November 2007

Excess Weight Increases Prostate Cancer Mortality
Efstathiou JA, Bae K, Shipley WU et al, Obesity and mortality in men with locally advanced prostate cancer. Analysis of RTOG 85-31. Cancer [early online publication]. November 12, 2007

     Researchers associated with a multi-center U.S. trial have reported that being overweight or obese is associated with higher risk of death from localized prostate cancer than in men of normal weight.
     Obesity has been associated with an increased rate of recurrence in men with localized prostate cancer in several studies. However, the association of obesity and death from prostate cancer is unclear. To assess the relationship between weight and prostate cancer survival, researchers evaluated information from a prostate cancer clinical trial.
     The study enrolled 945 men with prostate cancer that had extended through the prostate capsule (T3) or that involved nearby lymph nodes. Study participants were treated with radiation therapy with or without Zoladex® (goserelin).
     Weight was assessed using the body mass index (BMI). A BMI between 18.5 and 24.9 is generally considered healthy, a BMI between 25 and 29.9 is considered overweight, and a BMI of 30 or higher is considered obese. Information about BMI was available for 788 of the 945 study participants. Based on BMI, 31% of subjects were classified as normal weight, 51% were classified as overweight, and 18% were classified as obese.
Conclusions:
Five-year risk of death from prostate cancer was 6.5% among men with a BMI less than 25, 13.1% among men with a BMI between 25 and 29.9, and 12.2% among men with a BMI of 30 or higher. There was no significant relationship between BMI and death from causes other than prostate cancer.

calculate your BMI by entering your height and weight in http://nhlbisupport.com/bmi/
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Tomato and Broccoli active against Prostate Cancer ―at least in Rats.
Canene-Adams K et al, Cancer Res. 2007 Jan 15;67(2):836-43

      206 Male Copenhagen rats were fed diets containing 10% tomato, 10% broccoli, 5% tomato plus 5% broccoli (5:5 combination), 10% tomato plus 10% broccoli, or lycopene for about 22 weeks starting 1 month prior to receiving tumor implants.
     The authors compared the effects of diet to surgical castration or Proscar. Castration reduced prostate weights, tumor areas, and tumor weight (62%), whereas Proscar reduced prostate weights, but had no effect on tumor area or weight. Lycopene insignificantly reduced tumor weights by 7% or 18%, respectively, whereas tomato reduced tumor weight by 34%.
     Broccoli decreased tumor weights by 42% whereas the 10% tomato plus 10% broccoli combination caused a 52% decrease.
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Statin Drugs lower Risk of Advanced Prostate Cancer
Platz EA et al, J Natl Cancer Inst 2006; 98: 1819–1825

Obesity decreases PSA in Korean men in their sixties

Kim YK et al, Body mass index influences prostate-specific antigen in men younger than 60 years of age. International Journal of Urology 14 (11), 1009–1012 (2007)

The authors evaluated the association between BMI and PSA in a group of 8640 Korean men (aged 40-79 years) without prostate cancer who received a general health checkup.
Prostate-specific antigen levels decreased with increasing BMI (P trend <0.001).
The study demonstrates that increased BMI is associated with decreased PSA levels only in men younger than 60 years of age. When determining whether to carry out prostate biopsy as part of early prostate cancer detection, obesity should be considered as a factor associated with reduced PSA in healthy young men (<60 years old) with marginal PSA levels.

Figure: Mean prostate-specific antigen (PSA) by age and body mass index (BMI) category. Means are represented by BMI category, from left to right: normal; overweight; obese, and very obese. Vertical bar indicates 95% confidence interval.

Prediction of Indolent Prostate Cancer
Roemeling S et al, Nomogram Use for the Prediction of Indolent Prostate Cancer, Cancer. 2007 Nov 15;110(10):2218-21

Screening for prostate cancer in The Netherlands detected 1659 cancers. 458 of those (30%) were predicted to be indolent, with a probability greater than 60%. The predictions were based on the sum of risk factors listed in the score chart below.
The various sums form the bottom row of the nomogram below. They indicate the probability of having indolent cancer on the vertical axis. The higher the sum, the larger the probability that one has indolent cancer but even low scorers have a chance of indolent cancer, and high scorers don’t always do well.
 
