Prostate Cancer Treatment

by Hans R. Larsen, MSc ChE and William R. Ware, PhD

VITAMIN D AND PROSTATE CANCER MORTALITY
It is not all clear whether vitamin D influences the incidence of prostate cancer and there is weak evidence that high levels of 25-hydroxyvitam D (25(OH)D) may even correlate with the incidence of more aggressive forms of the disease, although a clear monotonic dose-response is lacking. However, vitamin D levels as measured by 25(OH)D appear to be strongly inversely correlated with progression and mortality associated with established disease. A study just published from Norway addresses this issue. This study involved 160 patients of which 97 were on hormone therapy. During the follow-up which had a mean time of 44 months (range 1.2 to 155), 61 patients died, the majority from prostate cancer. The vitamin D status was stratified according to low (< 50 nmol/L), medium (50-80 nmol/L and high (> 80 nmol/L) of 25(OH)D. The results were analyzed using several models, with the model which included age, tumor grade (differentiation) and patient functional status at the time of blood collection giving the strongest correlation between mortality from prostate cancer and vitamin D status, When those in the medium and high levels were compared to those with a low level of 25(OH)D, statistically significant risk reductions in prostate cancer-specific mortality of 67% and 84% respectively were found. When the analysis was restricted to patients receiving hormone therapy, the association was even stronger. It was concluded that the serum level of 25(OH)D may be involved in disease progression and is a potential marker of prognosis in patients with prostate cancer.

It is possible that the mechanism providing this benefit may involve a transcription factor called Stat3 which in active in malignant prostate cancer. Dr. William Grant of the Sunlight, Nutrition and Health Research Center in San Francisco has pointed out that vitamin D has been found to inhibit the action of Stat3 and increase cancer cell death and invasion and metastasis. It is also possible that the metabolite of 25(OH)D, 1,25-dihydroxyvitamin D is involved since it is known that prostate cancer cells contain the required enzyme to convert 25(OH)D to this metabolite. Grant points out that making sure that those diagnosed with prostate cancer have high 25(OH)D levels may be important for this reason.
Ahn J, Peters U, Albanes D et al. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 2008 June 4;100(11):796-804
Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 2009 Feb 10;100(3):450-4
Abdulghani J, Gu L, Dagvadorj A et al. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol 2008 June 1;172(6):1717-28
Grant WB. Vitamin D may reduce prostate cancer metastasis by several mechanisms including blocking Stat3. Am J Pathol 2008 November 1;173(5):1589-90

RADICAL PROSTATECTOMY IN MEN OVER 70 YEARS OF AGE
Data on survival and recurrence after a radical prostatectomy (RP) in men equal to or greater than 70 years of age has been limited due to the infrequency of such surgery and the long follow-up times required. A multicenter study has just reported which examined the effect of age on upgrading, upstaging and subsequent cancer control in men of this age group undergoing prostate surgery. This is an important subject due to the rapidly changing demographics. Between 2000 and 2050 it is expected that the number of men over 65 years will quadruple. In addition, life expectancy is expected to increase and there may be a decrease in the extent of comorbidities as more is learned about prevention of the major diseases that afflict that age group and more preventive measures are adopted. In addition, greater than 70% of prostate cancer is diagnosed in men over 65. Also, prostate cancer is not a benign disease in the elderly. Albertsen et al in a study of over 750 men with localized prostate cancer treated expectantly or with hormone therapy showed that prostate cancer continued to cause significant mortality in men aged equal to or greater than 70 and for those with Gleason scores of 6, 7 and 8-10, 32%, 40% and 60% respectively, died of prostate cancer.

Richstone et al have analysed data from a large series of men who had a RP, including over 250 who were of age equal to or greater than 70. This allowed a comparison of the clinical and pathological features in older vs. younger men. They found that as a group, those equal to or greater than 70 were more likely to be upstaged after surgery than the younger group, but the Memorial Slone-Kettering nomograms retained their validity. The upstaging did not affect cancer control. There was no difference in cancer specific survival in the older vs. the younger age groups (96% at 10 years) or PSA detected progression free probability (74% vs. 75%) at 10 years. This was in spite of the fact that men aged equal to or greater than 70 tended to have cancers of higher clinical and pathological stage or grade. The authors conclude that with careful attention to patient selection the RP is a viable treatment option for men aged equal to or greater than 70, but more research is needed to address questions of morbidity and quality of life.
Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years atdiagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998 September 16;280(11):975-80
Richstone L, Bianco FJ, Shah HH et al. Radical prostatectomy in men aged greater than or equal to 70 years: effect of age on upgrading, upstaging, and the accuracy of a preoperative nomogram. BJU Int 2008 March;101(5):541-6

CRYOABLATION VS. EXTERNAL BEAM RADIOTHERAPY
Cryoablation involves freezing the prostate and kills both normal and cancer cells. It was first introduced in the 1960s but was found to be associated with unacceptable complications. Improvements in the technique resulted in its reintroduction in 1998 and it has gained a considerable following. A Canadian study has just reported on a randomized comparison between radiation (RT) and cryoablation therapy (CRYO). Patients in the study had biopsy-confirmed disease, were clinically T2c or T3 (tumor involved both lobes or the tumor extended beyond the prostatic capsule), with a negative abdominal and pelvic CT scan, a negative bone scan, and a PSA of less than 25 ng/dL. Neoadjuvant (pre-treatment) hormone therapy was given to both groups followed by either CRYO or RT (dose of 68 Gy). This was followed by 3 additional months of hormone therapy. For the CRYO group, the treatment was repeated if a positive biopsy was found at 6, 12, 18, or 24 months. For the radiation group, salvage cryoablation was used if there was a positive biopsy at 24 months. The mean biochemical disease-free survival (based on PSA) was 41 months for the RT group and 28 months for the CRYO group. However, prostate cancer specific survival and overall survival were very similar for both groups and serious complications were uncommon in either group. Nevertheless, the authors conclude that the results of this prospective randomized trial indicate that CRYO was less favourable as compared to RT and is thus a suboptimal therapy for locally advanced prostate cancer.
Chin JL, Ng CK, Touma NJ et al. Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer. Prostate Cancer Prostatic Dis 2007 June 19;11(1):40-5

RISKS OF ANDROGEN DEPRIVATION THERAPY (ADT)
This therapy is also called hormone therapy. Two recent studies emphasize that hormone therapy has serious side effects which must be balanced against the benefits derived in terms of prostate cancer control. One study found that newly diagnosed prostate cancer patients who received ADT for at least a year had a 20% higher risk of serious cardiovascular disease compared to men not receiving ADT. The researchers comment that this result has particular relevance to the decision to use ADT in men in settings in which the benefit has not been clearly established. For men with metastatic disease, they suggest that ADT be accompanied by aggressive efforts to reduce cardiac risk through diet, exercise or the use of lipid lowering drugs. The second study concerned the risk of diabetes associated with ADT. The elevated risk associated with developing incident diabetes within one year was found to be 36% in men initiating ADT. This result was corrected for a number of potential confounding factors. The authors comment that this finding supports previous work that established a relationship between ADT and the metabolic syndrome. Taken together, the results of these two studies clearly complicate the risk-benefit analysis regarding ADT. However, additional studies are needed to examine the importance of the duration of treatment since neoadjuvant and adjuvant treatment can be for relatively short term, but very long term when used to deal with recurrence.
Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007 October 1;110(7):1493-500
Lage MJ, Barber BL, Markus RA. Association Between Androgen-Deprivation Therapy and Incidence of Diabetes Among Males with Prostate Cancer. Urology 2007 December;70(6):1104-8

PROSTATE CANCER TREATMENT AND PROGNOSIS
One task facing physicians treating prostate cancer is achieving a reliable prognosis after treatment based on the best available evidence. When the treatment involves surgery, the pathological examination of the removed prostate and associated tissues provides valuable information which is obviously unavailable when radiation therapy is employed as primary therapy. The long-term prognosis following surgery or radiation therapy in men with one or more high-risk factors has been studied by D'Amico and colleagues at the Dana Farber Cancer Institute. The risk factors were a PSA velocity of greater than 2 ng/mL per year during the year before diagnosis (biopsy), a biopsy Gleason score of equal to or greater than 7 or a PSA level equal to or greater than 10 ng/mL or a clinical T2b or higher disease (tumor palpable at DRE or evidence of invasion of surrounding tissue). Men with a PSA velocity greater than 2 ng/mL per year had a significantly higher risk of dying from prostate cancer compared with men having any other single high-risk factor. The authors conclude that these men should be considered for randomized trials evaluating the impact of what they term systemic agents (e.g. chemotherapy) on the normal standard of care for these individuals at high risk.

