle invasion) at RP remains controversial. A large multicenter trial sponsored by the Southwest Oncology Group found a nearly 30% relative reduction in metastasis and cancer-specific mortality with 12 years follow-up for those given adjuvant radiation therapy compared with those observed. However, if all men with these disease features were given adjuvant radiation, many would be overtreated. The problem is that of the men in the control group, fewer than one-third ever received radiation, even after PSA relapse, and radiation was given relatively late in these cases (Thompson et al, 2009). Retrospective studies have shown that administering salvage radiation at relatively low PSA levels results in improved outcomes, with stratification down to a PSA of 0.5 ng/mL. What is unknown is whether there is a benefit to true adjuvant radiation—that is, radiation given to a man with adverse pathology but an undetectable PSA—compared with early salvage—that is, deferring treatment among those with undetectable PSAs but administering radiation at the first sign of a rising PSA identified with an ultrasensitive assay (ie, with a PSA >0.01 but <0.1 ng/mL). Relatively good evidence supports earlier rather than later salvage radiation—that is, treating at as low a detectable PSA level as possible (Stephenson, 2007).

Morbidity associated with RP can be significant and is in part related to the experience of the surgeon. Immediate intraoperative complications include blood loss, rectal injury, and ureteral injury. Blood loss is more common with the retropubic approach than with the perineal approach because in the former, the dorsal venous complex must be divided. As noted earlier, laparoscopic approaches decrease such bleeding. Rectal injury is rare with the retropubic approach and more common with the perineal approach but usually can be immediately repaired without long-term sequelae. Ureteral injury is rare with any technique. Laparoscopic approaches carry the additional risks of laparoscopic access and insufflation, as well as risks related to transperitoneal access when this approach is used.

Perioperative complications include deep venous thrombosis, pulmonary embolism, lymphocele formation, and wound infection. Late complications include urinary incontinence and impotence. Reported rates of incontinence vary widely depending on the series, how continence is defined and reported, how long after surgery continence is assessed, and other factors. Age, urethral length, and surgeon experience are predictive of continence recovery. The return of continence after surgery may be gradual: many men regain continence by 2–3 months, but recovery can continue up to 1 year. Most academic series report long-term continence rates of 80–95%; rates from population-based studies are lower.

Preservation of potency varies as a function of age, preoperative sexual function, and preservation of one or both neurovascular bundles. However, the nerve-sparing procedure should be used selectively, for extracapsular extension may be a common finding in patients with presumed localized CaP. If extracapsular extension is present, preservation of the neurovascular bundle may increase the likelihood that the tumor will recur. However, it should also be noted that nerve sparing is not a binary decision: the cavernosal nerve is not a single, well-defined structure, but rather it is a network of small nerve fibers running among the fascial layers surrounding the prostate. On each side, those tissues may be completely spared, partially spared, or widely excised depending on the preoperative findings. Like continence, reported rates of potency preservation vary very widely—from 40% to 82% in men younger than 60 years when both nerves are preserved and drops to 20–60% when only one nerve is preserved. For men between the ages of 60 and 69 years, comparable rates are 25–75% with bilateral nerve sparing and 10–50% with unilateral nerve sparing. As with continence, these figures are derived for the most part of academic series and may not be achieved in all practices. Recovery of sexual function generally occurs within 6–24 months following surgery. Potency can be improved with early use of PDE-5 inhibitors and other, more aggressive approaches to “penile rehabilitation.” (See Chapter 38 for more information on impotence.)

Radiation Therapy—External Beam Therapy

Traditional external beam radiotherapy (XRT) techniques allow the safe delivery of 6500–7000 cGy to the prostate. Standard XRT techniques depend upon bony landmarks to define treatment borders or a single CT slice to define the target volume. These standard XRT techniques generally involve the use of open square or rectangular fields with minimal to no blocking and are characterized by the use of relatively small boost fields. Often, these XRT techniques fail to provide adequate coverage of the target volume in as many as 20–41% of patients with CaP irradiated.

