22 - Prostate Cancer | Smiths General Urology, Seventeenth Edition (LANGE Clinical Medicine)

Authors: Macfarlane, Michael T.

Title: Urology, 4th Edition

> Table of Contents > Part Two - Selected Topics > Chapter 22 - Prostate Cancer

Chapter 22

Prostate Cancer

Prostate cancer is the second most common cause of cancer deaths in men, with close to 35,000 deaths and more than 125,000 new cases per year in the United States. Blacks appear to have a 50% higher incidence and mortality. No clear etiologic factors have been identified, although a familial predisposition has been demonstrated, and an increased risk has been associated with cigarette smoking and a high-fat diet.

Pathology

Greater than 95% of prostate cancers are acinar adenocarcinomas. Other infrequent types include ductal carcinomas and carcinosarcomas.

Ductal Carcinomas

Accounting for less than 5% of prostate cancers, ductal carcinomas include transitional and squamous cell carcinomas, intraductal adenocarcinomas and mixed ductal carcinomas, and endometrioid carcinomas. Patients commonly have hematuria, positive urinary cytologies, and normal prostate-specific antigen (PSA). Treatment is cystoprostatectomy if localized to the prostate. Metastases are generally osteolytic rather than osteoblastic, and most do not respond to androgen withdrawal; however, if elements of acinar adenocarcinoma are present, hormonal therapy may be beneficial.

Carcinosarcomas

These uncommon tumors contain various mesenchymal elements and have a poor prognosis. (The remainder of this discussion will concern only acinar adenocarcinoma of the prostate.)

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Adenocarcinoma of the Prostate

Adenocarcinomas of the prostate arise primarily in the peripheral zone (70%); however, 20% arise in the transition zone and about 5% in the central zone. Spread is by direct local extension and by lymphatic and vascular channels. Invasion of the capsule followed by extension to the seminal vesicles and bladder base indicates a more aggressive tumor. Ureteral obstruction occurs in 10% to 35% of patients with advanced disease. Direct extension to the rectum is rare. Lymphatic drainage is primarily to the obturator and hypogastric nodes. Osteoblastic bony metastasis is the most common location of distant spread, usually in the axial skeleton, such as the lumbar spine, proximal femur, pelvis, thoracic spine, ribs, sternum, and skull. Visceral metastases are commonest in the lung, liver, and adrenals.

Gleason's Grading System

Gleason's system uses five different histologic patterns (1 5) to characterize the degree of glandular differentiation under low-power magnification. It grades the two most representative areas of the tumor, called the primary and secondary grades, and adds those two values, giving a final Gleason score (also known as Gleason's sum or combined Gleason's grade) between 2 and 10. Cytologic features play no role in the grade of the tumor. A high Gleason score indicates increased dedifferentiation, increased risk of nodal metastases, and a more malignant potential. There is good correlation between Gleason's sum and prognosis. Interobserver and intraobserver reproducibility is generally within one Gleason's sum. The presence of Gleason's pattern 4 or Gleason's sum 7 or more is predictive of a poor prognosis.

TNM Staging System

The clinical stage is an assessment of the extent of tumor based primarily on the digital rectal examination (DRE), PSA, and Gleason's grade, in addition to any imaging modalities. The pathologic stage is based on histologic examination of the prostate and lymph nodes after surgical removal. The criteria most predictive of the prognosis are Gleason's grade and pathologic stage, including the surgical margin status, presence of extracapsular disease, seminal vesicle invasion, and involvement of pelvic lymph nodes.

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Nomograms have been developed for the prediction of pathologic stage based on the clinical T stage, PSA level, and Gleason's score from needle biopsy specimens (Partin AW, et al. JAMA 1997;277:1445 1451). These tables have proved useful in counseling men with newly diagnosed prostate cancer about treatment alternatives.