In a related study, Freedland et al examined predicative factors for mortality after radical prostatectomy for prostate cancer. The study followed 379 men who had PSA recurrence (increasing PSA) after surgery for a mean of about 11 years. The prognostic factor used was PSA doubling time (PSADT) which is of course closely related to PSA velocity. Among patients with post-surgical PSADT of less than 15 months, prostate cancer accounted for 90% of the deaths. Only patients in the slowest PSADT subgroup (equal to or greater than 15 months had a greater risk of death from competing causes as compared to death from prostate cancer. The mean age at surgery was about 60 years. These two studies solidify the role of PSADT or PSA velocity in the assessment of the probability of post treatment mortality due to prostate cancer. Men with very short doubling times may want to seek out experimental drug programs and as well, examine alternative approaches such as pomegranate juice consumption.
D'Amico AV et al., 2007. Prostate cancer-specific mortality after radical prostatectomy or external beamradiation therapy in men with 1 or more high-risk factors. Cancer. 110(1):56-61
Freedland SJ et al., 2007. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. Journal of Clinical Oncology. 25(13):1765-1771

HORMONE THERAPY AND RISK OF CARDIOVASCULAR MORTALITY
This story might be filed under the heading "you can't win." The October 17 issue of the Journal of the National Cancer Institute includes a very interesting report on a study which examined the question of whether the use of hormone therapy (androgen deprivation therapy ADT) in patients treated for localized prostate cancer results in an increased incidence of either cardiovascular or all-cause mortality compared to those who received just surgery or radiation as the primary treatment. Part of the motivation for the study was the fact that ADT is being used increasingly in combination with local therapy to treat patients with localized disease who exhibit adverse features and as well, reports in the literature that ADT increases the risk of developing diabetes and cardiovascular disease. The study involved a follow-up with a median time of about 4 years (range 0.1-11.3). The mean duration of ADT was 4.1 months (range 1.0-32.9) and 1015 patients were involved. After statistically controlling for age and available cardiovascular risk factors, it was found that treatment with ADT was associated with a significant increased risk of death from cardiovascular causes in patients treated with radical prostatectomy for localized prostate cancer. Patients 65 years of age or older had a 5-year cumulative incidence of cardiovascular disease death of 5.5% vs. 2.0% for those treated with surgery alone. For younger patients, the equivalent figures were 3.6% vs. 1.2%. This phenomenon simply complicates the risk-benefit analysis but the absolute risk is small. These results are consistent with studies that suggested ADT can lead to conditions associated with the metabolic syndrome which in turn increases the risk of coronary artery disease. The authors suggest careful cardiovascular evaluation and intervention are advisable before initiating ADT in patients with localized prostate cancer.
Tsai HK et al., 2007. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 99(20):1516-1524

EXPECTANT MANAGEMENT OF PROSTATE CANCER WITH CURATIVE INTENT
Expectant management with curative intent is a relatively new approach to the persistent problem of over treating low-risk and indolent cancers and yet not missing the window of opportunity to achieve optimum treatment if the assessment appears wrong and the cancer is more aggressive than originally thought. Johns Hopkins and the Memorial Slone-Kettering Cancer Center have both developed programs and have been collecting data for some time. Now an update on the experience at Johns Hopkins has been published in the Journal of Urology. The Hopkins' criteria, which were found to be predictive of small volume, low-grade cancer, are as follows:

• Non-palpable prostate cancers (stage T1c)
• PSA density (PSA value divided by the prostate volume obtained from ultrasound) of 0.15 ng/mL/cm3 or less
• Gleason score of 6 or less with no Gleason pattern grade of 4 or 5, no more than 2 cores positive for cancer, and no more than 50% of any 1 core involved with cancer.

A total of 407 men have been involved with the Hopkins Expectant Management program. Of these, 239 remained on active surveillance at a median follow-up of 3.4 years (range 0.43 to 12.5), 103 (25%) underwent curative intervention at a median of 2.2 years after diagnosis (range 0.2 to 7.39) and 65 (16%) were either lost to follow-up (12), withdrew from the program (45) or died of causes other than prostate cancer. Older age at diagnosis and an earlier date of diagnosis were associated with crossover to curative intervention. Two men were found to have lymph node involvement at surgery, 5 and 7 years after entering the program. Both had relatively high PSA density during follow-up but met the biopsy criteria for remaining under surveillance. Finally, the authors reiterate the fundamental principle of their program. The majority of men diagnosed with prostate cancer today are older than 65 years, have low to intermediate disease risk but receive treatment. A substantial proportion of these men, according to this view, will gain no benefit from treatment in terms of additional years of life.
Carter HB et al., 2007. Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol. 178(6):2359-2364

HORMONE THERAPY FOR METASTATIC PROSTATE CANCER
Once metastasis has been diagnosed, an obvious question concerns the benefits of hormone treatment as opposed to waiting until palliative treatment is required. Worldwide, opinions and practice regarding the use of hormone therapy (HT) under these circumstances are variable, partly because of uncertainty concerning the impact of HT on overall survival. The only randomized study was limited by interpretation problems that arose when placebo patients "crossed over" to HT and confounded the survival analysis and results. A recent study by Lu-Yao et al based on a U.S. cohort has attempted to address the question of both prostate cancer specific survival and overall survival with or without HT. At the time this study was initiated a randomized design was not possible on ethical grounds, and instead a population cohort design was used. Only patients over 65 were included and the medical history, treatments and outcomes were obtained from Medicare and the Surveillance, Epidemiology and End Results databases. Essentially all those receiving HT were given a LHRH agonist or surgical castration. The final cohort consisted of 6098 patients diagnosed with metastatic cancer between 1991 and 1999. More than half were 75 years or older and most had aggressive disease (Gleason 8-10) and most did not have significant comorbidity. The most important result was that modern HT was associated with a 34.1% decrease in overall mortality and an approximately 13-month increase in overall survival as compared to those who were untreated until palliation was required. Median overall survival for those who received HT was 26 months. The much shorter survival times in this study as compared to those found in a recent Memorial Slone Kettering study may be due to the much older population, the high proportion of aggressive disease, and a time of diagnosis that was considerably further into the course of the metastatic disease due to a range of definitions of metastasis in the large databases used vs. closely following a group of patients in a single institution. Thus the most important conclusion appears to relate to the improvement of overall survival and cancer specific survival attributable to HT rather than the actual survival times.

The investigators also examined the impact of cancer grade on the response to HT. The best outcomes were with poorly differentiated disease (Gleason 8-10), with intermediate outcomes for moderately differentiated disease (Gleason 5-7) and interestingly enough, the worst outcomes for well differentiated disease (Gleason 2-4). In this latter group, treated patients were almost twice a likely to die of prostate cancer compared to untreated patients, although this result, which was not anticipated, lacked statistical significance and should be viewed with caution.
Lu-Yao G et al., 2007. Population based study of hormonal therapy and survival in men with metastaticprostate cancer. J Urol. 177(2):535-539

WATCHFUL WAITING FOR ELDERLY MEN WITH LOCALIZED PROSTATE CANCER
Wong et al have recently published a study which addresses some aspects of this problem for patients in the age range of 65 to 80 years. Previous studies had suggested that better survival among treated patients was only seen in younger men, i.e. less than 65 years of age. This present study was based solely on U.S. Medicare data regarding claims for treatment. Individuals with claims for a radical prostatectomy or radiation treatment during the first 6 months after diagnosis were considered to have been treated, whereas if there was no such claim, they were deemed to have been merely observed. Those receiving only hormone therapy were excluded. The main outcome measured was overall survival, thus addressing the question does treatment influence actual lifespan in this older cohort? The average duration of follow-up was 12 years. In this study, a 30% lower mortality risk was found over the study period for treated patients. In a subgroup analysis, there was a 27% mortality risk reduction for men between 75 and 80 years, a 35% reduction for black men, a 38% reduction for those diagnosed in the PSA era, a 29% reduction for men with no comorbidities, and a 21% reduction for men with tumors of the lowest stage and grade. These results will no doubt have an impact on advice provided by clinicians when men in this age group are agonizing over treatment options and the decision to treat or not to treat.

In an editorial, Litwin and Miller provide arguments that might temper rampant enthusiasm, at least among patients. In the study of Wong et al, there were over 44,500 men in the sample studied, but death attributed to prostate cancer was seen in only 2.1% of the total sample. In addition, prostate cancer was found to be responsible for only 6.8% of deaths in the observational group and 8.0% of the deaths in the treatment group. Thus the absolute difference was only 1.2%. As they point out, "many more men die with prostate cancer than of it." Furthermore, the editorialists remark that this was not a randomized study but rather an observational one, and that the potential for residual bias and confounding remains. For example, a Medicare claims-based analysis fails to take fully into account the nature or severity of concurrent medical conditions nor the general impression of the clinician regarding life expectancy, and in fact in their opinion, and they claim most urologists and radiation oncologists would agree, older men who receive surgery or radiation therapy are "inherently different from those managed expectantly." Also, they suggest that in the studied cohort, there might be an imbalance with respect to frailty, cognitive function and other important but unmeasured confounders. Litwin and Miller also remark on the fact that this study contradicts the Scandinavian trial which was randomized, and found that men under 65 experienced the greatest survival benefit from treatment. They conclude that improvement in the quality of care for men with prostate cancer may be best achieved by treating patients more discerningly rather than just treating more patients. They quote the often seen comment of Whitmore that "for men in whom cure is possible it may not be necessary, and for men in whom a cure is necessary it may not be possible."