Improved imaging and use of novel treatment planning (three-dimensional, conformal radiation therapy [3DCRT] and intensity-modulated radiation therapy [IMRT]) allow for better targeting, conforming, or shaping radiation volume more closely around the prostate, and the use of higher doses without exceeding tolerance of surrounding normal tissues. Such radiotherapy has resulted in dramatic reductions in acute and late toxicity of radiation treatment and improved tumor control compared with conventional dose radiotherapy. Doses ≥72 cGy appear to result in improved biochemical outcomes compared with lower doses. Day-to-day variations in patient/prostate position can be accounted for by the use of daily online CT scanning, transabdominal ultrasound imaging, and insertion of an endorectal balloon or imaging of radiopaque fiducial markers placed before treatment. Whole pelvic radiation, including regional lymph nodes, especially when combined with androgen deprivation, has demonstrated improved outcomes in those with intermediate and high-risk prostate cancer, though not all radiation oncologists agree with these findings.

In addition to the use of dose escalation and improved tumor targeting, several investigators have shown that the results of radiation therapy may be improved with the use of neoadjuvant, concurrent, and adjuvant androgen deprivation. On the basis of numerous randomized trials, androgen deprivation improves the outcome of radiation in those with intermediate- or high-risk disease. The use of short-term (3–4 months) neoadjuvant and concurrent androgen deprivation is recommended for those with intermediate-risk disease, whereas those with high-risk disease should receive neoadjuvant, concurrent, and long-term adjuvant (24 months) androgen deprivation (Bolla et al, 2002; Horwitz et al, 2008; Roach, 2003).

As with RP, men who receive radiation may experience side effects especially those related to urinary, bowel, and sexual function. Most such side effects are limited in extent. Although men who undergo surgery are more likely to suffer incontinence, men who undergo radiation are more likely to suffer obstructive or irritative voiding or bowel symptoms (urgency, frequency, diarrhea, hematuria, rectal bleeding, and tenesmus). Although the impact of surgery on sexual function occurs early and may improve with time, the impact of radiation on sexual function may not be seen for 18–24 months. Sexual side effects may be exacerbated with the concurrent use of androgen deprivation, especially if used long term (Wu et al, 2008). Long-term risks, such as urethral stricture, rectourinary fistula, and radiation cystitis, are uncommon but can be quite challenging to manage. There is a doubling of the risk of rectal cancer and bladder cancer starting 10 years after prostate radiation, though the absolute risks of these uncommon tumors remains low (Bhojani et al, 2010).

Novel radiation approaches include stereotactic radiation (eg, CyberKnife) and proton-beam radiation. As with robot-assisted surgery, these technologies are heavily marketed in some areas but have not yet been shown to offer any clear benefit with respect to cancer control or quality-of-life preservation. Unlike robot-assisted surgery, however, in which hospitals absorb the costs of the technology, costs for novel radiation modalities—including IMRT—are borne by payors, and generally much higher than those associated with surgery or brachytherapy.

Readers are referred to Chapter 25 for a more detailed discussion of radiation therapy in CaP.

Radiation Therapy—Brachytherapy

A resurgence in the interest in brachytherapy has occurred because of the technologic developments making it possible to place radioactive seeds under TRUS guidance. Previously, free-hand seed placement techniques were used; however, very high failure rates were observed and the technique was virtually abandoned. Currently, with the use of computer software, one can preplan a precise dose of radiotherapy to be delivered by TRUS guidance. Implants can be permanent (iodine 125 or palladium 103) in that the seeds are placed in the prostate, and the radiation dose is delivered over time or temporary in that the seeds are loaded into hollow-core catheters and both the seeds (iridium 192) and catheters are removed after a short period of hospitalization and radiation exposure. Permanent implants have a lower dose rate, but a higher total dose delivered compared to temporary implants which have a higher dose rate, but deliver a lower total dose. External beam radiation can be given to those with intermediate- and high-risk cancers, who receive permanent brachytherapy, and is routinely given to most who undergo temporary or high dose rate brachytherapy. Some clinicians are determining whether men with low-risk disease can be treated effectively with high dose rate brachytherapy alone without the use of neo- or adjuvant external beam radiation.

As opposed to external beam radiation, androgen deprivation does not appear to improve the outcomes of men with intermediate disease who are treated with brachytherapy. Androgen deprivation is often used to shrink the prostate prior to brachytherapy to facilitate seed placement, though this does come at the price of additional side effects (Potters et al, 2001). Men with high-risk disease who choose brachytherapy receive external beam radiation and adjuvant androgen deprivation as described for those managed with eternal beam techniques alone.

Readers are referred to Chapter 25 for a more detailed discussion of brachytherapy in CaP.

