THE "NEW" PROSTATE CANCER INFOLINK

In reviewing the many prostate cancer presentations given at the AUA during last week, we have noted several that are certainly worth bringing to the attention of our readers and that have not previously been reported.

The Importance of Regular PSA and DRE Testing

Griffen et al. reviewed data from their series of 35,456 men enrolled in a longitudinal prostate cancer screening study between 1989 and 2001. These men were all asked to return for PSA and DRE testing on an annual or semi-annual basis, depending on the results of their prior tests. Prostate biopsy was recommended for a suspicious DRE or a PSA level >4.0 ng/mL (until 1995) or >2.5 ng/mL (after 1995).

A total of 14,602 men (41 percent) had a suspicious PSA or DRE during at least one of their screening visits; 10,137 men (29 percent) underwent a biopsy, and 3,367 (9 percent) were diagnosed with prostate cancer. The breakdown of diagnosis in relation to number of screening vists was as follows:

• 2,332 men (69 percent) were diagnosed after at least 2 screening visits
• 1,936 men (57 percent) were diagnosed after at least 3 visits
• 738 men (22 percent) were diagnosed after at least 10 visits
• 33 men (10 percent) were diagnosed after at least 15 visits.

Overall, 520 (15 percent) of the detected cancers had a biopsy Gleason score >6. Specifically:

• 341 (66 percent of Gleason >6 cancers) were diagnosed after at least 2 screening visits
• 291 (56 percent) after at least 3 visits
• 144 (28 percent) after at least 10 vsists
• 57 (11 percent) after at least 15 vsists.

Of the 3,367 men who were diagnosed with prostate cancer, 2,193 underwent radical prostatectomy and 1,583 (72 percent) of these men had organ-confined disease with clear surgical margins.

The authors recommend that annual prostate cancer tests must be continued to be effective in accomplishing the goal of early diagnosis. They note that > 50 percent of the prostate cancers diagnosed during their study were detected after at least 3 screening visits, and 10 percent were not diagnosed until after at least 15 visits. Thy further point out that a considerable proportion of the men diagnosed with prostate cancer after many serial visits had high-grade disease, suggesting that a substantial number of significant prostate cancers would have been missed without continued annual screening.

The Risks for and Predictors of a Future Positive Biopsy in Men Having a Negative Result After a ”Repeat” Saturation Biopsy

Baccala et al. sought to determine the risk of future prostate cancer in patients having a negative result after a ”repeat” saturation biopsy, and the criteria that should be used in deciding whether to do a follow-up biopsy in a patient with such a negative result.

They retrospectively evaluated 576 patients who had a “repeat” saturation prostate biopsy between April 2002 and March 2007. The definition of a “repeat” saturation prostate biopsy was a patient who had had two biopsies or more with the last one being a saturation biopsy of 20 cores or more. The patient’s PSA was repeated yearly and any repeat biopsy was performed if the PSA rose significantly after their preceding biopsy. They excluded all patients who had a previous positive biopsy for prostate cancer. They analyzed PSA, age, race, number of previous biopsies, number of cores taken, presence of PIN, inflammation, and atypia on pathology specimens, total prostate volume, and digital rectal exam (DRE) results of all patients involved.

Baed on the 576 patients with repeat saturation biopsies, their results were as follows:

• 386 patients (67 percent) with an average age of 64 years had negative biopsies.
• Of these 386 patients with negative repeat saturation biopsies, 18 (4.7 percent) developed prostate cancer at some point in the future (cases), but the majority of patients (95.3 percent) remained prostate cancer free during the follow-up period.
• Only the presence of atypia and increasing PSA of >1 ng/ml were predictors of a future risk of prostate cancer.

Baccala et al. concluded that patients with a history of negative saturation biopsy of > 20 cores have only a 5 percent chance of developing prostate cancer in the future, and that only those patients with increasing PSA > 1 ng/mL and with atypia on their prostate biopsy should be followed more closely as they do have a chance of developing future prostate cancer even with a negative repeat saturation biopsy.

The Impact of Prior TURP on Surgical Margins in Patients Undergoing Robot-Assisted Laparoscopic Radical Prostatectomy

Hampton et al. at the City of Hope medical group examined their IRB-approved database to determine whether patients who had undergone a prior transurethral resection of the prostate (TURP) for treatment of urinary retentioan had higher rates of positive margins than those patients who had no history of TURP when subsequently treated for prostate cancer with robot-assisted laparoscopic radical prostatectomy (RALP).

According to their data, between July 2003 and March 2007, four urologic surgeons in their group (City of performed RALP on 2,041 patients. Consent to examine the patients’ records was obtained from 1,768 of these patients. Of the 1,768 patients, 51 (2.9 percent) had undergone a prior TURP. TURP patients were matched for age and nerve-sparing status in a 2:1 ratio with patients who had not undergone TURP prior to their RALP. Pathology records were reviewed to determine prevalence and location of positive margins. An analysis of the vailable data showe the following:

• Patients with a history of TURP before undergoing RALP had positive margin rates of 35.3 percent (18/51) compared with 17.6 percent (18/102) for patients without a history of TURP.
• The location of the positive margins was more prevalent at the bladder neck in TURP patients (13.7 vs. 2.0 percent) than non-TURP patients.
• Although urethral and radial resection positive margins were somewhat higher in TURP patients (11.8 vs. 5.9 and 21.6 vs. 14.7 percent, respectively), these results were not statistically significant.
• The two patient groups were statistically similar in other variables examined including race, body mass index, preoperative PSA, Gleason score, clinical, and pathologic stage.