Many men in the age group at issue are diagnosed with localized prostate cancer each year worldwide. Many men also have fathers or relatives who are or will find themselves in this situation. In keeping with modern practice, presumably the options of treatment and watchful waiting will be discussed during consultation with the clinician involved. As men and in fact also their wives and partners will find, this is a complex matter and it will be recognized that an informed decision requires knowledge of the factors involved. Younger men also should be offered the option of watchful waiting. One of the modern variations is watchful waiting until the point is reached where further delay will diminish the chances of a definitive cure. In the PSA era, this option appears to be attractive even for older patients. Some men may be able to avoid treatment altogether under one of these special protocols and yet not compromise either prostate-specific or overall survival. This approach has growing support and men need to become familiar with the criteria employed by at least two of the major U.S. prostate cancer centers. Studies will no doubt shortly extend the age limit justified by evidence-based data.
Wong YN et al., 2006. Survival associated with treatment vs observation of localized prostate cancer in elderly men. JAMA: The Journal of the American Medical Association. 296(22):2683-2693
Litwin MS, Miller DC, 2006. Treating older men with prostate cancer: survival (or selection) of the fittest? JAMA: The Journal of the American Medical Association. 296(22):2733-2734

POMEGRANATE JUICE FOR A RISING PSA
For individuals with PSA doubling times greater than 12 months who are on "observation" only, recent results from the University of California at Los Angeles may be of considerable interest. In this study participants who had been treated for prostate cancer with either surgery or radiation had rising post-treatment PSA with a level greater than 0.2 but less than 5 ng/mL and a Gleason Score of equal to or less than 7. Participants had to have enough PSA data to calculate a doubling time, no hormonal treatment prior to entering the study and no evidence of metastatic disease. In what the authors claim is the first clinical trial of pomegranate juice therapy for patients with recurrent prostate cancer; the protocol consisted of 8 ounces of pure juice daily until disease progression endpoints were reached. Data from 46 patients were used in the analysis. The study used the brand POM Wonderful which is widely available, both pure and diluted with other juices, in North American grocery stores. After 33 months of follow-up, the mean PSA doubling time significantly increased from 15 months at baseline to 54 months. In addition, 35% of the 46 patients involved actually achieved a decrease in PSA (apparent arrested progression) during the intervention and 4 achieved a PSA decline of greater than 50%. The authors point out that the PSA doubling time is increasingly being seen as an important surrogate biomarker for prostate cancer mortality, and men with greater doubling times can expect longer survival. While the mechanism of action of pomegranate juice is unknown, the authors discuss possibilities such as antioxidant and prostaglandin-inhibitory actions of the polyphenols present in the juice and the ability of these polyphenols to promote tumor cell death and inhibit proliferation and invasion.
Pantuck AJ et al., 2006. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res. 12(13):4018-4026

ARE PROSTATE CANCERS OVERTREATED?
The explosive increase in the use of the PSA (prostate specific antigen) testing and subsequent biopsies has markedly changed the nature of the cancers detected. In the period 1989 to 1992 it is estimated that about 30% of all diagnosed prostate cancer were low risk and localized. In the period 1999 to 2001 the rate of detection of low risk cancers had risen to 45%. This trend is still accelerating today as biopsy is becoming more common and some urologists are pushing to lower the threshold for biopsy from a PSA value of 4.0 ng/mL to 2.5 ng/mL. Peter Carroll, Associate Editor of The Journal of Urology, warns in a recent editorial, that over-detection of prostate cancer is becoming a serious problem. Over-detection is defined as detecting a cancer that would not become clinically apparent during the lifetime of the patient if left untreated. A recent European study found that the current over-detection rate is about 48%. In North America, at least, detection and treatment are, unfortunately, intimately linked, so over-detection leads to over-treatment as well - perhaps in close to 50% of all cases. Dr. Carroll suggests that aggressive treatment is embarked on much too frequently and that watchful waiting (active surveillance) ought to be given substantially greater emphasis, especially among older men with localized low-grade tumours.
Journal of Urology, Vol. 173, April 2005, pp. 1061-62

A RATIONAL APPROACH TO PROSTATE CANCER TREATMENT
TORONTO, CANADA. Dr. Laurence Klotz of the University of Toronto believes that localized prostate cancer is overtreated and that many men with "good risk" prostate cancer can avoid radical intervention (radiation or prostate removal) and still live long enough to die of causes other than prostate cancer. Dr. Klotz recently reported on an ongoing study involving 299 men over the age of 70 years with prostate cancer. At the start of the study in 1995 the men had a PSA (prostate specific antigen) value below 15 ng/mL, a Gleason score of 7 or less, and their cancer rated as stage 2b or less. The men were all placed under active surveillance, which included frequent PSA measurements and a repeat biopsy at 12-18 months after initial diagnosis.Dr. Klotz believes that the time it takes for the PSA level to double is a good indicator of the aggressiveness of the cancer. If the PSA level doubles in less than 2 years or progression is noted on repeat biopsy or digital rectal examination, then the patient should be offered radical intervention. The PSA doubling time should be based on 3 separate measurements during a minimum of 6 months and the final value should be greater than 8 ng/mL before radical intervention is considered.

The median PSA doubling time (DT) among the 299 patients was 7 years and 42% of the men had a DT of greater than 10 years. Only 21% had a DT less than 3 years. Only 2 patients died from prostate cancer during the first 5 years and after 8 years of follow-up the prostate cancer specific mortality in the group was only 1%. About 60% of the patients remained on active surveillance after 55 months, with the remaining opting for radical therapy either because of diagnosed progression or by personal preference. Dr. Klotz concludes that active surveillance with selective delayed intervention in patients whose PSA DT is less than 3 years may be a practical compromise between across-the-board radical therapy for all patients with localized prostate cancer and watchful waiting with palliative therapy only.
Klotz L. Active surveillance with selective delayed intervention: using natural history to guide treatment in good risk prostate cancer. Journal of Urology, Vol. 172, November 2004, pp. S48-S51

PROSTATE CANCER SURVIVAL TABLES
DETROIT, MICHIGAN. Urologists at the Henry Ford Health System have developed tables enabling physicians and their patients to estimate long-term survival for men with clinically localized prostate cancer. The tables are based on the patient's age, race, PSA and Gleason score, estimated annual income, and the number of other disease conditions (comorbidities) experienced by the individual. The tables are based on thorough analysis of data from 1611 men with clinically localized prostate cancer and 4538 matched controls. The mean age of the cancer patients was 69 years, 39% were black, and the average (median) PSA level was 8.5 ng/mL. Most of the patients (43%) had undergone radical prostatectomy, while 27% were treated with radiation therapy, and the remaining 29% either received no treatment or were treated with hormones (conservative treatment). Examples of estimated 10-year overall survival rates are as follows:

• 61- to 70-year-old, white male with a PSA level of 9.9 ng/mL or less, a Gleason score of less than 5, and no severe comorbid conditions. Average 10-year overall survival rate with:
  Conservation treatment - 75%
  Radiation therapy - 79%
  Radical prostatectomy - 89%
  No cancer (controls) - 85%
• 75-year-old, black male with a PSA level of between 10 and 19.9 ng/mL, a Gleason score of less than 5, and no severe comorbid conditions. Average 10-year survival rates with:
  Conservation treatment - 57%
  Radiation therapy - 63%
  Radical prostatectomy - 80%
  No cancer (controls) - 74%

DEFERRED TREATMENT SAFE FOR LOW-GRADE PROSTATE CANCER
NEW YORK, NY. It is not clear whether men diagnosed with low-grade, localized prostate cancer need immediate, aggressive treatment such as radical prostatectomy (removal of the prostate gland) or radiation therapy. A group of American and Australian researchers now report that deferring treatment until clear progression of the cancer is evident may be a safe, acceptable alternative. Their study involved 88 men who had been diagnosed with localized prostate cancer by needle biopsy or during an intervention (transurethral resection) to deal with an enlarged prostate. The men were between the ages of 44 and 79 years (average age of 65) and had Gleason scores (a measure of the aggressiveness of the tumor) of 2-7 with a median of 5. The average PSA level was 5.9 with a range of 0.09 to 30.2 ng/mL. The men, in consultation with their physician, had all decided to defer radical treatment until there was clear evidence that their cancer was progressing. They had a digital rectal examination (DRE) and PSA measurement every 3 months for the first year and every 6 months thereafter. A repeat biopsy was recommended 6 months after initial diagnosis or if the DRE or PSA tests showed abnormalities. In 61% of the repeat biopsies, no cancer was found. The patients with no cancer on repeat biopsy were highly unlikely to show progression of their cancer. (Editor's note: Could this indicate that their original diagnostic biopsy had produced a false positive result, ie. they did not have cancer in the first place?)