Clinical Staging
T1	Tumor not clinically apparent nonpalpable
T1a	Incidental finding at TURP 5% or less of tissue resected
T1b	Incidental finding at TURP >5% of tissue resected
T1c	Needle biopsy finding nonpalpable elevated PSA only
T2	Palpable tumor confined within the prostate
T2a	Tumor involves one lobe
T2b	Tumor involves both lobes
T3	Tumor extends through prostatic capsule
T3a	Unilateral extracapsular extension
T3b	Bilateral extracapsular extension
T3c	Tumor invades seminal vesicle(s)
T4	Tumor invades adjacent structures (bladder, sphincter, rectum, etc.)
Pathologic Staging
T2a	Organ confined unilateral
T2b	Organ confined bilateral
T3a	Unilateral extracapsular extension
T3b	Bilateral extracapsular extension
T3c	Seminal vesicle invasion
T4	Invasion of bladder or rectum
PSA, prostate-specific antigen; TURP, transurethral resection of the prostate.

Presentation

Prostate cancer is a disease of the elderly, with 75% of patients diagnosed between age 60 and 85 years and a mean age at diagnosis of 72 years. Recent surveys report that an increasing percentage of patients are being diagnosed with earlier stage disease than in the past. The widespread use of the serum PSA test has been important in early diagnosis.

Most patients are asymptomatic at the time of diagnosis. Prostate cancer is most commonly discovered today because of an elevated PSA or abnormal DRE or as an incidental finding on a transurethral resection of the prostate (TURP) specimen. Patients with locally advanced disease may present with lower urinary

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tract symptoms, hematospermia, decreased ejaculate volume, and impotence. Patients with metastatic disease at diagnosis (25%) may present with bone pain, weight loss, anemia, shortness of breath, lymphedema, neurologic symptoms, lymphadenopathy, or urinary retention.

Workup

History

Inquire about bone pain, recent weight loss, shortness of breath, asymmetric swelling of lower extremities, hip or leg pain, difficulty in walking, and voiding symptoms. A family history of prostate cancer is important.

Physical Examination

A DRE by an experienced examiner and a complete physical should be performed.

Laboratory Tests

Serum PSA is the single most important test in the initial diagnosis of prostate cancer. Once a diagnosis has been made, then further workup may include a complete blood count, chemistry panel, and liver function tests including alkaline phosphatase. An enzymatic prostatic acid phosphatase is rarely helpful in the era of PSA.

Prostate Biopsy

A histologic or cytologic diagnosis must be made before undertaking any form of therapy. Two techniques are most common: core-needle biopsy and fine-needle aspiration.

Core-Needle Biopsy

Core-needle biopsy using a spring-loaded gun and a transrectal approach is preferred. The transrectal approach is more accurate and less painful. Complications include sepsis and bleeding. Always give prophylactic antibiotics. Ultrasound-guided transrectal biopsies have become the gold standard because of the added ability to target hypoechoic defects and randomly sample the entire gland in a systematic fashion. A transperineal approach has

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a lower incidence of infectious complications but makes it more difficult to obtain an accurate specimen.

Fine-Needle Aspiration

Fine-needle aspiration is performed using a Franzen needle and a transrectal approach. It has the lowest complication rate but does not give tissue and therefore relies on accurate cytologic interpretation and also does not provide a Gleason grade.

Indications for Biopsy

A palpably suspicious DRE regardless of PSA level
PSA greater than 4.0 ng/mL regardless of DRE or transrectal ultrasound (TRUS)
PSA greater than the patient's age-specific range

Indications for Repeat Biopsy

Persistently abnormal or rising PSA
PSA between 4.0 and 10.0 ng/mL with a low percent free PSA (<15%)
Evidence of high-grade prostatic intraepithelial neoplasia on a prior biopsy

Transrectal Ultrasound

TRUS aids in the localization of prostate cancers and is indispensable for accurate needle biopsy of the prostate. However, TRUS has poor sensitivity and specificity for the detection of prostate cancer. Yet many prostate cancers tend to be hypoechogenic on ultrasound and most frequently are located in the peripheral zone. Negative findings on TRUS do not negate the indications for biopsy.

