new toolz n techniques for prostate cancer

New tools and techniques 
for managing prostate cancer

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Markian R. Iwaszko, MD Sameer A. Siddiqui, MD Matthew T. Gettman, MD
Department of Urology, Mayo Clinic Rochester, MN

The incidence is up, deaths have declined, and robotic-assisted prostatectomy is gaining favor.

Prostate cancer is the most commonly diagnosed cancer in men in the United States, and its incidence grows yearly. The American Cancer Society estimates 186,320 new cases of prostate cancer and 28,660 deaths in 2008.¹

Despite escalating rates of diagnosis, the mortality rate of prostate cancer continues to decline. This can be attributed to better utilization of PSA—prostate-specific antigen—screening in a population with a high prevalence of previously unrecognized disease.²

Fast Track Active surveillance involves quarterly PSA testing and DRE along with biennial biopsies. Watchful waiting holds off treatment until metastatic disease develops.

This article updates the medical and surgical standards for diagnosis and treatment of prostate cancer. Treatment options range from conservative to proactive, including robotic-assisted surgery.

EPIDEMIOLOGY

The incidence of prostate cancer peaked in 1992, five years after the PSA was introduced. It subsequently declined until 1995, at which point the incidence began to rise again, albeit at a slower rate.

However, the PSA has also contributed to the diagnosis of more organ-confined and less metastatic disease (FIGURE 1), improving survival rates.

Currently the 5- and 10-year survival rates of all stages of prostate cancer combined are 100% and 92%, respectively.¹

The true impact of screening on prostate cancer mortality, however, will not be fully realized until two randomized trials are completed: the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; and the European Randomized Study of Screening for Prostate Cancer.

FIGURE 1 PSA influence on prostate cancer diagnosis and outcomes Since the PSA test was introduced, more men have been diagnosed with prostate cancer but fewer have died from it. Source: Mayo Clinic, unpublished data.

RISK FACTORS

Well-defined risk factors for prostate cancer are age, family history, and race. Prostate cancer is diagnosed in few men under 50, but increases significantly with age. Microscopic evidence of prostate cancer at autopsy has been demonstrated in about 50% of men in their sixties and more than 75% of men over 85.³

The relative risk of developing disease also rises with the number of family members affected, the age at which they were affected, and the degree of relation.⁴

An individual is at significantly greater risk when the index prostate cancer is at a young age or in a first-degree relative. Chemoprevention has been proven to reduce the risk and incidence of prostate cancer (BOX).

Approaches for preventing prostate cancer Strategies for prostate cancer chemoprevention can be broadly separated into two areas: Hormonal. Prostate cancer is androgen-sensitive, affected by the influences of testosterone and its derivative, dihydrotestosterone, converted by the enzyme 5-alpha reductase. Androgens are responsible for the development and maturation of the prostatic epithelium and a lifetime of exposure undoubtedly plays a role in prostate carcinogenesis. The amount or duration of androgen exposure and its relationship in developing prostate cancer, however, is unknown. Finasteride, a 5-alpha reductase inhibitor, is the only agent proven to reduce the risk of prostate cancer in a placebo-controlled, prospective trial.5 However, finasteride has not been used widely. This is secondary to the increased finding of high-grade disease noted in participants in the treatment arm compared with the placebo. Hormonal manipulation with dutasteride, another 5-alpha reductase inhibitor, is now being studied to determine the effects on prostate cancer risk in men with prior negative biopsies.6 Nutritional. Vitamins A, D, and E, and the supplement selenium have been associated with prostate cancer risk reduction. Strong data in chemoprevention have been obtained in association with vitamin E and selenium through the SELECT trial.7 Diets high in lycopenes have been associated with reduced risk secondary to their antioxidant capability.8 On the contrary, diets high in polyunsaturated fat have been linked to an increased risk. However, within-country studies of dietary factors have not substantiated this finding.9—MRI, SAS, MTG

RACE AS A FACTOR

Black men have the highest reported incidence of prostate cancer worldwide. Comparatively, black men have a relative prostate cancer incidence of 1.6 compared with white men, and have a 2.4 times higher cancer-related mortality rate.¹

Authors have developed multiple theories to explain this discrepancy. They include genetic predisposition, or environmental, socioeconomic, and biologic influences. However, no data have suggested any factor is primarily responsible, so the difference in incidence and mortality rate is likely multifactorial.

Fast Track Radical prostatectomy is the most common robotic operation in the world.

ENVIRONMENTAL RISK FACTORS

Environmental factors have also proven somewhat influential in modifying prostate cancer risk. Asian men have the lowest rates of incidental prostate cancer, but immigrants to the United States from Japan and China have demonstrated an increased incidence.³ In a similar fashion, the increased westernization of Japan has led to incidence and mortality trends that mimic the United States.

SCREENING FOR DISEASE

Authors have not defined an absolute age requirement when screening should begin, but they have reached a consensus that biopsy is the definitive measure to obtain a diagnosis. The American Urological Association has recommended that men should at least begin screening at the age of 50 with PSA and digital rectal examination (DRE).¹⁰

In the individual at elevated risk, screening should begin earlier. No threshold PSA for biopsy has been established, although many clinicians have utilized a cutoff of 4.0 ng/mL.

The trade-off lies in the balance of detecting clinically significant prostate cancer while minimizing the need for unnecessary biopsies. As such, some institutions such as the Mayo Clinic favor the use of age-adjusted cutoff levels for PSA with an aim of increasing the sensitivity and reducing the specificity of the test.