During a median follow-up of almost 4 years (44 months) 22 patients showed progression. The overall probability of experiencing no progression was 67% 5 years after initial diagnosis and 55% after 10 years. In other words, more than half the patients showed no progression 10 years after initial diagnosis. A total of 31 patients were treated during follow-up - 17 because they showed clear progression of the cancer, 7 because of anxiety and their physician's concern that the cancer might be progressing, and another 7 underwent radical treatment because they were unable to live with the fear of cancer. The treatment consisted of radical prostatectomy in 17 cases, radiation therapy in 13 cases, and hormone therapy in 1 case. No recurrence had occurred in the patients treated with radical prostatectomy after an average 15-month follow-up. One recurrence was observed in the 13 radiation therapy patients after an average 20-month follow-up. The researchers conclude that deferring radical therapy may be a safe, acceptable alternative in men at low risk and that the results of a follow-up biopsy is the most significant prognostic factor for progression.
Patel, MI, et al. An analysis of men with clinically localized prostate cancer who deferred definitive therapy. Journal of Urology, Vol. 171, April 2004, pp. 1520-24
Editor's comment: This study clearly shows that not rushing into aggressive treatment is a viable option for men diagnosed with low-grade, localized prostate cancer. The most reliable indicator of the eventual need for treatment would seem to be a positive repeat biopsy result 6 months to a year after the initial biopsy.

IGF-1 AND ADVANCED PROSTATE CANCER
SAN FRANCISCO, CALIFORNIA. Insulin-like growth factor-1 (IGF-1) is a potent stimulator of prostate cancer cell growth. It is mostly found in the blood bound to its carrier, IGF binding protein-3 (IGFBP-3). Only the unbound form of IGF-1 has a cancer promoting effect. A team of researchers from Harvard Medical School and the University of California has just completed a major study aimed at determining if IGF-1 and IGFBP-3 levels can predict the risk of developing advanced stage prostate cancer. Their study involved 530 patients with prostate cancer and 534 controls matched for sex and smoking status. All participants were part of the Physicians' Health Study and were between the ages of 40 and 84 years at enrollment in 1982. Almost 15,000 of the men provided blood samples that were stored for future analysis. By the end of 1995, 786 cases of prostate cancer had been diagnosed among the 14,916 participants (5.2%). Sufficient blood plasma for IGF-1 and IGFBP-3 analysis was available for 530 of the cases and their matched 534 controls. The diagnosis of prostate cancer was made an average of 9 years after the drawing of the blood samples.

The researchers observed a strong association between IGF-1 and IGFBP-3 levels and the risk of advanced prostate cancer, but found no association with early stage disease. They found that men with IGF levels in the highest quartile had a 5.1 times higher risk of later developing advanced stage prostate cancer than did men in the lowest quartile. Men with IGFBP-3 levels in the highest quartile, on the other hand, had a 5 times lower risk of later advanced stage cancer (OR=0.2). Advanced stage prostate cancer was defined as stage C (extraprostatic, but no evidence of distant metastases) or stage D (distant metastatic or fatal). About 10% of the total 530 cases were stage D. The researchers speculate that IGF-1 not only stimulates tumour initiation and growth, but may also facilitate invasion and metastases. They conclude that measurement of IGF-1 and IGFBP-3 levels may predict the risk of advanced stage prostate cancer years before the cancer is actually diagnosed and may thus be helpful in aiding decision making about treatment.
Chan, June M., et al. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. Journal of the National Cancer Institute, Vol. 94, July 17, 2002, pp. 1099-1106
Chan, June M. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. Journal of the National Cancer Institute, Vol. 94, December 18, 2002, pp. 1893-94

THYROID HORMONE AND PROSTATE CANCER
NEW YORK, NY. Prostate cancer usually progresses very slowly and in many cases, especially among older men, requires no other treatment than "watchful waiting". The problem, of course, is to identify those cases that do require aggressive treatment (surgery and radiation) in order to prevent metastasis. Researchers at Mount Sinai School of Medicine now report that the thyroid hormone, triiodothyronine (T3), may be a useful marker for prostate cancer aggressiveness. It is well established that T3 is required for the growth of prostate cancer cells in vitro. The researchers measured T3 levels in 208 men aged 46 to 96 years. Twenty of the men had an enlarged prostate (benign prostatic hyperplasia or BPH), 161 had localized prostate cancer, and 27 controls had neither BPH nor prostate cancer. The researchers found that men with BPH had significantly higher levels of T3 than did the controls and the prostate cancer patients. Prostate cancer patients also had significantly higher levels than the controls, but lower levels than the men with BPH. The researchers conclude that T3 may be a useful biomarker for prostate cancer, but that more work is required to definitely establish this. They also suggest that new therapies for BPH and prostate cancer could perhaps be directed towards inhibiting the mitogenic (cell dividing) effects of T3.
Lehrer, Steven, et al. Serum triiodothyronine is increased in men with prostate cancer and benign prostatic hyperplasia. Journal of Urology, Vol. 168, December 2002, pp. 2431-33

THE DEMISE OF PC-SPES
LA JOLLA, CALIFORNIA. The herbal compound, PC-SPES, was touted as an effective prostate cancer cure in the mid- to late 1990s. Many patients and alternative medicine practitioners reported excellent results with it. By the summer of 2001 reports began to appear on the Internet of possible contamination with diethylstilbestrol, a synthetic form of estrogen. The California Department of Health Services tested several lots of PC-SPES and found that they were contaminated with diethylstilbestrol and warfarin. In February 2002 the Health Services issued a warning about the product and its manufacturer, BotanicLab, voluntarily recalled it. BotanicLab went out of business in June 2002 and PC-SPES is no longer available.Researchers at the University of California obtained several lots of PC-SPES manufactured between 1996 and 2001. They tested them and found that they, particularly the early lots, were effective in killing prostate cancer cells. They also found that the early lots were heavily contaminated with diethylstilbestrol and the anti-inflammatory drug indomethacin (Indocin). In July 1998, warfarin, an anticoagulant began to appear in the product in quantities that could affect blood clotting.
The researchers conclude that phytochemical (herbal) compounds may well have a place in the treatment of prostate cancer, but that manufacturing practices and quality control procedures need to be vastly improved before such compounds can be reliably tested in clinical trials.
Sovak, Milos, et al. Herbal composition PC-SPES for management of prostate cancer: identification of active principles. Journal of the National Cancer Institute, Vol. 94, September 4, 2002, pp. 1275-81
White, Jeffrey. PC-SPES: a lesion for future dietary supplement research. Journal of the National Cancer Institute, Vol. 94, September 4, 2002, pp. 1261-63 (editorial)

HOT CHEMOTHERAPY
Encasing chemotherapy drugs in liposomes (hydrated phospholipid globules) before injecting them is becoming increasingly popular as it encourages the drugs to enter only cancer cells and leave healthy ones alone. Researchers at the Duke Cancer Center in North Carolina have found that heating up the tumours with microwaves or hot water (in the case of breast cancer) while injecting the liposomes make them far more effective. In a trial involving 21 women with breast cancer the researchers found that a combination of heat and chemo drug/liposomes shrank or completely destroyed all 21 tumours involved. Other medical centers have had equally encouraging results and work is now underway to test the technique on prostate cancer.
New Scientist, May 25, 2002, p. 13