Score Chart for Predicting Indolent Prostate Cancer

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October 2007

Men, recently diagnosed with prostate cancer, share their experiences at our support group. They talk about a PSA higher than expected, the biopsy, their diagnosis, and the proposed treatment. We rarely hear about the prognosis.
   The prognosis is excellent for those with a Gleason sum of 6 and a PSA less than 15. Statistically, patients diagnosed with prostate cancer (PSA<15, GS <6) will live longer than those not diagnosed with prostate cancer! Please, read about this amazing result in the September 2007 issue of our newsletter (the HTML and PDF versions have a link to the original article).
   One explanation is the so-called Fernald effect:  People residing near the former Fernald uranium processing plant in south-western Ohio are living longer and enjoying healthier lifestyles than those in the general population because they are medically examined more frequently than the population further away from Fernald. Similarly, men with prostate cancer see a physician more often than those without prostate cancer.
   A few men decide upon a course of action shortly after their visit to the urologist. Most men see a radiation oncologist as well. Some make visits to specialists in Columbus, Cleveland or other cities outside Ohio. They tell us the same story: urologists propose surgical removal of the prostate (prostatectomy), and the radiation oncologists advise radiation.
   Recently, some surprising changes occurred. Both Dr. Bracken (urologist) and Dr. Barrett (radiation oncologist) advised Active Surveillance to two of our new members. Of course, this does not imply that such advice had not been given in the past, or by other physicians, but we certainly did not hear about it in our support group. Local therapy for everyone! At least, that was the impression we had here in PCNG.

