Introduction

Prostate cancer was a prominent topic at this year's annual meeting of the American Urological Association (AUA) in Anaheim, California. This is hardly surprising given the prevalence of the disease as well as the controversies (both within and outside the urologic community) that surround its diagnosis and management. This review will summarize some of the more exciting developments in the field of prostate cancer research which, this year, focused primarily on treatment patterns.

Localized Disease

Surgery remains a mainstay treatment for localized prostate cancer. However, the continued absence of definitive head-to-head studies comparing surgery to other treatment modalities makes it difficult to objectively evaluate its effectiveness. During the meeting, the latest version of the AUA Prostate Cancer Management Guidelines was released.^[1] The lack of definitive data on a number of issues is evident throughout the document. Still, radical prostatectomy remains an effective treatment for prostate cancer.^[2-4] An important advance over the past few years has been the acceptance and dissemination of robotic surgery.

Robotic Surgery. Despite its popularity among surgeons and patients alike, few studies have demonstrated any advantage of robotic surgery over open surgery. Few topics in urology engender as much discussion and debate. To help solve this argument, investigators from Vanderbilt University presented their data from a perspective study comparing urinary function between open and robotic radical prostatectomy.^[5] Three hundred and twenty patients were evaluated for urinary control using validated questionnaires. No differences in incontinence between the groups were noted at 3, 6, 9, and 12 months. This is a start, although additional objective and prospective studies are needed to establish what, if any, advantages there are to robotic and/or open surgery with regard to quality-of-life issues, including sexual function.

Lymph Node Dissection. The impact of lymph node dissection is particularly relevant to the increased acceptance of robotic surgery. In many centers that offer robotic prostatectomy, pelvic lymphadenectomy is not routinely performed. At last year's AUA conference, international data supported the use of an extended and more aggressive dissection in men with "high-risk" features (perhaps in combination with systemic therapy). Similar findings were presented again this year,^[6] and such an approach is becoming standard practice among urologists. A recurring question, however, is whether pelvic lymphadenectomies are necessary in all prostatectomy patients. Clearly, lymphadenectomy would be warranted if it could be shown to improve survival in patients with unanticipated nodal metastases. Investigators from the Mayo Clinic reviewed their experience in 10,261 men who underwent prostatectomy for all risk strata.^[7] Of this group, 507 had lymph node-positive disease. The 5- and 10-year rates of biochemical free survival were 69% and 56%, respectively, and the 5- and 10-year rates of cancer-specific survival were 94% and 86%. Patients treated with adjuvant androgen deprivation therapy had improved biochemical-free survival, but showed no differences in progression-free or cancer-specific survival. These studies continue to demonstrate excellent long-term cancer control in prostatectomy patients with lymph node metastasis. The timing of adjuvant therapy, if at all, needs to be established.

Watchful Waiting. The use of active surveillance is becoming increasingly popular among patients and their physicians. Criteria have been established to identify optimal candidates.^[8] For these select patients, long-term progression-free survival can occur in the absence of any definitive treatment. Stattin and associates^[9] reported on a series of 2,009 Swedish men followed with active surveillance. The men included in this analysis were younger than 70 years of age, with T1/T2 tumor with no signs of metastases, and serum prostate-specific antigen (PSA) below 20 ng/mL. At almost 5-year mean follow-up, 50% were free of biochemical progression and 86% were free of radiologic or symptomatic progression. A third of the men received treatment, more than half of those by patient choice. Survival data were not presented. The University of Miami experience with active surveillance was also presented.^[10] One hundred and twenty-four men enrolled over a 14-year period were followed (for an average of 3.4 years). There were no prostate cancer-related deaths in the entire cohort, and 80 men (85%) remained on active surveillance without evidence of disease progression. While active surveillance with delayed intervention is believed to be a viable management for many men with early prostate cancer, specific recommendations on how to follow these patients have not been established. Many physicians use a confirmation biopsy before initiating active surveillance. Data from Johns Hopkins University suggest that in the modern era of routine 12-core biopsies, such confirmatory repeat biopsies are not indicated.^[11] As more men and their physicians embrace the use of active surveillance, standardized follow-up protocols incorporating PSA serology, digital exams, and biopsies will be established.

High-Risk and Locally Advanced Disease

While there is a trend toward less aggressive treatments in men with early prostate cancer, the opposite tendency is occurring in high-risk and locally advanced patients. Studies continue to demonstrate favorable outcomes in a significant proportion of men with adverse clinical features when they are treated aggressively with surgery with the intent to cure. Risk stratification is still inadequate, however, and improved identification and classification of men with high-risk and locally advanced disease is needed.^[12]

High-risk Disease. Men with high-grade (Gleason score ≥ 8), high-volume, and high PSA-producing clinically localized tumors have a particularly poor prognosis. Treatment strategies for these "high-risk" patients are evolving and often involve multimodal therapy, combining surgery (or radiation) with systemic therapy. Unfortunately, as investigators from Memorial Sloan Kettering demonstrated, the definition of "high-risk disease" can be quite variable, especially with regard to extraprostatic extension and the definition of biochemical recurrence.^[13] Because of these differences, not only are treatments inconsistent from institution to institution, but outcomes also vary widely. This can make it confusing for surgeons and patients alike in deciding who will most benefit from definitive therapy and which treatment to use. Such confounding features were revealed in a multi-institutional study evaluating outcomes in 8620 men with high-risk features treated with radical prostatectomy.^[14] Of the total study population, 5-year and 10-year biochemical-free survival was 78.6% and 68.7%, respectively. While this demonstrates the effectiveness of radical prostatectomy in the high-risk population, specific features resulted in poorer outcomes. Five- and 10-year biochemical-free recurrence for patients with clinical T3 disease, Gleason score ≥ 8, and preoperative PSA ≥ 20 ng/mL are given in the Table.