PROSTATE BIOPSIES OFTEN UNNECESSARY
SHREVEPORT, LOUISIANA. It is common practice to perform a biopsy of the prostate on men whose PSA (prostate specific antigen) level exceeds 4.0 ng/mL. The results of the biopsy, which is expensive, uncomfortable and anxiety-provoking, are negative in most cases (65 to 85 per cent negative) indicating that no cancer is present. Urologists at the Louisiana State University point out that acute prostatitis (inflammation of the prostate gland) and benign prostatic hypertrophy (enlarged prostate) can also give high PSA readings. They now report on a just completed trial designed to determine if men with chronic prostatitis also have high readings and if so, how often these abnormal readings actually are an indication of prostate cancer. Their trial involved 95 men who had been diagnosed with chronic prostatitis and who had an elevated PSA level (average of 8.48 ng/mL), but no abnormalities in digital rectal examination. The men were all assigned to a four-week course of antibiotics (fluoroquinolones or doxycycline) and anti-inflammatories (ibuprofen or celecoxib). At the end of the four weeks 44 of the men (46.3 per cent) had a PSA level of less than 4 ng/mL (mean of 2.48 ng/mL) and were deemed to be free of prostate cancer. The remaining 51 men underwent double sextant transrectal ultrasound guided biopsy. Thirteen patients (25.5 per cent) were found to have prostate cancer, 37 (72.5 per cent) had chronic inflammation, and one patient had an enlarged prostate. The researchers conclude that treatment of chronic prostatitis in men with high PSA levels can substantially reduce the need for biopsies. It is of interest to note that the PSA levels in the men eventually diagnosed with prostate cancer only declined from an average of 8.32 to 7.92 ng/mL after four weeks of antibiotic therapy.
Editor's Note: The moral of this story is that one should always ensure that one does not have acute or chronic prostatitis before submitting to a prostate biopsy.
Bozeman, Caleb B., et al. Treatment of chronic prostatitis lowers serum prostate specific antigen, Journal of Urology, Vol. 167, April 2002, pp. 1723-26

BOTANICLAB RECALLS PC SPES
BotanicLab (www.botaniclab.com) has issued a voluntary recall notice for its PC SPES product. It has been found highly effective in the treatment of prostate cancer. The recall notice was prompted by a test carried out by the California Department of Health that revealed the presence of a small amount of a warfarin-like compound. Further testing is underway to determine if the compound is actually warfarin or a natural component of the eight herbs contained in PC SPES.
California Department of Health Services, Office of Public Affairs, Press Release 02-03, February 7, 2002

TOMATO SAUCE AND PROSTATE CANCER
CHICAGO, ILLINOIS. Several studies have observed that tomatoes and tomato products, especially tomato sauce, have a protective effect against prostate cancer. Researchers at the University of Illinois now report that tomato sauce is also effective in slowing down and perhaps even reversing existing prostate cancer. Their study involved 32 patients with prostate cancer who were scheduled to undergo a radical prostatectomy. The participants underwent a baseline examination to determine their lycopene levels, their PSA (prostate specific antigen) level, and the level of oxidative damage to their DNA (in leukocytes). They were then fed a pasta dish with tomato sauce (3/4 of a cup of commercial spaghetti sauce) once a day for three weeks. The additional daily lycopene intake from the sauce was 30 mg.At the end of the three-week period lycopene levels in the blood plasma had doubled and lycopene levels in prostate tissue had tripled. The average PSA level had declined from 10.9 ng/mL to 8.7 ng/mL - a drop of 17.5 per cent. The DNA damage indicator in leukocytes dropped by 21.4 per cent after the intervention. The DNA damage level in actual prostate tissue (removed during surgery) was found to be 28.3 per cent lower in the tomato sauce group than in a reference group of seven prostate cancer patients who had not consumed the tomato sauce diet. The researchers conclude that their study "suggests a role for tomato sauce and possibly for lycopene in the prevention and treatment of prostate cancer."
Chen, Longwen, et al. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. Journal of the National Cancer Institute, Vol. 93, December 19, 2001, pp. 1872-79

TESTOSTERONE REPLACEMENT IN MEN
CHARLOTTESVILLE, VIRGINIA. The National Institute on Aging Advisory Panel on Testosterone Replacement in Men has just issued a report summarizing the current knowledge about testosterone deficiency and replacement in older men. The panel concluded:

• A total testosterone level below 250 nanograms/mL is associated with decreased sexual function and osteoporosis.
• It is possible that as many as 5 to 50 per cent of older men would be candidates for testosterone replacement therapy.
• Most studies have shown a small increase in lean body mass and bone mineral density and a reduction of fat mass with testosterone replacement.
• It is possible that testosterone replacement may be favourable as far as heart disease is concerned, but unfavourable in regard to prostate cancer.
• Further studies are urgently required to determine if testosterone replacement therapy increases the risk of prostate cancer and benign prostatic hypertrophy (enlarged prostate). It is also possible that it could increase the level of prostate specific antigen (PSA) with the possible consequence of unnecessary biopsies and surgery.
• If testosterone replacement therapy is warranted it should be administered in the form of a gel or patch.

PC-SPES: A CURE FOR PROSTATE CANCER?
GADSDEN, ALABAMA. PC-SPES is a mixture of eight herbs - seven of them Chinese. It has been used in alternative medicine for some time in the treatment of prostate cancer. Now the results of three clinical trials confirm its effectiveness, not only in decreasing PSA (prostate specific antigen) levels and slowing down progression of the cancer, but also in alleviating pain and improving quality of life. One major trial included 33 patients with androgen-dependent (AD) prostate cancer and 37 patients with androgen-independent (AI) disease (a more severe form). The patients received three capsules of PC-SPES three times a day (BotanicLab, http://www.botaniclab.com). Patients with AD disease saw an average 80 per cent decrease in PSA levels over a 23-week period - two patients experienced a reduction in bone metastasis. All patients experienced loss of libido, impotence and a precipitous fall in testosterone levels. PSA levels also declined in the AI group, but to a somewhat lesser degree (greater than 50 per cent). Another study of patients with AI disease concluded that PC-SPES significantly reduced pain and improved quality of life scores. Dr. John Pirani of Clinical Urology Associates concludes that PC-SPES is a valid therapy option for prostate cancer. However, it is not entirely benevolent. It can cause nipple tenderness and breast enlargement. If taken in excessive dosages it can cause internal bleeding because of its content of warfarin-like compounds. Medical doctors at the University of Washington warn that PC-SPES should only be taken under the supervision of a physician and dosages in excess of six capsules a day should be avoided.
Pirani, John F. The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology, Vol. 58, suppl. 2A, August 2001, pp. 36-38
Weinrobe, Mark C. and Bruce Montgomery. Acquired bleeding diathesis in a patient taking PC-SPES. New England Journal of Medicine, Vol. 345, October 18, 2001, pp. 1213-14 (correspondence)

PROSTATE CANCER AND LYCOPENE
DETROIT, MICHIGAN. Epidemiological studies have shown that a high intake of tomatoes markedly reduces the risk of prostate cancer. It is believed that this beneficial effect is due to lycopene, the most common carotenoid in tomatoes. A team of researchers from Wayne State University, McGill University, University of Maryland, and the University of Hawaii has just concluded a clinical trial aimed at evaluating the benefits of lycopene supplementation in prostate cancer patients. The study included 26 men with clinically localized prostate cancer who were scheduled to undergo radical prostatectomy (removal of the prostate gland). The men were randomized into a control group and an intervention group. The intervention group received one 15-mg lycopene capsule with breakfast and dinner for three weeks prior to surgery. Blood samples were taken before the start of supplementation and three weeks later just before surgery. The removed tumors and surrounding tissue were examined by pathologists.The researchers conclude that lycopene supplementation lowers PSA levels; they observed an average 18 per cent decrease in the lycopene group as compared to a 14 per cent increase in the control group. The level of the tumor suppressing protein Cx43 in the malignant part of the tumor was found to be substantially higher in the lycopene group. It was also apparent that tumors tended to be smaller and more sharply defined (less encroachment into surrounding healthy tissue) in the lycopene group. No adverse effects of the lycopene supplementation were reported by the patients or their physicians. The researchers conclude that lycopene is likely to be beneficial for both prevention and treatment of prostate cancer, but urge larger trials to confirm this.
Kucuk, Omer, et al. Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiology, Biomarkers & Prevention, Vol. 10, August 2001, pp. 861-68 [72 references]

PROSTATE CANCER AND OSTEOPOROSIS LINKED
BOSTON, MASSACHUSETTS. Men with advanced prostate cancer undergoing hormone treatment or castration (androgen-deprivation therapy) experience rapid bone loss markedly exceeding that associated with menopause in women. This bone loss, in turn, leads to a two- to six-fold increase in bone fractures especially those involving the hip. Medical doctors at the Massachusetts General Hospital now warn that the osteoporosis and fracture risk is magnified by the fact that many men with advanced prostate cancer have osteoporosis or low bone density before they even start androgen-deprivation therapy. The study involved 41 men with locally advanced, lymph node positive or recurrent prostate carcinoma with no evidence of bone metastases. The men underwent dual-energy x-ray absorptiometry (DXA) and quantitative computed tomagraphy (QCT) to determine their bone density. The prostate cancer patients tended to have significantly lower bone density in the hip and lumbar spine area than did age-matched controls and young adult men. The QCT values for trabecular bone mineral density of the lumbar spine indicated that 63 per cent of the 41 men had osteoporosis. Seventeen per cent of the men had a vitamin D deficiency and 59 per cent had a calcium intake below the recommended daily intake of 800 mg/day. The researchers point out that a vitamin D deficiency is a risk factor for both prostate cancer and osteoporosis. They also emphasize that there is no established causal relation between prostate cancer risk and calcium intake above 800 mg/day. They conclude that prostate cancer patients should be routinely screened for bone mineral density before androgen-deprivation therapy is initiated.
Smith, Matthew R., et al. Low bone mineral density in hormone-naive men with prostate carcinoma. Cancer, Vol. 91, June 15, 2001, pp. 2238-45

