• Decision-making in localized prostate cancer: Quality of life issues
• New events in the treatment of prostate cancer at Cornell
• What's New - Overview

Sun Exposure, Vitamin D and Prostate Cancer

A study was published in the June 15, 2005, issue of Cancer Research regarding sun exposure, vitamin D receptor (VDR) gene polymorphisms, and risk of advanced prostate cancer (PCa). This population-based, case-control study was conducted among non-Hispanic white men ages 40-79 from the San Francisco Bay area. The researchers found that reduced risk of advanced PCa was associated with high sun exposure, and that significant reductions in risk of advanced PCa was found among those with high sun exposure and VDR polymorphisms (ORs ranging from 0.46-0.67 for various genotypes). The authors concluded that sun exposure and VDR polymorphisms play an important role in the etiology of PCa.

Etiology and Natural history

Both environment and genetics have an apparent role in causation of prostate cancer. The relative contribution of these two factors may be analyzed in twin studies. An analysis of a twin cohort from Sweden, Denmark and Finland suggested that hereditary factors are more important in prostate cancer than in other cancers. It was estimated that 42% of the risk of prostate cancer may be attributable to genetic factors (Lichtenstein et al., 2000.) The value of detection of prostate cancer by PSA screening has been questioned by some as having limited value. A study from Sweden indicated that the 15-year cancer specific survival of men with PSA less than 10 ng/mL was only 50%, calculated from the time of PSA sampling(Hugosson et al., 2000.) Another study from California analyzed the mean time to death from prostate cancer for men with T1-2 and nonmetastatic T2-3 disease. They demonstrated a steep increase in mortality at 16 years after diagnosis (Horan & McGehee, 2000.) The role of "watchful waiting" in management of prostate cancer was further explored in a study of patients from Denmark with clinically localized disease who were managed with initial noncurative intent (Brasso et al., 2000.) They found that the diagnosis of prostate cancer accounted for a significant need for hospital care in the years after diagnosis. When evaluating quality of life, the need for medical care in this group of patients must be considered. The clinical outcome of patients more than 70 years of age at the time of diagnosis was reported from Stanford. The men who were older had more aggressive tumors, perhaps because these tumors had grown longer than for younger men (Sung et al., 2000.) Although several medical groups have proposed providing information before PSA screening, little data exist on evaluation of how this information affects patient's choices. An illustrated informational pamphlet did not change patient's choices regarding screening in a recent study from Milwaukee (Schapira & VanRuiswyk, 2000.)

Evaluation/detection

Appropriate use of prostate-specific antigen (PSA) testing for early detection and diagnosis of prostate cancer was formulated in a "best practice policy" statement by the American Urological Association (Carroll et al., 2001.) They published recommendations of regular screening of men over age 50 (African-American men or those with a family history over age 40-45) using PSA and digital rectal examination. Cut-points for biopsy are based on age-specific PSA evaluations, and screening is only recommended for men with a life expectancy of more than 10 years. The use of PSA for staging and follow-up of patients after definitive treatment of prostate cancer was published in an accompanying article that serves as a worthwhile reference (Carroll et al., 2001.) Now that standard approaches for PSA screening has been proposed, Ross et al., based on a Monte Carlo simulation based on a Markov model, recommended PSA testing at ages 40 and 45, followed by biennial testing after age 50. This approach prevented the same number of deaths with fewer tests and less PSA tests & biopsies (Ross et al., 2000.) Derivative evaluations of PSA and PSA subtypes continue to clarify the roles of these tests. A prospective evaluation of complexed PSA versus free/total PSA measurements for the diagnosis of prostate cancer showed similar value of these two tests, with the complexed PSA measurement having better receiver operating curve characteristics than total PSA (Mitchell et al., 2001.) A novel histologic marker for prostate cancer, increased prostatic lysophosphatidylcholine acyltransferase activity, was evaluated by a group from Arkansas (Faas et al., 2001.) The measurement of this enzyme level in blood as a potential tumor marker has not yet been investigated. Clinical management of premalignant lesions of the prostate (high grade PIN) management guidelines were proposed in a literature review by the WHO Collaborative Project and Consensus Conference (Haggman et al., 2000.) It was recommended that further evaluation of these lesions only be performed in patients who are suitable for treatment with curative intent, that patients found to have high grade PIN should have prompt repeat biopsy whether PSA and/or rectal exam are normal or not. Patients with PIN who have a repeat negative biopsy after a diagnosis of PIN should be reevaluated in 1 year. The presence of low-grade PIN is of no clinical significance and should not be commented upon in pathologic evaluations. The pattern of rebiopsy should include both the site of prior high grade PIN & adjacent sites as well as a general sextant pattern of the prostate (Park et al., 2001.) The rate of cancer detection in this series was 51% after initial identification of PIN. Another study from Austria also confirmed that the presence of PIN is an independent predictor of cancer. Total PSA and percent free PSA are not necessary to identify patients for repeat biopsy (Horninger et al., 2001.) Several diseases, including prostate cancer, have been shown to have improved 5-year survival in recent studies. Welch et al. (2000) reported that changes in 5-year survival over time may not reflect improved survival from cancer treatment, especially when changing patterns of diagnosis are ongoing. The value of prostate cancer screening was reported for the Tyrol region of Austria, where an improved rate of organ-confined disease was seen after initiation of PSA-based screening (Horninger et al., 2000.) The rate of organ-confined tumors increased from 29% in 1993 to 66% in 1997. Subsequent data from this region have suggested a decrease in prostate cancer mortality associated with screening, beginning approximately 8 years after its introduction.