  The optimum management for patients with low-risk clinically localized prostate cancer continues to be controversial. Widespread PSA testing has led to stage migration and the early diagnosis of localized disease. Once diagnosed, patients are considered candidates for radical treatment, such as RRP, radiotherapy or brachytherapy; for some, radical treatment might be over-treatment.
  Thompson [12] suggested that risk stratification might be the key to the greater use of AS in managing patients with prostate cancer, and a critical element when counseling patients making treatment decisions. Low-risk patients on AS potentially could avoid treatment-related complications and meet the goals of metastasis-free survival and optimum HRQoL.
   D’Amico et al. [16] defined the ‘low-risk’ patient as one whose Gleason score is ≤ 6, the PSA level <10 ng/mL and a stage of ≤ T2a. Based on the idea that low-risk prostate cancer was curable but did not necessarily need to be cured, AS became a reasonable management strategy to reduce the risk of over-treatment in an era of PSA-screened tumours [5].
   Klotz [17] characterized low-risk patients as having indolent disease; when he applied the Kattan nomogram to patients with T1c, Gleason 3 + 3 and a PSA level of <5 ng/mL at diagnosis, there was a 91% probability that the patient would be disease-free at 5 years. Even after delaying treatment until the PSA level was 15 ng/mL, patients had an 81% probability of being disease-free. Thus, 2.3 years on AS is only likely to alter the outcome in 1–2% of patients [18]. Carter et al. [3] also reported that the relative risk in the AS group of incurable prostate cancer was not significantly different at 2 years than in a group who initiated treatment immediately. …
…Studies that addressed differences in HRQoL <Health Related Quality of Life> between AS and treatment have been more equivocal. Analysis of patients with clinically localized prostate cancer from the Surveillance, Epidemiology, and End Results (SEER) review confirmed that the ‘no treatment’ group scored important HRQoL factors (erectile dysfunction, limitation on activities, socio-economic consequences, or negative effects on spousal or other important relationships) more positively than patients who chose radiotherapy or RRP.
   Only eight (8%) of the present patients on the AS protocol were treated; factoring in the seven lost to follow-up, ≥ 85% of patients with a mean follow-up of 46.7 months (median 35.5) and mean PSA DT of 13.1 years (median 7.2) are likely to have indolent disease and, thus far, have avoided treatment.  …
…Klotz [22] reported on 299 patients followed prospectively on AS. Patients who were aged ≤ 70 years were eligible for surveillance, with a Gleason score of ≤ 6 and a PSA level of ≤ 10 ng/mL. Intermediate-risk patients were aged ≥ 70 years and could enroll if they had a PSA level of ≤ 15 ng/mL and a Gleason sum of ≤ 3 + 4. In 2001, Klotz changed the criteria for treatment and included patients with a PSA DT of <3 years or progression to Gleason ≥ 3 + 4; only 8% had a grade increase to ≥ 4 + 3 on repeat biopsy.
   Overall, the disease-specific survival was 99.3%, as two patients died from prostate cancer.To compare the present data with other published findings for AS we attempted to calculate PSA DT, PSA velocity and PSA density. In all, 92 patients with three or more PSA values were analysed to determine the PSA DT (no treatment, mean 13.1 years; treatment, 3.5 years); using the same population, PSA velocity was also calculated (no treatment 1.21 ng/mL per year, median 0.487; treatment 2.55, median 2.4). …
   Also, PSA DT … was a significant predictor of progression but PSA velocity was not. The mean PSA DT for the treatment group (3.5 years) was > 2 years, the time suggested by both Klotz [22] and Warlick et al. [23] to intervene with curative treatment.
   Clinical progression, as measured by a change in the DRE, did not alone initiate treatment. Alterations in the DRE prompted a repeat biopsy and the biopsy results then validated the need for intervention.
   In our experience with AS, 85% of men … remained on AS long-term. For those on AS there might be the psychological implications of living with a diagnosis of prostate cancer. We found that it is essential for the physician to continue a dialogue with the patient, reassessing the patient’s commitment to long-term observation (and with PSA level, DRE and repeat biopsy results) as a reasonable management strategy. …
   In conclusion, while there is controversy about the use of AS as a management strategy, we have shown that men with low-risk prostate cancer who are closely monitored with PSA tests and repeat biopsies might have a reasonable alternative to immediate intervention, without compromising curability.

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September 2007

Secondary hormonal therapy (HT) follows the primary or initial HT. When the PSA begins to rise while on primary HT some medications can bring the PSA down again. That is secondary HT. This lowering of the PSA lasted about 1 1/2-2 years for several PCNG members. This is rather typical: (Smith DC 1997; Lam JS et al 2006; Small EJ & Ryan CJ 2006). After that period the PSA begins to rise again and the cancer has become truly hormone independent = androgen independent = hormone refractory prostate cancer.
A period of 1.5-2 years does not look impressive but it implies that chemotherapy could begin that much time later, a blessing only those with a successful secondary HT can fully appreciate.

Secondary hormonal therapy usually begins by adding an anti-androgen (AA) such as Casodex, 50 or 150 mg/day, or Eulexin to a LHRH such as Lupron or Zoladex (ADT1) when the PSA begins to rise. But if the rise occurred when the patient was already taking both a LHRH and an AA (ADT2), the AA is removed. That is because in some men the androgen receptor, in which the entrance for a testosterone molecule is blocked by a similarly configured AA molecule, began acting as if the AA was actually testosterone. Removal of the AA may result in a PSA decrease in 15-20% of the patients. This is known as AAWR: Anti Androgen Withdrawal Response.

In some patients replacement of Casodex with Eulexin lowered the PSA (Nishimura K et al, 2007).

Ketoconazole and estrogen are the most common secondary hormonal drugs after the AA manipulations. Ketoconazole cream and shampoo, sold over the counter, are effective against ringworm, jock itch; athlete's foot; and flaking, scaling, and itching of the scalp caused by dandruff. Of course, the concentration of ketoconazole in those medicaments is minute.