Cryosurgery

There has been a resurgence of interest in cryosurgery as a treatment for localized CaP in the past several years. This is due to an increased interest in less invasive forms of therapy for localized CaP as well as several recent technical innovations, including improved percutaneous techniques, expertise in TRUS, improved cryotechnology, and better understanding of cryobiology.

Freezing of the prostate is carried out by using a multiprobe cryosurgical device. Multiple hollow-core probes are placed percutaneously under TRUS guidance. Most surgeons routinely perform two freeze–thaw cycles in all patients, and if the iceball does not adequately extend to the apex of the prostate, the cryoprobes are pulled backward into the apex and additional freeze–thaw cycles are undertaken. The temperature at the edge of the iceball is 0°C to −2°C, while actual cell destruction requires −25°C to −50°C. Therefore, actual tissue destruction occurs a few millimeters inside the iceball edge and cannot be monitored precisely by ultrasound imaging. Double freezing creates a larger tissue destruction area and theoretically brings the iceball edge and destruction zone edge closer together. An intraurethral warming device minimizes urethral freezing and subsequent sloughing, thus minimizing risk of severe urinary symptoms and/or retention.

With modern (third generation) cryoablation systems, severe complications such as rectourethral fistulas are much less common than they once were. However, erectile dysfunction is very common after cryotherapy, more so than after nerve-sparing surgery or radiation therapy, and cryotherapy has not been widely adopted for primary treatment. However, it is frequently effective for men with biopsy-confirmed locally persistent/recurrent disease after radiation.

Focal Therapy

Prostate cancer tends to be an infiltrative disease, with cancerous glands interspersed with normal ones, and is frequently multifocal. Therefore, focal therapy—treating only the tumor while sparing the normal prostate and surrounding structures—is more challenging than for tumors that grow as discrete lesions. Multiple modalities are under investigation for this purpose—including limited cryotherapy, high-intensity focused ultrasound (HIFU), interstitial laser therapy, and others. There are several challenges to these approaches, chief among which is that PSA is not a reliable indicator of cancer status after focal ablation, so repeat biopsies after treatment are generally indicated. Ultimately, widespread adoption of focal therapy awaits validation of better imaging modalities currently under development that will identify—and ideally grade–prostate lesions with greater accuracy.

Recurrent Disease

Overview

A substantial number of men who are treated with either surgery or radiation for presumed clinically localized prostate cancer will relapse based on evidence of a detectable or rising serum PSA after treatment, respectively. Although a persistently detectable serum PSA after surgery is considered a failure, what constitutes biochemical failure after radiation is a matter of some debate. By one count, 152 different definitions have been proposed: 53 after surgery and 99 after radiation therapy. The AUA endorsed the common surgical definition of PSA ≥0.2 ng/mL with a confirmatory value >0.2 ng/mL (Cookson, 2007). The American Society for Therapeutic Radiology and Oncology (ASTRO) adopted the definition of three consecutive rises in serum PSA above nadir. However, this has since been modified to improve its specificity by defining failure as a rise of at least 2 ng/mL greater than the nadir level. It must be recognized that these definitions are neither intended nor able to allow comparisons between surgery and radiation patients, because the surgical definition will identify recurrence about 5 years earlier than the radiation definition (Nielsen et al, 2008). Biochemical failure may have a variable natural history after any kind of initial treatment and may signify localized disease, systemic disease, or a combination of the two. After either form of treatment, an interval to PSA failure <3–6 years and a posttreatment PSADT <3 months place a man at increased risk for metastases and subsequent prostate cancer–specific mortality.

Following Radical Prostatectomy

The likelihood of recurrence following RP is related to cancer grade, pathologic stage, and the extent of extracapsular extension. Cancer recurrence is more common in those with positive surgical margins, established extracapsular extension, seminal vesicle invasion, and high-grade disease. For those patients in whom a detectable PSA level develops after RP, the site of recurrence (local vs distant) can be established with reasonable certainty based on the interval from surgery to the detectable PSA concentration, PSADT, and selective use of imaging studies. Indeed, the likelihood of ultimate prostate cancer–specific mortality following PSA recurrence after RP ranges from 1% to 99%, depending on the Gleason score, time to recurrence, and PSADT (Freedland et al, 2005). Patients at low risk (eg, long interval to recurrence, slow PSA kinetics) and/or those with limited life expectancy may be observed, those with suspected local recurrence (particularly in the setting of positive margins) may benefit from salvage radiation therapy, and those with probable or documented distant disease should receive systemic therapy with androgen deprivation.