Treatment with intravesical BCG for transitional cell carcinoma will typically result in a 2-fold increase in PSA, as seen in a recent study for 75% of patients. The effect on PSA is self-limited and will resolve within 3 months. Development of nodules may also occur and are usually associated with benign disease. Followup PSA 3 months after BCG therapy is recommended (Leibovici et al., 2000.) The role of imaging studies after diagnosis of clinically localized prostate cancer was evaluated in a population-based analysis of 3,690 patients (Albertsen et al., 2000.) This group found that bone scan, MRI and CT scan had a low yield, especially when the Gleason score was 6 or less. For all men with a PSA of 4 to 20 ng/mL, the positive yield of bone scan and CT was 5% and 12%, respectively. Optimal imaging protocols for patients with early prostate cancer are yet to be developed.

Prostatectomy

Radical retropubic prostatectomy has been performed on more than ten thousand men a year between 1989 and 1995. A nationwide sample of American hospitals examined the relationship of hospital surgical volume to complications. Mortality and length of stay as well as hospital charges were lower in high volume centers, although overall in-hospital mortality was relatively low (0.25%) (Ellison et al., 2000.) One of the most interesting changes in radical prostatectomy technique is the recent demonstration of the effectiveness of a laparscopic approach to prostatectomy. Vallancien et al. initially reported on a cohort of 120 patients who underwent laparoscopic prostatectomy at Mountsouris in France. They demonstrated a progressive decrease in complications and operative time in this series of cases (Guillonneau & Vallancien, 2000.) The same authors have subsequently reported on a series of 260 consecutive cases at this center. Operating time was approximately 3 hours for the last 120 cases with a transfusion rate <1% and conversion rate of 0%. Minimal postoperative pain and removal of the urethral catheter at 3 days were apparent advantages of this technique (Guillonneau & Vallancien, 2000.) Guillonneau et al. also reported robotic-assisted laparoscopic pelvic lymph node dissection for locally advanced prostate cancer in ten patients (Guillonneau et al., 2001.) A similar number of lymph nodes was removed with this technique, relative to that of open surgical node dissection, with a shorter operative time for the laparoscopic technique. A series of 20 patients undergoing radical prostatectomy with a laparoscopic approach was also reported with similar short-term results to that expected with open surgery (Jacob et al., 2000.)

The role of bladder neck preservation during radical prostatectomy was reported on by Poon et al. (2000) who found that bladder neck preservation did not affect return of urinary control. Other investigators have shown a marginally higher positive margin rate with preservation of this structure, at least in pathologically more advanced tumors (Marcovich et al., 2000.) The risk of detection of lymph node metastases is vanishingly low in most men found to have localized prostate cancer now. A retrospective study of men with favorable tumor characteristics were retrospectively analyzed in a report from the Cleveland Clinic. They found no difference in biochemical relapse if the patients had lymph node dissection or no lymph node dissection (Fergany et al., 2000.) A review of the use of neoadjuvant hormonal therapy for radical prostatectomy series confirmed the impression that lower surgical margin rates in these series has not been translated into improved disease-free survival. Therefore, there is no support for this practice (Scolieri et al., 2000.) Four year follow-up of a study from Europe confirmed the absence of benefit for neoadjuvant hormonal therapy before radical prostatectomy (Schulman et al., 2000.) Not surprisingly, 93% of urologists recommend prostatectomy, whereas 72% of radiation oncologists consider surgery and radiation equal treatments for men with clinically localized tumors and a life expectancy over 10 years (Fowler et al., 2000.)