Against prostate cancer one takes one or two 200-mg keto tablets ever eight hours. The drug blocks both adrenal and testicular androgens, and has a 50 per cent response ―i.e., the PSA is reduced― for an average of four months. The daily 600-mg dose is easier to take and appears as effective as the 1200-mg daily dose for most patients.

Ketoconazole blocks the synthesis of steroids like cortisone. At the dose of 200-mg every eight hours, ketoconazole doesn’t cause any problems if a man’s stress level is low. But if the stress level is high, replacement hydrocortisone at doses of 20-mg each morning and 10-mg each evening is given.

Ketoconazole is better absorbed in an empty but acid stomach. Take it with orange juice but not with grapefruit juice, which disables the liver’s ability to clear ketoconazole from the body. Ketoconazole also interferes with the body’s ability to clear half of all prescription drugs, including Lipitor, Zocor and Taxotere.

Estrogen can be given orally or non-orally, known as parenteral ―intramuscular or intravenous injections and transdermal patches. Several of our PCNG members have received or are receiving estrogen patches. The blood level of estradiol, an estrogen, is also measured regularly as it can vary widely ―according Ockrim JL et al, 2003, it should be about 1,000 pmol/l = 272 pg/ml. Some men apply two 0.1 mg/day patches, others up to ten.

Estrogen has cardiovascular toxicity related to how it is given. Eat it, and the metabolism of the estrogen in the liver will create problems. Some toxicity remains after parenteral (non-oral) dosing, but this toxicity manifests itself generally within the first six months of therapy (Ockrim JL et al, 2006). However, after six months parenteral estrogen will be good for heart and blood vessels. This implies that estrogen cannot be given for short periods. Changing patches weekly or after half a week (Vivelle–Dot) is also not as convenient as a Lupron or Zoladex injection every three or four months. But the patches cost a lot less.

LHRHs cause osteoporosis, and the overall fracture risk is increased 3.5 fold. This implies that many patients on primary hormonal therapy use bisphosphonates such as Fosamax or Actonel. The much more active Zometa infusion, also a bisphosphonate, is prescribed for patients with metastases in the bone.

By contrast, preliminary evidence demonstrated that bone density increased 1.9-3.6 per cent in men with prostate cancer and treated with estrogen (Ockrim JL et al, 2004).

Some men might be very relieved with estrogen patches as they will induce complete or partial relief in the 90 per cent of patients who suffered hot flashes with LHRHs (Gerber GS et al, 2000).

Secondary hormonal treatment implies postponement of chemotherapy. Fortunately, relatively few of all men diagnosed with prostate cancer will have to deal with hormonal therapy, and fewer still with secondary HT. But knowing about the success of estrogen patches as the major tool in secondary HT may make men, presently on primary HT, consider using those patches earlier than is common today.

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August 2007

About half of all patients diagnosed with prostate cancer are ‘low risk’ patients
Innovations and Challenges in Prostate Cancer: Summary Statement for the 6th Cambridge Conference
Philip W. Kantof et al. The Journal of Urology, v. 178, Supplement, September 2007, p. S5-S8.

    Although curative therapy has been shown to decrease cancer specific and overall mortality for select men with prostate cancer, all available therapies may have a significant negative effect on patient health related quality of life.
    Furthermore, as more men are diagnosed with curable tumors at younger ages, the course of the disease is lengthening. Thus, patients and physicians must consider seriously the long-term implications of disease management decisions. Risk assessment at diagnosis based on available clinical data can help guide clinician-patient decision making with respect to the optimal treatment strategy.
    Patients with a PSA level of less than 10 ng/ml, a biopsy Gleason score of 6 and a clinical stage of T1c or T2a have typically been classified as low risk. …
    Current results show that the proportion of prostate cancer patients assigned to the low risk group as defined has stabilized at just less than half of patients with newly diagnosed prostate cancer in the first 6 years of the new millennium. … Rates of active surveillance in patients at low risk have increased since the start of this decade but, despite the ongoing downward trends in risk, a period of surveillance rather than immediate treatment is likely underused as a first management option for many such men.