Indications for Transrectal Ultrasound of the Prostate

To aid prostate needle biopsy
To measure prostate size for PSA density

Imaging Studies

Routine intravenous urography is not recommended. Pelvic imaging with computed tomography or magnetic resonance imaging is only warranted in men with a high risk of metastases (PSA >20 ng/mL, high grade and locally advanced on DRE). They are not routinely used because of low sensitivity in detecting the local extent of disease.

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Nuclear Bone Scan

A bone scan is the most sensitive (97%) test for bony metastases. Look for multiple asymmetric areas of increased uptake in the axial skeleton. Skeletal radiographs may help confirm a positive bone scan. Positive bone scans generally precede radiographic visualization by 3 to 6 months. Serial follow-up scans, after definitive therapy, are often misleading and unnecessary. Repeat scans are indicated in the setting of a rising PSA and for new complaints of bone pain. A bone scan also provides information about possible upper tract obstruction. The probability of a positive bone scan in men with a PSA of less than 10 ng/mL is low.

Lymphangiograms

Lymphangiograms are rarely performed. They have only a 50% sensitivity for detecting pelvic metastasis, and proper interpretation depends on experience.

Pelvic Lymph Node Dissection

A node dissection is the most accurate means of identifying lymphatic involvement and should precede radical surgical treatment. A laparoscopic pelvic lymph node dissection is an option for the patient at high risk for metastatic disease or to stage patients before radiotherapy. Five percent to 10% of men with clinically localized prostate cancer are found to have positive pelvic lymph nodes.

Treatment Options

Total (Radical) Prostatectomy

Any candidates for total prostatectomy should have a better than average life expectancy by virtue of their present age (usually <70 years) and good general health. A radical retropubic prostatectomy, preceded by a negative pelvic lymph node dissection, offers the best chance for cure to patients with clinically localized disease. A nerve-sparing procedure can be performed to preserve potency. Complications following a radical prostatectomy are directly related to the skill and experience of the surgeon. Serious incontinence is less than 2% and impotence is less than 25%. A laparoscopic prostatectomy (hand or robotic assisted) is an option; however, insufficient data are available to demonstrate equivalent results. Laparoscopic prostatectomy is considerably more difficult and takes twice as long to perform, and regional anesthetics are contraindicated.

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Radiotherapy

Irradiation has been used for curative, palliative, or prophylactic treatment for prostate cancer. Modalities include external-beam and interstitial radiation implants.

External-Beam Radiotherapy

Standard external-beam radiotherapy typically delivers a total of 65 to 75 Gy to the prostate over 6 to 7 weeks. Newer techniques of three-dimensional conformal radiotherapy, including intensity-modulated radiation therapy (IMRT) and dynamic IMRT, use complex treatment planning software algorithms achieving exceedingly high doses of radiation delivered to the target, while significantly smaller doses of radiation are given to the adjacent normal tissue. Overall survival data are close to those obtained with surgery in the short term (5 years). However, long-term (10 15 years) biochemical failure rates are considerably higher than those with radical prostatectomy. Complications are generally self-limiting and mainly include diarrhea, rectal irritation, dysuria, and frequency. The appearance of impotence is often delayed and can be expected in about 50% of patients. Neoadjuvant hormonal downsizing of the prostate with luteinizing hormone releasing hormone (LHRH) agonists decreases the target volume and is recommended for large glands.

Interstitial Radiotherapy (Brachytherapy)

Interstitial radiotherapy (brachytherapy) uses the permanent implantation of radioactive seeds under ultrasound guidance. This potentially allows a more accurate and uniform seed distribution than with previous implant techniques and, thus, a more homogeneous radiation dose to the entire prostate gland. Iodine-125 (¹²⁵I) and palladium-103 (¹⁰³P) are the most common seeds used. The principal advantage of brachytherapy is its ability to theoretically deliver more radiation to the prostate with less dose to the surrounding normal tissues. Primary brachytherapy is recommended for older patients (age 70) with low PSA (<10 ng/mL), low-grade (Gleason's sum 6 or less), and low-stage (cT2a or less) prostate cancers. PSA-free survival is not as good as with radical prostatectomy and may not even be as good as with external-beam radiotherapy. Relative contraindications to brachytherapy include very large or very small prostates, severe lower urinary tract symptoms, or a prior TURP.