Although seminal vesicle invasion is usually an unfavorable prognostic factor, a retrospective review from Hopkins suggested that some men with seminal vesicle invasion do not have a poor prognosis. Patients with Gleason score 5 or 6 and seminal vesicle involvement did well long-term, as long as margins were negative (Epstein et al., 2000.) Biochemical PSA progression after prostatectomy is variably defined in different series. A study from San Diego and the Mayo Clinic reported that the PSA cut point of 0.4 ng/ml was most effective at defining PSA progression after radical prostatectomy (Amling et al., 2001.) The presence of perineural invasion on biopsy has been suggested as a strong indicator of capsular penetration. A study from Boston confirmed that resection of the neurovascular bundle on the side corresponding to perineural invasion on biopsy may decrease the positive surgical margin rate (D'Amico et al., 2001.) A Cox proportional hazards model on a large data base of pT2 and pT3 patients was used to create a scoring algorithm for risk of recurrence after prostatectomy (Blute et al., 2001.) Since the patients in this data set were treated from 1990-1993, it is not clear how predictive this model would be for patients diagnosed one decade later in the PSA era of detection.

Prospective evaluation of erectile dysfunction was performed using a small subset of 2,956 patients diagnosed with prostate cancer and treated with radical prostatectomy, radiation or watchful waiting. Very few men treated with prostatectomy (10%) or radiation (15%) had post-treatment erectile function (Siegel et al., 2001.) These results are not consistent with that obtained and reported by centers of excellence for prostate cancer surgical treatment. Rabbani et al. (2000) reported similar results in preservation of sexual function after radical prostatectomy to that previously reported by centers of excellence in this technique. Return of erectile function adequate for sexual activity took up to 40 months to be realized and correlated with age and number of neurovascular bundles preserved. The use of a nerve stimulator during radical prostatectomy has been proposed as a method of identifying cavernous nerves intraoperatively to improve postoperative sexual functioning. A study from Nashville suggested that intraoperative Cavermap device stimulation results do not allow precise anatomical localization of the cavernous nerves (Holzbeierlein et al., 2001.) The authors suggest significant background related to anesthesia, surgical manipulation or other undefined factors limiting the value of this device. Walsh (2000) reported that review of intraoperative videotapes allowed introspection into minor alterations in surgical techniques that may affect sexual function postoperatively. A study of pelvic floor re-education after radical prostatectomy suggested only a limited benefit to these exercises as an aid to minimizing the duration and extent of urinary leakage after radical prostatectomy (Van Kampel et al., 2000.) Use of preoperative epoetin alpha in men undergoing radical retropubic prostatectomy was reported from NYU (Rosenblum et al., 2000.) The authors used 600 IU/kg at two weeks and one week prior to radical prostatectomy. The safety of this treatment was shown with increases of an average of 2.9% in hematocrit levels preoperatively.

Radiation therapy

The role of radiotherapy after isolated biochemical recurrence following prostatectomy was reported in a series of 166 consecutive patients from Mayo Clinic followed for a median of 52 months (Pisansky et al., 2000.) These authors reported a 46% biochemical NED rate 5 years after salvage radiation. Seminal vesicle invasion, tumor grade and pre-radiation PSA were independent factors associated with relapse. One in 6 patients had a chronic complication from treatment. Patients treated for prostate cancer with primary radiation therapy were found to have a statistically significant increase in the risk of development of a second malignancy compared to those patients treated with surgery but no radiation (Brenner et al., 2000.) Second tumors most commonly involved carcnimoas of the bladder, rectum and lung as well as sarcomas in the treatment field.

Modern prostate brachytherapy has had a resurgence of interest in the past several years, based in large part on the excellent results reported by Ragde et al. from Seattle. The authors have recently reported a 10-year followup of patients after brachytherapy (Ragde et al., 2000.) The proportion of men who were treated with brachytherapy alone was small (67 patients), and the overall disease-free rate was only 70%. This is low because many men had very well differentiated tumors (Gleason's sum score 2-5), and no patients had Gleason score 7 or above. Comparable results for surgery would be expected above 90% (Polascik et al., 1998.) Radiation techniques using external beam now involves 3-dimensional conformal treatment with dose escalation. Whereas prior treatment involved only 65 cGy, it is now clear that optimal results include 75-80 cGy to the prostate with trials at higher doses (Hanks et al., 2000.) A study from Georgia reported that 35% of men treated with external beam radiation combined with seed implantation had "bounces" of their PSA, defined as an increase of 0.1 ng/ml or more (Critz et al., 2000.) Median time to PSA bounce was 18 months and median bounce height was 0.4 ng/ml. These authors felt that the "bounce" had no prognostic significance. Stone et al. (2000) reported that 11% of patients with brachytherapy had positive biopsies, with 16% of patients treated by neoadjuvant hormonal therapy followed by brachytherapy. PSA, Gleason score and isotope used did not predict outcome of the biopsy. Given that no men after prostatectomy have cancer remaining in the prostate gland inside a patient, it is hard to argue that brachytherapy will have the same treatment outcomes as surgery.