First Management Option of Low Risk Patients is Active Surveillance (Watchful Waiting)
Contemporary Trends in Low Risk Prostate Cancer: Risk Assessment and Treatment.
Cooperberg, Matthew R. et al.: The Journal of Urology, Volume 178, Supplement, September 2007, p. S14-S19

    With 218,890 new cases anticipated for 2007 prostate cancer accounts for almost 30% of all male cancers. A total of 27,050 men are expected to die of the disease this year, a mortality rate that is surpassed only by that of lung cancer, and yet this represents only a small fraction of the number of men who are diagnosed. Curative therapy has been shown to decrease prostate cancer specific and overall mortality for select men with the disease.
    However, all available treatments exert a potentially significant negative impact on patient health related quality of life. Furthermore, as more men are diagnosed at younger ages with curable tumors, the time course of the disease is growing ever longer. Men may expect to live many years after treatment or in some men without treatment and, thus, they must consider seriously the long-term implications of their disease management decisions. Risk assessment at diagnosis based on available clinical data can help guide clinician-patient decision making with respect to the optimal treatment strategy. Patients with PSA less than 10 ng/ml, a biopsy Gleason score of 6 or less and a clinical stage of T2a or less have typically been classified as low risk.
    A growing body of literature supports a role for a trial of active surveillance for carefully selected men with low risk tumors. However, we have previously found that on a national level the use of active surveillance (watchful waiting) decreased sharply in patients at low risk throughout the 1990s even as low risk tumors accounted for a steadily increasing proportion of diagnosed tumors.
    Of the 10,385 CaPSURE patients included in this analysis 4,232 (41.6%), 2,761 (26.6%) and 3,301 (31.8%) had low, intermediate and high risk prostate cancer at diagnosis, respectively. (CaPSURE is a database of men with biopsy proven prostate cancer, recruited from 31 academic and community based urology practices across the United States --as of July 15, 2006, 13,124 men had been recruited by participating urologists, none in Ohio.)

    The figure to the left shows trends in the distribution of patients among the risk groups. The proportion of patients at low risk almost doubled from 1990 to 1994 (27.5%) to 2000 to 2001 (46.4%) and remained relatively constant since. The greatest decrease was among patients at high risk, from 46.0% in 1990 to 1994, 29.9% in 2000 to 2001 and 25.1% in 2004 to 2006, whereas the proportion of patients at intermediate risk was relatively constant.. … The proportion of patients at low risk with clinical stage T1c disease increased dramatically and continued to increase from 29.9% in 1990 to 1994, to 78.3% in 2004 to 2006…. With regard to treatment trends among patients at low risk, we previously reported a sharp decrease in use of active surveillance from 20.3% in 1993 to 1995, to 7.9% in 1999 to 2001, and raised concern regarding possible overtreatment among patients at low risk. A recent analysis from the population based SEER registries reached similar conclusions regarding the underuse of surveillance among patients at low risk, estimating overtreatment rates of 10% of patients with RP and 45% of those with radiation therapy in whom cancer was diagnosed in 2000 to 2002.
    With increasing appreciation of the role of active surveillance for select patients with low risk tumors we now find a reversal of the trend, with active surveillance increasing from 6.2% of patients in 2000 to 2001, to 10.2% in 2005 to 2006. The use of brachytherapy decreased from a peak of 19.4% in 2000 to 2001, to 13.0% in 2005 to 2006, whereas the use of RP increased to almost 60% of patients at low risk. The use of primary ADT (Androgen Deprivation Therapy) and NADT (Neoadjuvant ADT = ADT before other treatment) decreased from peaks of 10.6% and 15.2% in 2000 to 2001, to 6.6% and 11.6%, respectively, also marking a reversal of trends previously documented in CaPSURE and SEER…. CaPSURE practice sites have not been chosen at random and, thus, they do not constitute a statistically valid sample of the United States patient population. However, they represent a broad range of geographic locales, and a mix of academic and community sites, which we believe to be the best available sample for the analysis of temporal trends in “real world” practice.