Following Radiation Therapy

A rising PSA level following definitive radiotherapy is indicative of cancer recurrence. For those who undergo radiation and experience biochemical failure as defined earlier, the site of recurrence may be identified using PSA kinetics, time to failure as noted earlier, prostate biopsies, and selective use of imaging. Up to one-third of patients will experience a “PSA bounce” following radiation (especially brachytherapy), which is defined by a rise in serum PSA followed by a decline. Such patients are not at an increased risk of cancer recurrence and repeat prostate biopsy should be deferred in such patients. Most patients who fail radiation therapy, irrespective of the site of recurrence, currently are managed with androgen deprivation. Those with documented local recurrence may be candidates for salvage prostatectomy, cryosurgery, or additional radiation. However, morbidity can be high with these forms of treatment, as is subsequent relapse.

Metastatic Disease

Initial Endocrine Therapy

Since death due to CaP is almost invariably a result of failure to control metastatic disease, a great deal of research has concentrated on efforts to improve control of distant disease. It is well known that most prostatic carcinomas are hormone dependent and that the large majority of men with metastatic CaP respond initially to various forms of androgen deprivation. Testosterone, the major circulating androgen, is produced by the Leydig cells in the testes (95%), with a smaller amount being produced by peripheral conversion of other steroids. Free testosterone enters prostate cells and is converted to DHT, the major intracellular androgen. DHT binds to a cytoplasmic receptor protein and the complex moves to the cell nucleus, where it modulates transcription. Androgen deprivation may be induced at several levels along the pituitary–gonadal axis using a variety of methods or agents (Table 23–4).

Use of a class of drugs (LHRH agonists) has allowed induction of androgen deprivation without orchiectomy or administration of diethylstilbestrol. There are four LHRH agonists currently approved by the FDA for the treatment of prostate cancer: goserelin acetate, triptorelin pamoate, histrelin acetate, and leuprolide acetate. These can be delivered by injection monthly or as depot preparations lasting 3–6 months. A subcutaneous implant that releases leuprolide acetate at a constant rate for 1 year is also available. A second-generation LHRH antagonist (degarelix) was recently released. LHRH antagonists avoid the “flare” phenomenon associated with LHRH agonists, in which serum testosterone concentrations increase before falling. Such an increase could cause symptoms in those with advanced cancer. Currently, administration of LHRH agonists is the most common form of primary androgen blockade used in the United States. Orchiectomy, once common, is much less commonly performed today. Like LHRH agonists, estrogens achieve castration by feedback inhibition of the hypothalamic–pituitary axis and, perhaps, by a direct cytotoxic effect. Although effective, their use is limited due to an increased risk of negative cardiovascular effects. Transdermal preparations are under investigation.

Because of its rapid onset of action, ketoconazole should be considered in patients with advanced prostate cancer who present with spinal cord compression or disseminated intravascular coagulation. Although testosterone is the major circulating androgen, the adrenal gland secretes the androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Prostate cancer cells have also been identified to synthesize androgen directly in the setting of LHRH agonist therapy, thus escaping castration via autocrine pathways. Ketoconazole and the novel agent abiraterone inhibit androgen biosynthesis throughout the body—in the testes and adrenals and within the tumor cells (De Bono et al, 2011).

Some investigators believe that suppressing both testicular and adrenal androgens (combined androgen blockade) allows for a better initial and a longer response compared with those methods that inhibit production of only testicular androgens. Complete androgen blockade can be achieved by combining an androgen receptor antagonist (flutamide, bicalutamide, or nilutamide) with the use of an LHRH agonist or orchiectomy. When patients with metastatic prostate cancer are stratified with regard to extent of disease and performance status, those patients with limited disease and a good performance status who are treated with combined androgen blockade (an LHRH agonist and antiandrogen agent) seem to survive longer than those treated with an LHRH agonist alone (Crawford et al, 1989). However, another study comparing the use of an antiandrogen with and without an orchiectomy failed to demonstrate a survival difference between the two arms (Eisenberger et al, 1998). A meta-analysis of monotherapy and complete androgen blockade for the treatment of men with advanced prostate carcinoma suggested that there might be a small survival advantage to complete androgen blockade. This advantage must be balanced against an increased risk of side effects and costs among those on combined therapy (Samson, 2002), often for a number of years.