COMPARISON OF PROSTATE CANCER TREATMENTS
BOSTON, MASSACHUSETTS. At present there are three major conventional treatment options for non-metastatic prostate cancer. Expectant management essentially means to watch and see if the cancer gets worse. Prostate tumours grow very slowly (doubling every four years) so for many men, especially older ones, this approach is quite viable. Expectant management often includes androgen-deprivation therapy (castration or estrogen). External beam radiotherapy involves the shrinking or destruction of the tumour by radiation. Radical prostatectomy involves surgical removal of the entire prostate gland. This procedure carries a substantial risk of subsequent impotence (60 per cent incidence rate) and incontinence (39 per cent incidence rate). Researchers at several major American hospitals and universities have just released a major study of the long-term outcome of the three standard therapies. The study involved 2311 men aged 55 to 74 years at time of diagnosis during 1971 to 1984. By 1994 584 men had died from prostate cancer and 828 from other causes. The 10-year survival rate in the case of prostate cancer was 75 per cent for expectant management, 67 per cent for radiotherapy, and 86 per cent for radical prostatectomy. The researchers emphasize that these percentages are not directly comparable. For example, the members of the expectant management group were considerably older (45 per cent between the ages of 70 and 74 years) than the members of the other two groups (17 per cent between the ages of 70 and 74 years). In all cases men who underwent androgen-deprivation therapy had poorer survival than men who did not.

The results of this study differ somewhat from the results of a similar study carried out at the Johns Hopkins School of Hygiene and Public Health. This study concluded that patients who underwent radiation therapy had an 81 per cent higher risk of dying from prostate cancer than did men who received no treatment (watchful waiting). Patients who received hormones or were castrated increased their risk of dying by 85 per cent (compared with no treatment) while men who just underwent surgery with no additional treatment had a 23 per cent lower death rate (from prostate cancer) than did men who had not received any treatment. It is not clear whether the poorer survival rate among men who had androgen-deprivation therapy is due to the fact that this therapy is actually detrimental or due to the fact that it is preferentially prescribed for men with more advanced cancer.
Barry, Michael J., et al. Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostatectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer, Vol. 91, June 15, 2001, pp. 2302-14
Newschaffer, Craig J., et al. Causes of death in elderly prostate cancer patients and in a comparison nonprostate cancer cohort. Journal of the National Cancer Institute, Vol. 92, April 19, 2000, pp. 613-21

ALTERNATIVE CANCER TREATMENTS
TAMPA, FLORIDA. The National Institutes of Health has been funding several studies into the use of alternative and complementary cancer therapies. It is estimated that between 85 and 90 per cent of all cancer patients being treated at major centers now use some form of alternative therapy in combination with conventional treatment. Electroacupuncture has been found highly effective in reducing nausea and vomiting during chemotherapy. Extracts from the maitake mushroom show promise in the treatment of gastrointestinal, breast, lung and ovarian cancers, but large-scale clinical trials are still needed. PC-SPES, a mixture of eight Chinese herbs, is now widely used to treat prostate cancer. Dr. Abraham Mittelman, MD of the Westchester Medical Center reported at a recent meeting of the American Cancer Society that PC-SPES has been found to significantly lower prostate specific antigen (PSA) levels, reduce bone metastasis and lymph node swelling, and markedly alleviate pain. Dr. Mittelman says that several clinical trials of PC-SPECS are underway, but that the herbal mixture is already available for use and can be purchased over the Internet (www.pc-spes.com). He recommends that a physician monitors the treatment as phlebitis and blood clots in the lungs have occurred in a few patients taking PC-SPES. Dr. David Golde, MD at the Memorial Sloan-Kettering Institute also reported at the Cancer Society meeting that while vitamin C may generally be beneficial to cancer patients high doses can counteract the effects of radiation and chemotherapy.
McCann, Jean. Alternative remedies for cancer: an update. Journal of the National Cancer Institute, Vol. 92, June 7, 2000, p. 872

PROSTATE CANCER: TO TREAT OR NOT?
BALTIMORE, MARYLAND. The number of men diagnosed with prostate cancer has increased dramatically since the introduction of the PSA (prostate specific antigen) test. Widespread use of the PSA test has led to more men undergoing biopsies, prostate surgery, radiation therapy, and castration (orchidectomy) - this despite the fact that no randomized clinical trial has ever demonstrated that screening and treatment will increase the life expectancy of men diagnosed with prostate cancer.Researchers at the Johns Hopkins School of Hygiene and Public Health now report that aggressive treatment of prostate cancer is associated with an increased risk of dying from other cancers. Their study involved 1996 prostate cancer patients (diagnosed from 1987 through 1989) and 6586 men with benign prostatic hyperplasia (enlarged prostate) who did not have prostate cancer. The men were all 67 years of age or older at the time of diagnosis. By the end of 1995 1207 of the patients in the prostate cancer group had died (60 per cent) as compared to 2906 patients in the non-prostate cancer group (44 per cent). Prostate cancer as such was the cause of death in 39 per cent of the prostate cancer group with the remaining 61 per cent dying from other causes such as heart disease, stroke, and other cancers. The percentage of prostate cancer patients who died from prostate cancer rather than from other causes was significantly higher among men with advanced prostate cancer than among men with localized tumors only.

Combining all deaths from prostate cancer (no distinction was made by severity) it was found that patients who underwent radiation therapy had an 81 per cent higher risk of dying from prostate cancer than did men who received no treatment (watchful waiting). Patients who received hormones or were castrated increased their risk of dying by 85 per cent (compared with no treatment) while men who just underwent surgery with no additional treatment had a 23 per cent lower death rate (from prostate cancer) than did men who had not received any treatment. Of particular interest is the finding that the adjusted odds of dying from other cancers was 29.9 per cent among aggressively-treated prostate cancer patients as compared to only 13.7 per cent among non-treated (watchful waiting) patients and 18.9 per cent among non-prostate cancer patients. It was also clear that the risk of dying from prostate cancer decreases with age. Men whose prostate cancer was diagnosed at age 85 or older had a 44 per cent lower risk of dying of prostate cancer than did men whose cancer was diagnosed between the ages of 67 and 74 years. The researchers caution that bias in reporting cause of death may have influenced the study results and recommend additional studies to support or discard the hypothesis that early detection and treatment lead to decreased prostate cancer mortality.
Newschaffer, Craig J., et al. Causes of death in elderly prostate cancer patients and in a comparison nonprostate cancer cohort. Journal of the National Cancer Institute, Vol. 92, April 19, 2000, pp. 613-21
Albertsen, Peter. When is a death from prostate cancer not a death from prostate cancer? Journal of the National Cancer Institute, Vol. 92, April 19, 2000, pp. 590-91 (editorial)

EFFECTS OF PROSTATECTOMY CAN BE DEVASTATING
SEATTLE, WASHINGTON. It is estimated that almost 180,000 American men will be diagnosed with prostate cancer in 1999. More than 70 per cent of these cancers will be localized and will be treated with radical prostatectomy (removal of the prostate gland) or radiation or in some cases will be left alone and watched carefully for further growth (expectant management). The most commonly chosen option is radical prostatectomy. It has long been known that this surgery can have serious after effects specifically impotence and incontinence. However, what has been less clear is just how frequent these complications are.

Researchers at the Fred Hutchinson Cancer Research Center have just released the results of a major study which paints a grim picture of the seriousness and frequency of the after effects of radical prostatectomy. The study involved 1291 black, white, and Hispanic men between the ages of 39 and 79 years who had been diagnosed with localized prostate cancer between October 1, 1994 and October 31, 1995. All the men had undergone radical prostatectomy within six months of diagnosis. The men completed questionnaires or had personal interviews about their urinary and sexual functions at baseline and 6, 12 and 24 months after diagnosis.