Active Surveillance (Watchful Waiting) has its drawbacks
The Relationship Between Anxiety and Time to Treatment for Patients With Prostate Cancer on Surveillance.
Latini, David M.et al: The Journal of Urology, Volume 178, issue 3, September 2007, p. 826-832.

… The proportion of men selecting surveillance in a national PCa registry ranges from 5.5% of all men to 8% of men presenting with low risk disease. Some men remain on surveillance for substantial periods with almost 60% still on surveillance more than 18 months after diagnosis. … If one calculates 5.5% of the estimated number of new PCa cases in the United States each year and adds the number of men diagnosed in previous years remaining on surveillance, the number of American men on surveillance may be substantial.
Choosing active treatment for PCa over surveillance is not without drawbacks. Men undergoing treatment report localized and systemic symptoms, resulting in poorer HRQOL. Given the cost of treatment in dollars and decrements in HRQOL, there has been ongoing debate about the tight linkage between PCa detection and treatment, and whether some men with PCa need any treatment at all.
    However, the surveillance process also imposes a burden. In a systematic review of studies of anxiety in men with PCa, of which most focused on men being screened for PCa or on men who had been treated and were presenting for PSA followup, Dale et al found that events such as a screening visit or followup PSA measurement evoked an increase in anxiety that decreased significantly after a normal result. These results are particularly relevant for men on surveillance because they must undergo repeated testing every 3 to 6 months and make repeated treatment decisions. Earlier Patel et al reported that repeated testing and decision making cause some men to seek treatment before it may be medically necessary. In their study of 88 men on surveillance 7 who did not show progression based on objective measures of disease status requested treatment because of anxiety…
    We analyzed data from CaPSURE, a national observational prostate cancer registry. A total of 105 participants had localized disease, selected surveillance vs treatment and had at least 3 prostate specific antigen values available after baseline. Cancer anxiety was measured with a 3-item scale (α = 0.78). We calculated the rate of change in prostate specific antigen with time (prostate specific antigen velocity) and used the same formula to calculate the rate of change in cancer anxiety.
    Men diagnosed with localized PCa who select surveillance instead of active treatment face a series of repeated PSA tests and other diagnostic procedures, usually culminating in a decision to undergo treatment within a few years of diagnosis. This process can substantially raise the anxiety of men about their current and future health.
    After controlling for baseline sociodemographic and clinical characteristics, and disease progression we found that the anxiety change rate was an independent predictor of being treated. That is, increasing anxiety in some men was associated with treatment receipt, in addition to an objective measure of disease progression.
    There were no significant differences between groups in insurance type. Thus, decisions about treatment were unlikely to be related to having an insurance plan that was more favorable to treatment….
Earlier CaPSURE analysis showed that 41% of men on surveillance were treated within a median of 1.7 years after diagnosis. In that study progression to treatment was related to younger age, a higher level of formal education, higher PSA and higher Gleason grade. Treated men had higher baseline and followup PSA as well as a significantly greater PSA change than men remaining on surveillance. While these results suggest important factors related to treatment in men on surveillance, our current results underscore the importance of patient anxiety on treatment decision making.
    Previous studies demonstrated heightened anxiety in men on surveillance. One group reported that patients requested treatment because of anxiety, despite no objective evidence of disease progression.

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July 2007

We had a Great Meeting in June!

Tom

How did our wives respond when we got the news?

At our last meeting our featured presenter, Neil Frankl, RN, facilitated a discussion of the psychosocial impacts of a prostate cancer diagnosis. Rather than speak to us from the lectern, he invited us to form one large circle for personal sharing. He focused us specifically on the question of how our wives responded when we got the news and how that news impacted our relationships: emotionally, sexually and on our interpersonal communication.