Table. Five- and 10-Year Biochemical-Free Recurrence (BCR) by Selected Risk Factors

While all of these men are high-risk, men with those particular features need to be identified as particularly worrisome subpopulations. This variable and inconsistent response of high-risk patients to radical prostatectomy was shown in several other studies,^[15,16] again signifying that an improved risk-stratification system is needed. Such a development will also help identify which patients with locally advanced disease are likely to have better outcomes, as not all of these men respond similarly to surgery, as seen below.

Locally Advanced Disease. The surgical treatment of locally advanced (clinical stage T3) prostate cancer has been controversial. Historically, despite a 25% to 30% incidence of pathologic downstaging to stage T2, the rates of residual and recurrent disease have been high. Several studies presented at the meeting demonstrate favorable long-term outcomes in men with locally advanced disease. In the study with the longest follow-up, Freedland and associates^[17] summarized the Johns Hopkins University experience with clinical stage T3 disease. They were able to identify 56 men treated with surgery alone for clinical T3 disease with a median follow-up of more than 10 years. Of the 56 men, 51 (91%) had pathologic T3 disease. At 15 years, biochemical-free survival was 49%, metastasis-free survival was 73%, and cause-specific survival was 84%. These results are comparable to those obtained with combined radiation and androgen-deprivation therapy, currently the standard treatment for locally advanced prostate cancer, and suggest that both surgery and radiation should be considered for men with pathologic stage T3 stage for intended cure as well as amelioration of symptoms of both local and systemic disease. Given the inherent side effects of surgery and the potential need for more extensive resection (ie, non-nerve-sparing surgery) in men with locally advanced disease, identifying those patients best-suited for surgical treatment is paramount. The authors determined that PSA doubling time was predictive of failure: a PSA doubling time of less than 9 months was a significant predictor of prostate cancer death, whereas no patient with a PSA doubling time of more than 9 months died of prostate cancer. In addition, the finding of lymph node metastasis at the time of surgery was also predictive of prostate cancer death; these men may benefit from the early application of adjuvant systemic therapy. The mechanisms of early subclinical (micro-) metastatic dissemination and the impact of systemic therapy on its progression is currently being elucidated.^[18]

Surgical Margins. It has long been known that a positive surgical margin in a radical prostatectomy specimen has a significant impact of disease recurrence. This was confirmed in several studies which demonstrated a significant increase in biochemical recurrence after prostatectomy in pathologically localized disease.^[19,20] Not all patients with positive margins have the same outcome, however. In a multi-institutional study evaluating outcomes in 8620 men, the effect of a positive surgical margin was evaluated in men with favorable risk (PSA < 10 ng/mL, Gleason score ≤ 6, pathologic stage T2/N0), unfavorable risk (PSA > 20 ng/mL, Gleason score ≥ 8, pathologic stage T3 or N1), and intermediate (everything in between).^[21] While the presence of a surgical margin increased the risk for recurrence in all patients, the impact of a positive surgical margin was greatest in the favorable group (whose risk of 5-year biochemical recurrence was 4.3 times higher for those with positive margins than those with negative margins) as compared with the intermediate group (where the risk for biochemical recurrence was 2.3 times higher in men with positive margins), and unfavorable (1.5 times higher risk for positive margins). This is not surprising because the men with intermediate and unfavorable features are more likely to harbor metastatic disease, resulting in a greater risk for systemic failure. The appropriateness and timing of adjuvant therapy for these patients needs to be established.

Advanced Disease

Androgen-deprivation therapy remains the cornerstone of treatment of metastatic disease. New chemotherapeutic and targeted agents as well as new combinations of established and novel agents are being investigated. Preliminary studies using these agents indicate improvements in survival for patients with androgen-independent disease and delayed disease progression when used in the adjuvant setting after surgery or radiation. However, larger phase 3 trials are needed to establish the optimal agent(s) and regimens for advanced disease. Until then, androgen-deprivation therapy will remain at the forefront.

Androgen-deprivation Therapy. The use of androgen-deprivation therapy is ubiquitous in advanced disease, and is often incorporated in the treatment platforms for high-risk localized, locally advanced, and recurrent prostate cancer. Because of the increased use of androgen-deprivation therapy, there is an increased awareness of the side effects from this form of treatment. Bone loss and its treatment is well documented.^[22,23] Now, several studies have focused on the cardiovascular complications of androgen-deprivation therapy, which are being seen more often corresponding with its increased utilization.^[24,25] Physicians need to be especially cognizant of these effects and intervene as soon as they present.

The Future

Exciting advances in the management of prostate cancer are occurring every day. At next year's meeting, expect to see data in the following areas: (1) definitive prospective comparison studies of cancer control and quality-of-life outcomes in open and robotic prostatectomy; (2) expanded stratification of risk among patients with localized disease; (3) improved standardization of adjuvant and salvage therapies for preventing and treating recurrent disease; and (4) results from phase 3 trials investigating new systemic therapies for prostate cancer.

References