At 18 or more months following surgery 59.9 per cent of the men were impotent and 38.9 per cent reported involuntary urination (incontinence) at least once a day. Only 37.8 per cent of the men reported no problems with incontinence and only 14 per cent reported no problem with sexual function. Prior to surgery 77.8 per cent reported no problem with incontinence and 50.3 per cent reported no problem with sexual function. The after effects of prostatectomy were less pronounced among younger men and among men with higher education and higher income. The decline in sexual function was most pronounced among white men and least pronounced among black men. Nerve-sparing surgery improved the outcome somewhat with 65.6 per cent of men having non-nerve-sparing surgery being impotent after 18 months as compared to 56 per cent among men having had bilateral nerve-sparing surgery. Surprisingly, 75.5 per cent of the men were satisfied with their surgery and 71.5 per cent said that they would choose radical prostatectomy again.
Stanford, Janet L., et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer. Journal of the American Medical Association, Vol. 283, January 19, 2000, pp. 354-60

TOFU FIGHTS PROSTATE CANCER
HELSINKI, FINLAND. Japanese men who consume a low-fat diet with a high content of soy products are much less likely to die from prostate cancer than are men who eat a normal Western diet. Soy products such as tofu are known to have a high content of isoflavonoids, the so called phyto-oestrogens. Researchers at the University of Helsinki and the National Cancer Center Research Institute in Tokyo believe that dietary isoflavonoids inhibit the growth of prostatic cancer cells and that this protective effect explains the lower mortality among Japanese men. The researchers analyzed blood samples from 14 Japanese men (average age: 55 years) and 14 Finnish men of similar age. They found that the isoflavonoid content in the blood from the Japanese men was seven to 110 times higher than the level in the Finnish men. A decreased risk for prostate cancer has also been found among Adventist men who eat a diet rich in beans, lentils, peas, and dried fruit.
Adlercreutz, Herman, et al. Plasma concentrations of phyto-oestrogens in Japanese men. The Lancet, Vol. 342, November 13, 1993, pp. 1209-10

WATCHFUL WAITING MAY BE BEST OPTION FOR PROSTATE CANCER
FARMINGTON, CONNECTICUT. Researchers at the University of Connecticut have reached the conclusion that the frequency of prostate cancer operations is growing at a rate completely out of proportion to the actual increase in the number of cases of prostate cancer. A recent study in Wisconsin found that between 1989 and 1991 the incidence of diagnosed prostate cancer rose by 33 per cent (mainly due to the increasing use of the PSA test). However, the frequency of prostatectomies (surgical removal of the prostate) rose by 226 per cent. The side effects of prostatectomy are very serious. Among men aged 65 to 69 years, 1 per cent die from the operation, 34.5 per cent become impotent, and 4.5 per cent become incontinent. The researchers strongly recommend that doctors counselling their patients about the options regarding treatment for localised prostate cancer place more emphasis on the idea of just keeping an eye on things and avoiding drastic measures unless the cancer spreads. This approach, "watchful waiting" or "expectant management", is used extensively and successfully in Europe. Recent studies have shown that there is no clear evidence that prostate surgery improves the overall survival of patients especially older ones. As one doctor put it "most patients die with prostate cancer rather than of it."
Bilgrami, Syed and Greenberg, Bernard R. Why so many operations for localised prostate cancer? The Lancet, Vol. 344, September 10, 1994, pp. 700-01

TREATMENT OPTIONS FOR PROSTATE DISORDERS
BOSTON, MASSACHUSETTS. Dr. Floyd Fowler, Jr. of the University of Massachusetts provides food for thought in a recent editorial in the Journal of the American Geriatrics Society. Dr. Fowler discusses the treatment options for benign prostatic hyperplasia (BPH) and prostate cancer and concludes that less or no treatment at all is often the best option. He points out that most men eventually develop some symptoms of BPH, but that this disorder rarely is life-threatening. Dr. Fowler suggests that the decision regarding treatment for BPH should be left up to the patient. If he can live with getting up to urinate three or four times a night then no treatment is probably the best option. The choice between treatment and no treatment of prostate cancer is more complicated, but again, the patient must be fully informed before a decision is made. A recent survey of Medicare patients who had undergone radical prostatectomy showed that fewer than 10 per cent of the patients felt that their doctor had explained to them that no treatment at all (watchful waiting) could have been a viable alternative. This despite the fact that incontinence and impotence are very common side effects of prostate surgery.In a related article, Dr. Brian Budenholzer, MD recommends that PSA screening be discouraged in men who do not have symptoms of prostate cancer. He points out that there is no evidence that it is of benefit to such men and that having the test can cause harm.
Fowler, Floyd J., Jr. Prostate conditions, treatment decisions, and patient preferences. Journal of the American Geriatrics Society, Vol. 43, No. 9, September 1995, pp. 1058-60
Budenholzer, Brian R. Prostate-specific antigen testing to screen for prostate cancer. The Journal of Family Practice, Vol. 41, No. 3, September 1995, pp. 270-78

OXYGEN THERAPY CURES BLEEDING BLADDER INFLAMMATION
AMSTERDAM, THE NETHERLANDS. Patients who receive radiation treatment for bladder or prostate cancer or cancer of the uterus, cervix or ovary may develop a bleeding bladder inflammation many years later. These patients are difficult to treat and often require numerous blood transfusions. Now Dutch doctors report that oxygen therapy is effective in halting the bleeding and curing the inflammation. Their experiment involved 40 patients with radiation-induced cystitis (bladder inflammation) and severe bleeding. The patients were given twenty treatments of 100 per cent oxygen inhalation at 3-bar pressure for 90 minutes in a multiplace hyperbaric chamber. The treatments were given in daily sessions 5 or 6 times a week. The bleeding disappeared completely or lessened significantly in 37 of the patients. The doctors point out that the oxygen therapy had no adverse side effects and that it saved 36 of the patients from having their bladder surgically removed.
Bevers, R.F.M., et al. Hyperbaric oxygen treatment for haemorrhagic radiation cystitis. The Lancet, Vol. 346, September 23, 1995, pp. 803-05

VITAMIN A MAY PREVENT PROSTATE CANCER
HOUSTON, TEXAS. Vitamin A (retinol) and its biologically active metabolite, retinoic acid, are known to be useful in the prevention and treatment of certain cancers such as acute promyelocyte leukemia. Now researchers at the Baylor College of Medicine report that vitamin A may also play a role in the prevention and treatment of prostate cancer. The researchers analyzed prostate tissue from patients with stage 3+ prostate cancer, tissue from patients with benign prostate hyperplasia (enlarged prostate), and normal tissue. They made several interesting observations:

• All tissues tested contained retinol and retinoic acid in various concentrations. The retinol concentration in tissue from enlarged prostates was 2.5 times higher than in normal tissue or tissue from cancer patients. Tissue from cancer patients contained near normal levels of retinol, but only barely detectable levels of retinoic acid.
• The prostate contains enzymes which enables it to convert retinol supplied in the diet to the biologically active retinoic acid.

NO TREATMENT MAY BE A VIABLE OPTION FOR PROSTATE CANCER
OREBRO, SWEDEN. Swedish researchers have previously reported that watchful waiting is a viable option when dealing with localized prostate cancer. Now researchers from the Orebro Medical Centre and the University of Uppsala confirm this conclusion based on data from 15 years of follow-up. Their study involved 642 men with an average (mean) age of 72 years who had been diagnosed with prostate cancer in the period March 1977 to February 1984. Three hundred to the men had localized tumors (stage T0-T2). The majority of men in this group (223) were given no treatment initially, but were treated with estrogen or orchiectomy (castration) if the cancer progressed. The remaining 77 men were treated immediately with radiation, estrogen, orchiectomy or radical prostatectomy. After 15 years of follow-up the researchers concluded that there was no difference in survival rate between the group given immediate treatment and the group "treated" by watchful waiting. Considering the many and very serious side effects of aggressive prostate cancer treatments it is clearly an important finding that such treatments can safely be postponed in patients with localized tumors. The overall 15-year survival rate in the 300 men diagnosed with localized cancer was 81 per cent (corrected for causes of death other than prostate cancer). For men who were initially diagnosed with locally advanced cancer (stage T3-T4) the corrected 15-year survival rate was 57 per cent and for men whose cancer had spread to other sites (metastasis) at time of initial diagnosis the survival rate was only 6 per cent; this despite aggressive treatment with estrogen, orchiectomy, and chemotherapy. The researchers conclude that watchful waiting is a viable option in the case of localized prostate cancer and that the benefit of radical initial treatment is limited. Patients with locally advanced or metastatic disease, on the other hand, need aggressive therapy to improve their poor prognosis. The Swedish researchers are ambivalent about the value of routine PSA screening fearing that it may do more harm than good.