The range of responses was as broad as couples are different. At one end of the spectrum of reactions, some wives (and husbands) were traumatized and speechless and found it difficult to discuss the matter itself, let alone how they were feeling about each other through the process. Others found ways to share not only with wives but also with children, siblings and work colleagues. Thinking through some of the "right words" can make wider sharing more comfortable.

Two points emerged in this connection. First, each couple has its own distinctive communication style, some more open and interactive, others less. The way they react emotionally to cancer treatment reflects their basic style to begin with. Second, as many have found, getting lots of information from PCNG, the internet and from a variety of medical people helps to relax the anxiety for dealing with PC and if spouses share this educational process, their level of intimacy can increase.

Other anecdotes shared included the point that sometimes the wife is the person to lead the PC information gathering process which can have a positive impact on a more Gary Cooper-type husband. There were a few comments about being more concerned with finding the "facts" about doctors and treatment choices and deferring emotional sharing until later.

Several men described how they shared their diagnosis with their adult children. Some were pleasantly surprised at how their children responded with warmth and caring and offered concrete help.
Generally, members perceived that we underestimate the depth of impact on our couple communication, our sexual intimacy and the practical changes in our life routines.

There were suggestions that doctors' offices should incorporate some support component from a mental health professional as part of their treatment protocol.
Finally, Tom Young made reference to two excellent books on impotency, sexual intimacy and the rekindling of physical contact.

Jack Peltz

In every struggle the only ones who can truly grasp…..

My husband Bruce was diagnosed with prostate cancer in April 2007. He had a laparoscopic, robotic prostatectomy by Dr. Eric Kuhn at Good Samaritan Hospital on June 5.
We attended the PCNG (USToo) meeting on June 27. Bruce was reluctant, but recognized it could be helpful to meet with others experiencing the broad range effects of prostate cancer.

Robert Young’s quote in the newsletter continues to speak to us:

In every struggle the only ones who can truly grasp
your fear, your pain, your grief, your stamina
that may sometimes fail are those who share the
battlefield with you. It is no different when
the enemy is prostate cancer, and the fight
is for your integrity as a man as well as your life.

Reflecting on our experience that evening, we are mindful of the common, yet potent words used to describe the PCNG: Support Group. To further define this, we can glean specific meanings from the dictionary: Support: “To hold up or add strength to.”  Group: Military – Army: “A flexible administrative and tactical unit consisting of two or more battalions and a headquarters.”

If we think in terms of military usage, we could think of the Prostate Cancer Networking Group of Greater Cincinnati as a tactical unit designed to sustain those whose minds, spirits, and bodies are under attack.

Prostate cancer in a very real sense is the enemy to the experiencing of abundant life in our minds, our spirits and our intimate relationships.

Our comrades-in-arms are those who are fighting with us, be it the medical community, our families, or others whom we have come to know through these unusual life circumstances.
Meeting with some new comrades at the PCNG on June 27 brought encouragement to our spirits that we are not in this battle alone. Bruce and I found it helpful to dialogue on a deeper level than normal with others on the same battlefield.

Jessa Schreiber

June 2007

The 2007 National Conference on Prostate Cancer
Sponsored by the Prostate Cancer Research Institute (PCRI)

“State of the Art Treatments:  Making a Positive Impact on Quality of Life”

September 7-9, 2007 -- Marriott Hotel, Los Angeles Airport

See http://www.prostate-cancer.org for more information

Registration is $60 per person ($85 after 7/23/07; $100 after 9/6/07).  You can register on-line or by phone: 310-743-2117.