The authors concluded that, in their series, patients undergoing RALP some time following TURP had higher rates of positive margins and the location of the positive margins in these patients was more likely to be located at the bladder neck than was the case for non-TURP patients. They suggest that surgeons practising RALP should keep this information in mind when performing prostatectomies for cancer in men with a prior histtory of TURP.

Post-Surgical Penile Rehabilitation Following Radical Prostatectomy

Erectile dysfunction (ED) is a common consequence of radical prostatectomy (RP) with a reported prevalence in 9 to 93 percent of patinets. Mulhall and Donatucci debated current views on how and when penile rehabilitation is given and whether it works effectively. The purpose of penile rehabilitation is to provide oxygen to the corpora cavernosa for both prevention and recovery of erectile function in post-RP patients.

Dr. Mulhall too k the position that the goal of penile rehabilitation is to prevent structural alterations and thus to maximize the chance of a man returning to his preoperative sexual performance. He stated that minor neuropraxia results in vascular, neural and smooth muscle injury, and that the erect penile state and oxygenation turns off TGFβ and decreases collagen production. He went on to argue that hyperbaric oxygen and cavernosal nerve injury had improved return of erectile function compared to controls in a rat experiment. The later men present with their ED post-RP, the worse their venous leak problem and resultant structural changes and fibrosis in the penis.

Mulhall went on to argue that early use of PDE5 inhibitors such as Viagra preserves penile processes in animal models, and that three clinical trials of injection therapy and sildenafil improved erectile response post surgery. Biopsies of penile tissue at 6 months post-RP in men treated with PDE5 inhibitors had preservation of smooth muscle content. Smooth muscle preservation in both the corpora and endothelium are the reasons that penile rehabilitation makes sense, he concluded.

Dr. Donatucci argued that a sufficient body of evidence supporting penile rehabilitation may not be presently available. He took the position that an effect in animals does not equate with the same response in humans, and only focuses on a specific mechanism not the entire system. He also noted that nerve sparing is not a standardized event, that there is a lack of standardized algorithms, and that outcomes at specific centers can not be translated to general populations.

Donatucci also showed that clinical trials that were not positive between on-demand and daily use of PDE5 drugs. He observed that there are seven ongoing trials for penile rehabilitation. However, most of these trials are single investigator and not multi-center trials, and that some are in radiotherapy patients and not in surgical series. He concluded that, in his opinion, there is not enough evidence to support penile rehabilitation in an evidence-based fashion at the present time.

The “New” Prostate Cancer InfoLink certainly concurs with Donatucci’s position to the extent that large, weel-structured, randomized, multicenter trials would certainly help us to understand the value of penile rehabilitation in prostate cancer patients (post-surgery and post radiation therapy). In the meantime, patients need to take the best advice they can get regarding the use of PDE5 inhibitors, injection therapy, and other forms of post-treatment penile rehabilitation if this is an issue that is of importance to them and their partner.

Salvage Radical Prostatectomy  Following Failure of Radiation Therapy in Treatment of Localized Disease

The use of radical prostatectomy to salvage men with prostate cancer who fail radiotherapy (RT) is still controversial. Historically, low cure and high complication rates have limited its use. With increases in the number of men opting for RT as primary therapy for prostate cancer, salvage radical prostatectomy (SRP) is re-emerging as a potential treatment for recurrent disease. The CALGB 9687 trial was a small prospective study designed to evaluated the efficacy and morbidity of SRP in a contemporary multi-institutional series.

Forty-one eligible men with biopsy-proven recurrent prostate cancer after RT with  >60 cGy as primary treatment for cT1-2NxM0 prostate cancer were enrolled. The men had to have a pre-RT PSA of  < 30 ng/mL and a Gleason sum < 7. Eligibility for SRP included a positive biopsy, no metastases, PSA < 20 ng/mL. They most also have completed RT > 18 months earlier and completed any hormonal therapy  > 3 months earlier. Pathological finding, surgical morbidity, quality of life, and disease-free and overall survival were evaluated.

The results of the study to date are as follows:

• 24 patients had external beam RT, 11 had brachytherapy, and 6 had both.
• Median time to post-RT PSA nadir was 30 months and the median time between RT and SRP was 63.6 months.
• The median age at time of SRP was 63.9 years and the median PSA was 4.1 ng/mL.
• Median operative time was 251 minutes.
• Pathologic staging showed 44 percent pT2, 53.7 percent pT3, and 2.5percent pT4; 17 percent had a positive surgical margin.
• All men underwent pelvic lymphadenopathy and 88 percent were pN0.
• 24 percent required blood transfusion.
• Three rectal (7 percent) and 1 obturator nerve (2 percent) injuries occurred.
• Four men (10 percent) had anastomotic urinary leaks; bladder neck contractures occurred in 12 (29 percent); and 17 men (45 percent) had incontinence (> 3 pads/day) prior to SRP.
• Among all 41 patients, the time to first incontinent-free rates at 3, 6, and 12 months post-surgery were 90, 18, and 9 percent respectively.
• Prior to SRP, 32 percent were impotent.
• Erectile dysfunction-free rates post-SRP at 3, 6, and 12 months were 87, 25, and 14 percent.
• The 5-year biochemical-free survival rate was 55 percent, and the 5-year overall survival rate was 85 percent.

The investigators conclude that SRP is an effective treatment modality for recurrent prostate cancer after RT. Modern surgical techniques allow relatively low complication rates that include moderate increases in baseline incontinence and impotence by 1 year after SRP. The large percentage of patients found to have locally advanced disease and regional lymph node metastases suggest that men who fail RT for prostate cancer should be selected carefully for SRP.