In commenting on the Swedish study medical doctors at the Johns Hopkins University School of Medicine point out that the overall mortality rate from prostate cancer is substantially higher in Sweden than in the USA. They also point out that prostate cancer mortality has dropped significantly (by 6.3 per cent) in the USA between 1971-1990 and 1991-1995. They credit much of this improvement to the increased use of PSA testing and point out that "it is reasonable to expect that the 70-year-old man who is dying of prostate cancer today was once a 55- or 60-year-old man with clinically localized disease that was not diagnosed." However, the American doctors do not question the main finding of the Swedish study that watchful waiting may indeed be a viable option for some patients with small, localized tumors.
Johansson, Jan-Erik, et al. Fifteen-year survival in prostate cancer: a prospective, population-based study in Sweden. Journal of the American Medical Association, Vol. 277, No. 6, February 12, 1997, pp. 467-71
Walsh, Patrick C. and Brooks, James D. The Swedish prostate cancer paradox. Journal of the American Medical Association, Vol. 277, No. 6, February 12, 1997, pp. 497-98 (editorial)

AGED GARLIC EXTRACT KILLS PROSTATE CANCER CELLS
NEW YORK, NY. A team of research scientists from the Memorial Sloan-Kettering Cancer Center and Cornell University report that certain extracts from aged garlic is highly effective in halting the growth and proliferation of human prostate cancer cells in vitro. Human prostate cancer cells (LNCaP cells) were cultured for 24 hours and then exposed to a saline solution containing 50 ppm of either S-allylcysteine or S-allylmercaptocysteine. Both of these water-soluble garlic components are found in crushed garlic that has been aged for at least a year; they are not present in fresh garlic. The researchers incubated the cancer cells for an additional 1, 4, 6 and 8 days and then measured the number of active cells. They found that S-allylmercaptocysteine reduced the number of cancer cells by more than 50 per cent after 6 and 8 days. Incubation was then continued for another 4 days after rinsing and removal of the S-allylmercaptocysteine. A new cell count showed that the inhibitory effect of S-allylmercaptocysteine continued even after its removal. S-allylcysteine also inhibited cancer cell growth, but to a much lesser extent than S-allylmercaptocysteine. Both compounds were also effective in regenerating the important antioxidant glutathione and in reducing the amount of certain proteins necessary for the proliferation of cancer cells. The researchers conclude that aged garlic components or derivatives may be useful in controlling the proliferation of prostate cancer cells. Note: This study was partly supported by Wakunaga of America Company, Ltd., a major manufacturer of aged garlic products.
Pinto, John Thomas, et al. Effects of garlic thioallyl derivatives on growth, glutathione concentration, and polyamine formation of human prostate carcinoma cells in culture. American Journal of Clinical Nutrition, Vol. 66, August 1997, pp. 398-405
Heber, David. The stinking rose: organosulfur compounds and cancer. American Journal of Clinical Nutrition, Vol. 66, August 1997, pp. 425-6 (editorial)

RED CLOVER COMBATS PROSTATE CANCER
SYDNEY, AUSTRALIA. It is becoming increasingly clear that a diet high in phyto-estrogens and low in meat, animal fats and dairy products is protective against prostate cancer. Phyto-estrogens consist of two major groups - isoflavonoids found in soy and legumes and lignans found in nuts, cereals, fruits, berries and vegetables. Now Professor Frederick Stephens of the University of Sydney reports on a case where a 66-year-old physician with prostate cancer took a concentrated phyto-estrogen based on red clover for just one week and thereby caused his tumour to regress. The patient had been diagnosed with a high PSA level (13.1 micrograms/liter) in March 1996 and a subsequent needle biopsy had confirmed the presence of a low grade adenocarcinoma. He was scheduled for a radical (suprapubic) prostatectomy and, on his own initiative, decided to take a daily dose of 160 mg of a phyto-estrogen product based on red clover (Promensil tablets - 4 X 40 mg/day) for the seven days preceding his operation. After the operation the biopsy tissue and the tumour tissue were compared. It was clear that the tumour tissue showed a high degree of apoptosis (cell death) resembling the effect of high-dose estrogen therapy and consistent with tumour regression. Professor Stephens concludes that this case history provides further evidence that phyto-estrogens may prevent prostate cancer. He also points out that there were no adverse effects of the phyto-estrogen treatment.
Stephens, Frederick O. Phytoestrogens and prostate cancer: possible preventive role. Medical Journal of Australia, Vol. 167, August 4, 1997, pp. 138-40

HERBAL TREATMENT FOR PROSTATE CANCER
NEW BRUNSWICK, NEW JERSEY. Estrogenic compounds are often used in the treatment of prostate cancer. They work (sometimes) by lowering testosterone concentrations and thereby slowing tumour growth. Researchers at the Cancer Institute of New Jersey now report on their testing of PC-SPES a herbal combination which also has estrogenic activity and which has been found to inhibit the growth of both prostate and breast cancer cells. PC-SPES is a combination of eight herbs - chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto, and scutellaria (scullcap). The herbal combination was tested on eight patients with biopsy-proved prostate cancer. The patients took PC-SPES for at least one month (four 320 mg capsules /day). Their blood levels of testosterone and prostate-specific antigen (PSA) were measured before, during and two to six weeks after taking the preparation. Testosterone levels decreased markedly in all eight patients during treatment (to an average 237 ng/dL), but increased again (to an average 879 ng/dL) within three weeks after the PC-SPES was discontinued. PSA levels also decreased markedly in all eight patients after treatment with PC-SPES, but increased again (although not to original levels) within three weeks of discontinuing treatment. In one patient PSA levels decreased from 122 ng/mL to 0.4 ng/mL during treatment with PC-SPES. Side effects were similar to those observed with conventional estrogen therapy (loss of libido and breast tenderness). The researchers conclude that "our results suggest that PC-SPES may prove useful in the treatment of hormonally sensitive prostate cancer." They then, somewhat curiously, go on to say "but when used concurrently with standard or experimental therapies PC-SPES may confound the results."

Dr. Julian Whitaker MD, of the Whitaker Wellness Institute is much more enthusiastic about PC-SPES. He points out that it has been used with excellent results at the Institute for almost a year. He estimates that the herbal combination has now been used by over 1700 prostate cancer patients with improvement in about 70 per cent of cases.
DiPaola, Robert S., et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. New England Journal of Medicine, Vol. 339, September 17, 1998, pp. 785-91
Whitaker, Julian. Health & Healing, Vol. 8, November 1998, pp. 1-4

DHEA PROTECTS AGAINST PROSTATE CANCER
CHICAGO, ILLINOIS Prostate cancer is the second most common cause of cancer death in Western male populations. It is estimated that about 18 per cent of American men will develop prostate cancer during their lifetime. Some researchers believe that many more have the beginnings of prostate cancer, but die from other causes before the cancer becomes invasive and fatal. Research has shown that the hormone DHEA (dehydroepiandrosterone) inhibits the growth of both human and rat prostate cancer cells in vitro (in test tubes). Now a team of researchers from the National Cancer Institute, the New York University School of Medicine, and the ITT Research Institute reports that DHEA confers significant protection against prostate cancer progression when given to laboratory rats as part of their diet. Their experiment involved rats which were given carcinogenic chemicals to induce precancerous lesions in the prostate. One group of rats had 1000 or 2000 mg of DHEA added to each kilogram of feed starting one week before inducing the cancer. Other groups had 2000 mg of DHEA added per kilogram of diet one week before induction, 20 weeks after induction or 40 weeks after induction. The rats received the DHEA until the experiment was concluded 13 months after cancer induction. Control rats received no DHEA. The researchers found a very significant decrease in the progression to full prostate cancer among the rats given DHEA in their diets. This effect was evident whether the DHEA was given one week before or 20 or 40 weeks after cancer induction. They conclude that DHEA or a suitable derivative may be effective in preventing the development and progression of prostate cancer in humans, but caution that more work is required to ensure the DHEA's hormonal effects (conversion to testosterone and estrogenic activity) are not detrimental.
Rao, K.V.N., et al. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Research, Vol. 59, No. 13, July 1, 1999, pp. 3084-89

TESTOSTERONE SUPPLEMENTATION AND PROSTATE CANCER
KIRKLAND, WASHINGTON. Conventional medicine wisdom has it that high levels of male sex hormones (androgens) are associated with an increased risk of prostate cancer and a more rapid tumour growth. This has led to the use of chemical or physical castration in an attempt to reduce natural androgen production and thereby deprive the tumour of the androgen it supposedly requires to keep growing. Unfortunately, the effect of castration is often temporary and subsequent tumours tend to be more virulent than the original one. Dr. Richmond Prehn, MD of the University of Washington challenges the assumption that high androgen levels are a risk factor for prostate cancer. Dr. Prehn points out that androgen levels decline with age whereas prostate cancer incidence rises sharply. He suggests that declining androgen levels may not only lead to benign prostate hyperplasia (BPH), but may also be the initiator of uncontrolled cell growth which may ultimately lead to cancer. He further suggests that "androgen supplementation beginning early in the middle years might, among other possible benefits, largely prevent prostate cancer." Dr. Prehn cautions that androgen supplementation may be contra-indicated in older men who already have the seeds of prostate cancer. He also suggests that an alternating regimen of androgen deprivation and androgen supplementation should be evaluated as a therapy for prostate cancer.
Prehn, Richmond T. On the prevention and therapy of prostate cancer by androgen administration. Cancer Research, Vol. 59, September 1, 1999, pp. 4161-64