Ongoing trials are studying the use of intermittent androgen deprivation to determine whether this might result in a delay in the appearance of the hormone-refractory state. Intermittent therapy, compared with continuous therapy, may be associated with improved quality of life as serum testosterone levels may normalize during periods off therapy. High-dose antiandrogen monotherapy (bicalutamide 150 mg/day) is an alternative to castration both in patients with locally advanced and metastatic disease who are interested in maintaining libido and erectile function. In those with locally advanced disease, no significant difference in overall survival has been demonstrated between bicalutamide monotherapy and castration. However, in those with metastatic disease, castration is associated with better survival, and antiandrogen monotherapy is not commonly used in the United States.

The timing of initial endocrine therapy in CaP has been an area of great debate for many years. Data from the Veterans Administration Cooperative Studies from the 1960s did not demonstrate a clear survival advantage for early intervention with androgen ablation therapy in patients with advanced CaP. However, a randomized study from the Medical Research Council comparing early with delayed endocrine therapy in patients with advanced CaP demonstrated improved survival as well as lower complication rates (cord compression, ureteric obstruction, bladder outlet obstruction, and pathologic fractures) in patients treated with early endocrine therapy (Medical Research Council, 1997).

In patients who undergo RP and are found to have microscopic lymph node involvement, early endocrine therapy has also resulted in a survival advantage (Messing et al, 2006). Most would agree that androgen deprivation should be instituted in all those with metastatic disease, whether symptomatic or not. In addition, there may be an advantage to early therapy in those without radiographic evidence of cancer, but who relapse after initial therapy and are found to have rapid PSADTs as such patients are at great risk of developing metastatic disease early and dying of their disease. Androgen deprivation is not without side effects including hot flashes, anemia, loss of libido and sexual function, loss of bone mineral density, increased weight and body fat, and cognitive changes. In addition, increases in total cholesterol, low- and high-density lipoproteins, and serum triglycerides have been reported. Men on androgen deprivation should be monitored for such side effects as treatment for most is readily available. Many men diagnosed with prostate cancer suffer from low bone mineral density, which can be exacerbated with androgen deprivation therapy. Many agents may prevent generalized and localized bone loss, including calcium and vitamin D supplements and, if significant, bisphosphonates. Anemia is usually mild, but may be managed with recombinant erythropoietin. Although there are a number of treatments for men with hot flashes that are especially troublesome, medroxyprogesterone acetate (300–400 mg IM monthly) is an effective treatment with limited side effects.

Ultimately, most prostate cancers will adapt to survive without androgens, at which point they are denoted “hormone refractory” or “castrate resistant.” The armamentarium available for treatment of advanced prostate cancer in this health state is evolving very rapidly. Briefly, interventions now available include the following:

• Cessation of antiandrogen therapy if the patient has been on combined androgen blockade.
• Secondary hormonal therapy aimed at the androgen biosynthesis pathway (ketoconazole, abiraterone).
• Immunotherapy via administration of autologous dendritic cells primed for recognition of prostatic acid phosphatase (sipuleucel-T).
• Receptor activator of NFκB (RANK) ligand antibody therapy to slow development and progression of bone metastases (denosumab).
• Taxane-based chemotherapy (docetaxel, cabazitaxel).

Other drugs currently in late-stage development include MDV3100, a novel antiandrogen, and XL184, a multityrosine kinase inhibitor.

These agents all have nonoverlapping mechanisms of action, and there is no a priori reason an individual patient could not receive all of them. However, no data exist to guide optimal sequencing of these strategies. Moreover, the costs of expensive novel treatments accumulate very quickly, and there is a clear need for much better personalization of treatment based on biomarkers and other predictors of response currently in development.

Readers are referred to Chapter 19 for a detailed discussion of the therapy for hormone-refractory prostate cancer.

Prostate Gland Anatomy

Benign Prostatic Hyperplasia

Prostate Cancer

Epidemiology and Guidelines

Genetics, Pathobiology, and Pathology

Screening and Chemoprevention, and Biopsy

Serum Tumor Markers

Staging and Risk Assessment

Imaging

Prostate Biopsy

Radical Prostatectomy

Radiation

Active Surveillance

Cryotherapy and Hifu

Quality of Life

Relapse and Androgen Deprivation

Secondary Therapy and Chemotherapy