Palliative Radiotherapy

Palliative radiotherapy (30 Gy over 10 sessions) is effective local treatment for painful skeletal metastases.

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Prophylactic Radiotherapy

Prophylactic radiotherapy to weight-bearing areas such as the spine or femoral neck may help prevent pathologic fractures.

Hormonal Therapy

Normal metabolic functions of prostatic cells are androgen dependent. Testosterone is the major circulating androgen; 90% is produced by the testis (Leydig's cells) and 10% by the adrenals. Androgenic activity in the prostate results from intracytoplasmic conversion of testosterone to dihydrotestosterone (DHT) by the enzyme 5- -reductase. Testicular testosterone production is under the control of LH from the anterior pituitary and the negative feedback effect of testosterone. The anterior pituitary is in turn under control of hypothalamic LHRH. Prostate tissue will atrophy without testicular androgen production. Adrenal androgens are insufficient to sustain normal prostatic metabolism. Prostate cancer is best viewed as a heterogeneous population of both androgen-dependent and androgen-independent cells. Suppression of testosterone stimulation results in atrophy of this androgen-dependent cell population only. The primary tumor volume will decrease by an average of 30% to 40% after androgen withdrawal. Reintroduction of androgens will result in regrowth of the tumor.

The major side effects of androgen withdrawal are loss of libido and potency. Other long-term side effects include hot flashes, osteoporosis, fatigue, loss of muscle mass, and weight gain with increased fat deposition.

Endocrine treatment of prostate cancer is purely palliative. No hormonal treatment regimen of prostate cancer has yet demonstrated improved overall survival.

Methods of Androgen Suppression

Bilateral Orchiectomy

Bilateral orchiectomy (castration) is the single most effective method of suppressing testosterone. It is safe, is immediate, and does not require continued patient compliance. Serum testosterone levels will decrease to 5% to 10% of the original levels within 3 to 12 hours after castration. Hot flashes appear to be less severe and self-limiting with castration compared with LHRH agonist therapy.

Estrogen

Estrogen administration lowers circulating testosterone levels by suppressing pituitary luteinizing hormone (LH) secretion. The

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most commonly used estrogen is diethylstilbestrol (DES). Doses of 5 mg/day have significant cardiovascular side effects, including deep venous thromboses. DES 1 mg orally (PO) daily (qd) is considered safe and produces castrate testosterone levels in most patients. Castrate levels of testosterone will be reached within 21 to 60 days after beginning 3 mg/day DES. Gynecomastia will develop in 70% if pretreatment radiation therapy to the breasts (8 10 Gy over 1 3 days) is not given at least 2 days before starting estrogens.

Progestins

Progestins inhibit pituitary LH release and act as an antiandrogen by binding to DHT receptors, blocking 5- -reductase conversion of testosterone to DHT. However, low-dose DES (0.1 mg daily) must also be given to prevent suppression escape after 6 months of therapy. Megestrol acetate is the most frequently used progestin.

Luteinizing Hormone Releasing Hormone Agonists

Leuprolide (Lupron) and goserelin (Zoladex) are superactive synthetic LHRH agonists that suppress LH and testosterone after an initial stimulation phase. The initial stimulation phase lasts 2 to 3 weeks and causes a flare phenomenon both biochemically and clinically with increased PSA and symptoms such as bone pain. The flare phenomenon can be suppressed by giving antiandrogens such as flutamide (Eulexin), bicalutamide (Casodex), or nilutamide (Nilandron) beginning at the time of initiating LHRH or 1 week before. Flare suppression is recommended for patients with a large tumor burden or symptoms of advanced disease.