OTHER DETERMINANTS FOR BIOPSY

Besides absolute PSA levels, the following measures have been utilized as guides for obtaining biopsy:

• PSA density (PSA divided by prostate volume) has been shown to account for an increased risk of prostate cancer and not prostatic growth secondary to benign hyperplasia. A threshold value of 0.15 can indicate a need for prostate biopsy with PSA levels between 4–10 ng/mL.¹¹

• PSA velocity determines the trend at which the PSA rises. PSA can fluctuate physiologically through short periods secondary to manipulation, infection, or benign growth. However, when comparing men with and without prostate cancer, the rate of PSA rise seen in malignancy is more rapid, generally exceeding 0.75 ng/mL annually.¹²

• Free PSA/PSA ratio, or the unbound portion of total PSA, can aid in stratifying individuals at risk. At levels of 4–10 ng/mL, free PSA/PSA ratios can help distinguish elevations in PSA associated with benign growth compared with malignant expression. Ratios vary, but typically men with a ratio below 0.10 have greater than 50% chance of having prostate cancer diagnosed upon transrectal needle biopsy.¹³

TREATMENT OPTIONS

The choice of treatment for prostate cancer is typically dictated by patient preference, age and health status, serum PSA, clinical stage, and grade. Options include active surveillance, androgen deprivation, external beam radiation therapy, brachytherapy, and radical prostatectomy.

The American Urologic Association recently published guidelines to facilitate decision-making for treatment (TABLE 1).¹⁴

TABLE 1Risk stratification for decision-making¹⁴

Risk Level	PSA score	Gleason score	Clinical stage
Low	<10	<6	T1c or T2a
Intermediate	10–20	7	T2b
High	>20	8–10	T2c
Source: American Urology Association

CONSERVATIVE APPROACHES

The significant disparity between prostate cancer incidence and mortality suggests that some men may not benefit from treatment of localized prostate cancer. Autopsy studies have shown that up to 75% of older men have at least microscopic evidence of prostate cancer.3

The patient selecting active surveillance undergoes quarterly PSA testing and DRE along with biennial biopsies. If the PSA rises or DRE or biopsy, or both, demonstrate stage or grade progression, treatment is indicated.

Active surveillance is different than watchful waiting, which also employs a conservative approach. The latter waits until the patient develops metastatic disease that requires palliative therapy.

The suitable candidate for active surveillance has a lower-risk tumor and a life expectancy typically less than 10 years. The patient with a high-risk tumor, including high grade and high stage, or greatly elevated PSA is not a candidate for active surveillance.

BRACHYTHERAPY

Interstitial brachytherapy involves the placement of radioactive iodine or palladium seeds via a transperineal approach, and under guidance of a transrectal ultrasound.

This treatment is usually reserved for the patient with low-risk disease, although some physicians have used this treatment in the intermediate-risk patient.¹⁵ Brachytherapy also has been used in combination with androgen deprivation and external beam radiation therapy.

EXTERNAL-BEAM RADIATION THERAPY

Prostate cancer has been treated with external beam radiation therapy (EBRT) since the 1930s. Computed tomography-based treatment planning has improved the accuracy of delivery, limiting toxicity to adjacent organs, such as the bladder and rectum. Aside from a few exceptional circumstances, the patient of almost any age or general medical condition is a candidate for EBRT.

EBRT with dose escalation is typically used in the low-risk patient. The intermediate-risk patient usually undergoes EBRT with a short course (6 months) of hormonal treatment. The high-risk patient has a longer course of adjuvant hormonal, typically up to 3 years.

Evidence-based recommendations Digital rectal examination and PSA are complementary and should be utilized in combination for assessing prostate cancer risk. Level of evidence: 1b—individual randomized clinical trial (RCT). Utilization of free PSA percentage can enhance differentiation of prostate cancer from benign prostatic disease. Level of evidence: 1b. Watchful waiting reserved for individuals with shorter life expectancy due to higher rates of local progression, metastases, and cancer-specific mortality. Level of evidence: 1b. Robotic-assisted laparoscopic prostatectomy achieves functional results similar to open radical retropubic prostatectomy. Level of evidence: 2a—systematic review of cohort studies.—MRI, SAS, MTG

RADICAL PROSTATECTOMY

In this operation, the entire prostate gland and attached seminal vesicles and ampulla of the vas deferens are removed. Radical prostatectomy can be performed by a retropubic incision (most common), perineal incision, or robotic-assisted or laparoscopic technique.

Because the entire gland is removed, radical prostatectomy is an excellent curative treatment for low- and intermediate-risk disease. The high-risk patient may benefit from a short course of adjuvant hormonal treatment or EBRT. Salvage EBRT can also be used for recurrent disease after prostatectomy.

ROBOTIC-ASSISTED PROSTATECTOMY

Known as RALP, robotic-assisted radical prostatectomy uses the da Vinci Surgical System (Intuitive Surgical, Inc, Sunnyvale, CA). It has become increasingly common in the United States. More than 50% of all prostatectomies in the United States may be performed robotically (FIGURE 2).

Radical prostatectomy is the most common robotic operation in the world. Early results suggest that RALP is comparable to radical prostatectomy, although long-term outcomes concerning erectile function, continence, and disease recurrence are still pending.

FIGURE 2 Robots gaining larger share of prostatectomies By 2006, the last year for which statistics are available, robotic-assisted procedures accounted for 48% of the prostatectomies in the United States. Source: Intuitive Surgical, Inc.

COMPLICATIONS OF TREATMENT

Immediate complications of prostate cancer therapy can include perioperative problems such as anemia, ileus, deep-vein thrombosis, pulmonary embolus, and cardiovascular morbidity. These tend to be associated more with prostatectomy due to the more invasive nature of these surgical procedures.

Late complications include urinary incontinence and erectile dysfunction, and can manifest in varying degrees depending on the treatment modality instituted, history of pelvic surgery and radiation, and skill of the surgeon.

Disclosure

The authors had no affiliations to disclose.

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