Use of 6 months of neoadjuvant hormonal therapy prior to 3-dimensional radiation thaerapy was analyzed in a retrospective study published in JAMA. The authors found that intermediate and high-risk patients had better 5-year PSA outcomes when treated for 2 months before and 4 months after radiation therapy. Erectile function after radioactive seed implantation was noted to decrease progressively at 3 and 6 years after treatment, in an actuarial analysis of men from New York (Stock et al., 2001.) Of men potent before treatment, 36% and 70% had declines in sexual function at 3 and 6 years, although many of these men were still able to have sexual activity.

Hormonal therapy/Advanced disease

Hormonal therapy is the standard approach for men with advanced or symptomatic prostate cancer. Isolated elevations of PSA in men after failed local therapy or advanced asymptomatic cancer have been treated in select cases. Herr & O'Sullivan (2000) reported significant impairment in physical and emotional health of patients treated if asymptomatic. Interestingly, the symptoms of fatigue, loss of energy, emotional distress and lower overall quality of life was lower in treated men, especially men treated with combined androgen blockade. A meta-analysis of randomized trial comparing maximal androgen blockade versus monotherapy with GnRH agonist or castration demonstrated no difference in survival rates with either treatment (Prostate Cancer Trialist's Collaborative group, 2000.) These observations support the practice of antiandrogens only during the first month of GnRH agonist therapy. Not surprisingly, the use of combined androgen blockade or GnRH agonist alone was confirmed to be much more expensive than surgical castration (Mariani et al., 2001.) Lack of patient acceptance of surgery is capitalized upon by U.S. drug marketing to dramatically increase the cost of prostate cancer treatment. Hormonal therapy accounts for over one-half of all HCFA costs for treatment of prostate cancer. GnRH agonists increase testosterone, PSA levels and disease symptomatology in the first weeks of treatment before castrate levels of testosterone are achieved. A GnRH antagonist has been introduced recently that will promptly achieve castrate testosterone levels in 75% of patients within the first week of treatment (Tomera et al., 2001.) Abarelix is given in monthly shots and does not result in LH, testosterone or PSA levels.

Use of antiandrogens as monotherapy resulted in preservation of sexual function for only 20% of treated men (Schroder et al., 2000.) Given the significant side effects with this form of treatment (i.e., gynecomastia) antiandrogen monotherapy is of limited value. Use of intermittent androgen suppression has been proposed in uncontrolled trials with limited data. A study of 43 patients who were treated for 18 or more months until PSA levels reached a nadir below 4 ng/ml (or stable levels) were then taken off treatment and treatment was restarted if symptoms occurred from cancer progression or PSA reached 20 ng/ml. In the first cycle off treatment, patients stayed off treatment for only 6 months, with 4 months off treatment in the second cycle. The duration off treatment is little more than that required for testosterone levels to return to baseline levels. The value of intermittent androgen therapy appears little, as return of sexual activity did not occur during treatment "breaks." It has been understood for several years that osteoporosis occurs during androgen deprivation. Daniell et al. (2000) reported that 2.4% of bone loss was lost in the first year after initiation of hormonal therapy with 7.6% in the second year. Average bone mineral density loss was 1.4 to 2.6% per year in years 3-8 of uninterrupted androgen deprivation. Bone loss was increased in men who were obese, younger than 75 years or without regular exercise. The use of stilbesterol and hydrocortisone as second line treatment for men with androgen-independent prostate cancer growth was studied by Farrugia et al. (2000.) They reported response in 83% of patients, remarkably similar to that reported for the herbal medication combination, PC-SPES. It appears that much of the activity of PC-SPES is attributable to the estrogenic activity of the phytoestrogenic soy protein in this compound. The use of rye bran and soy protein for prostate cancer prevention have been suggested by others. Its use was supported by an in vitro observations in human LNCaP prostate adenocarcinoma cell line (Bylund et al., 2000.)

Advanced prostate cancer may cause ureteral obstruction as a pre-terminal event. A study from Greece supported the safety of percutaneous urinary diversion in these patients (Pappas et al., 2000.) However, survival was <8 months after diversion and many of these patients will have very poor quality of life during this time period. An observational approach to these patients with informed consent and discussion among family members may be an alternative approach. The phenomenon of low PSA, metastatic, androgen-independent prostate cancer was presented by Sella et al. (2000.) These patients usually have small cell cancer (87%) with or without adenocarcinoma. Some patients have anaplastic tumors. Involvement of liver, lymph nodes and lung was common as well as pelvic masses and lytic bone metastates. Each patient had elevation of at least one of these tumor markers: CEA, CA19-9, CA15-3, or CA 125. Knowledge of this condition is important, as patients may be treated with cisplatin-based chemotherapy.