LHRH agonists are injected monthly or every 3 months. Compliance can sometimes be a problem, and the cost of these medications is extremely high.

Antiandrogens

Antiandrogens block end organ action of testosterone by competing for androgen receptors. These agents include steroidal antiandrogens; cyproterone acetate and megestrol acetate; and pure antiandrogens, flutamide (Eulexin), bicalutamide (Casodex), or nilutamide (Nilandron). Pure antiandrogens are not effective as monotherapy and are used primarily to suppress the flare phenomenon of LHRH agonists or for total androgen blockade. Total androgen blockade does not result in a survival advantage in randomized trials.

5- -Reductase Blockers

5- -Reductase blockers inhibit the intracellular conversion of testosterone to DHT. These agents have not been proven useful in the treatment of prostate cancer.

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Other Therapies

Other therapies include bilateral adrenalectomies, pituitary ablation (hypophysectomy), glucocorticoid suppression of ACTH, and prolactin inhibitors. None of these is recommended for patients with prostate cancer.

General Guidelines for Using Hormone Therapy

Clear benefits of early hormone therapy in terms of patient survival have not been proven. Therefore, delaying hormone therapy appears reasonable in asymptomatic patients who are still sexually active.
Indications for immediate treatment include pain, neurologic symptoms, bladder outlet or ureteral obstruction, anemia, weight loss, edema, or shortness of breath.
Hormone therapy does not prolong survival in patients with metastatic disease.
Total androgen blockade (i.e., blocking adrenal androgens) has no survival advantage.
Orchiectomy is the safest and most dependable method of testosterone suppression.
LHRH agonists should be avoided in patients with significant spinal metastases.
DES 1 mg PO qd is still an acceptable and cost-effective alternative for patients who refuse orchiectomy and are not at increased risk for cardiovascular side effects. Prophylactic breast irradiation is recommended. Testosterone levels should be checked if PSA fails to suppress.

Chemotherapy

Overall results from chemotherapeutic trials have been disappointing. Recent studies of docetaxel-based chemotherapy regimens in patients with androgen-independent metastatic prostate cancer have demonstrated short-term (6 to 9 months) improvement.

Treatment Guide

Local Disease

Total prostatectomy offers the best chance for a durable long-lasting cure from localized prostate cancer. Failure can only occur

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because of understaging the disease. All tumor within the prostate is permanently eradicated. If the prostatectomy is performed by an experienced surgeon, the side effects are generally negligible in appropriately selected patients. Patients who fail locally after a radical prostatectomy may still be eligible for cure with adjuvant external-beam radiotherapy.

External-beam radiotherapy using three-dimensional conformal techniques is an excellent primary alternative for patients with localized disease who may be older or who are poor surgical candidates. Interstitial radioactive seed implantation should be limited to patients with low-grade, low-stage disease and no contraindications. All forms of radiation therapy have the added risk of local failure in the retained prostate in addition to failure because of understaging. Total prostatectomy after local failure of radiotherapy has limited application because of the high complication rate.

Advanced or Metastatic Disease

Endocrine therapy is the primary treatment for patients with locally advanced or metastatic disease.

Emergency Treatment

Occasionally, patients present with untreated metastatic prostate cancer and signs of incipient spinal cord compression (e.g., lower extremity weakness and lax anal sphincter tone). These patients need emergency treatment to decrease tumor mass and relieve cord compression. Motor function is lost first with spinal cord compression, and pinprick sensation is the last to go. Patients who have retained pinprick sensation may safely be given a trial of other forms of treatment before resorting to a decompression laminectomy. Neurologic consultation should be obtained.

Options

Emergency bilateral orchiectomies
Ketoconazole [400 mg PO every 8 hours (q8h)]
Intravenous DES (Stilphostrol)
Radiotherapy
Emergency decompression laminectomy