A recent study on men who developed prostate cancer suggests that earlier PSA testing, with less frequent follow-up is the best approach for detection of prostate cancer at a curable stage.

This report, published in The Journal of the American Medical Association and summarized by Reuters Health, suggests that the standard protocol of annual prostate-specific antigen (PSA) screening in men older than 50 years is less efficacious and less cost-effective than testing at ages 40 and 45, followed by biennial screening starting at age 50.

"Earlier and less frequent screening not only prevents more prostate cancer deaths but also utilizes fewer PSA tests and fewer biopsies for every life saved," Dr. H. Ballentine Carter told Reuters Health. "It is truly the most cost-effective strategy."

Dr. Carter, from Johns Hopkins Hospital, Baltimore, Maryland, and a multicenter team developed a computer model to compare the costs and benefits seven prostate cancer screening strategies with no screening. They evaluated different age ranges for PSA testing (from 40 to 75 years), different testing intervals, and different PSA thresholds for triggering prostate biopsy.

"Compared with annual PSA testing beginning at age 50 years," Dr. Carter's group found, "the strategy of PSA testing at ages 40 and 45 years followed by biennial testing beginning at age 50 years was estimated to simultaneously reduce prostate cancer mortality and number of PSA tests and biopsies performed per 1000 men."

The standard strategy, according to the team, "prevents 3.2 deaths, with an additional 10,500 PSA tests and 600 prostate biopsies," compared with no screening. By comparison, the strategy the team recommends "prevents 3.3 deaths, with an additional 7,500 PSA tests and 450 prostate biopsies."

The investigators note that strategies that set the PSA threshold for prostate biopsy at below 4.0 ng/mL or used age-specific PSA thresholds "were not more efficient than use of a PSA threshold of 4.0 ng/mL."

Reference: JAMA 2000;284:1399-1405.

Herbal Remedy PC-SPES Active Against Advanced Prostate Cancer Reported by Reuters

WESTPORT, CT (Reuters Health) Nov 20 - PC-SPES, a mixture of extracts from eight different herbs, is effective in many patients with advanced prostate cancer, according to phase II study results reported in the November 1st Journal of Clinical Oncology.

Dr. Eric J. Small, from the University of California at San Francisco, and colleagues tested the safety and effectiveness of PC-SPES in 33 men with androgen-dependent prostate cancer and 37 men with androgen-independent prostate cancer who had evidence of disease progression.

In the androgen-dependent cancer group, PC-SPES lowered the median PSA level from 7.9 ng/mL to undetectable levels in 26 (81.3%) patients, and all men in this group experienced declines of at least 80%, the report indicates. The PSA nadir was reached after a median 23 weeks and, as late as 74 weeks after treatment, no patient had shown evidence of progression.

Similarly, PC-SPES treatment of men with androgen-independent disease resulted in PSA declines of more than 50% (from a baseline median of 60.7 ng/mL) in 54% of patients, the authors report. The PSA nadir was reached after a median 10 weeks, and the median time to progression among responders was 18 weeks.

Endocrine side effects were common in both groups, with testosterone levels consistently falling below 50 ng/mL, the results indicate. This was reflected clinically in complete or near-complete loss of libido, inability to have an erection, hot flushes, and breast tenderness and/or enlargement in most or all patients.

In general, however, treatment was well tolerated, according to the report. Other common side effects included leg cramps, diarrhea, and nausea. Three men developed pulmonary emboli requiring discontinuation of treatment.

"PC-SPES seems to have activity in the treatment of both androgen-dependent and androgen-independent prostate cancer and has acceptable toxicity," the authors conclude. "Further study is required to determine whether its effects exceed those expected with estrogen therapy."

How PC-SPES works remains something of a mystery. "There may exist literally hundreds of unique compounds in an herbal mixture such as PC-SPES," the investigators write, "making it difficult to identify the active agent(s) and impossible to assure inter- and intralot variability."

Copyright © 2000 Reuters Ltd. All rights reserved. Republication or redistribution of Reuters content is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon.

J Clin Oncol 2000;18:3595-3603.

Editorial note: Although PC-SPES has created tremendous interest as a "natural" treatment, side effects are significant, and it is not clear that this herbal agent is any more effective (and it's clearly more expensive) than taking estrogens alone. --PS, M.D.