Peter Scardino, MD

The Surgical Management of Localized Prostate Cancer:
Opportunities and Limitations

“Dr. Scardino started by citing the Bill-Axelson trial that shows a decrease in metastatic rate, disease specific and overall survival in patients treated with RP (Radical Prostatectomy vs. watchful waiting).  He said RP provides excellent control of localized CaP (Cancer of the Prostate).  He thought overtreatment was an issue and RP should be reserved for CaP that poses meaningful threat.  Among 6,490 patients having an RP at MSKCC (Memorial Sloan-Kettering Cancer Center) since 1983 there is a freedom from PSA progression in 75%.  The 15 year CaP specific survival rate is 93%.  Even 40% of men with pT3 tumors are alive at 15 years and 45% with a PSA >20ng/ml are alive at 15 years.

He discussed the role of RP in high-risk CaP.  In the literature up to 20% meet these criteria and 38% meet it using the criteria of PFAV>2ng/ml/yr.  The 15 year freedom from progression in this group, however is above 45%.  This suggests that perhaps avoiding RP in high risk patients is not appropriate.

The goals of RP are complete cancer removal, with minimal morbidity, early return to normal activities and no positive surgical margins or loss of continence or potency.  However, nationwide the complications occur to a significant extent.  Recovery of urinary continence was 96% and recovery of erections was 67%, and at 2 years only 60% are cancer free, continent and potent.  He then evaluated to what degree outcomes are related to variables such as surgeon volume.  While mortality did not differ among different surgical volumes, the incontinence and impotency rates did.  He showed a significant degree of heterogeneity regarding continence rates among surgeons at MSKCC.  Positive surgical margins also differed among surgeons and this had significant implications for patients. 

Biochemical recurrence (BCR) from 4 institutions (7,800 men) found that BCR was higher if a patient was operated on earlier in a surgeons' individual career.  Also, a 5-year BCR of 18% was found for more inexperienced surgeons compared to 11% for experienced surgeons.  Most disturbing said Dr. Scardino was that among those with high volume career total RP's, there was still variability.  This points to differences in surgical technique.  Fellowship trained and non-fellowship trained surgeons had similar outcomes at the onset of their careers, but fellowship trained urologists had improvement in outcomes to a greater extent than non-fellowshiptrained urologists.  Research in surgical technique is an important area to continue to improve outcomes for patients.”
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April 2007

Early Stage Prostate Cancer—Do We Have a Problem with Over-Detection, OverTreatment or Both?

Peter R. Carroll, Associate Editor
The Journal of Urology, v. 173 (2005), 1061-1062

We have seen profound changes in prostate cancer presentation and treatment during the last 20 years. Mortality rates are decreasing, and whether this is the result of improved early detection methods or treatment strategies is a matter of debate. What is clear is that the disease we most often see today is not the disease urologists saw 20 years ago.

The cancers we are finding are significantly smaller, of lower stage (most not palpable or stage T1C) and generally amenable to curative treatment using current available technology, usually surgery or radiation. However, some have argued that such an achievement has come at a price of increasing the risk of over-detection, that is detecting a cancer that would not become clinically apparent during the lifetime of the patient if left untreated. The risk of over-detection has been estimated to be between 16% and 56%²...

Given the increasing numbers of men with low risk disease, do all of them need immediate and/or aggressive treatment? This question brings up another problem. In this country detection and treatment are tightly linked. If prostate cancer is detected at any stage, grade or volume in almost any age group it is almost uniformly treated. Are at least some of these men candidates for active surveillance? Interestingly, despite the increasing numbers of men with favorable disease characteristics, prostate cancer treatment patterns appear to be more aggressive today compared to those of a decade ago³. The rates of watchful waiting have declined significantly⁴.  Even more remarkably, it appears that the majority (75%) of men 75 years old or older with low risk disease are treated rather than considered good candidates for active surveillance. Treatment no matter how “minimally invasive” or expertly done is usually costly and accompanied by some trade-offs with regard to health related quality of life⁵.  Such trade-offs are acceptable to those men at significant risk of dying of disease but may be less acceptable to those who may never know they had the disease if it were not for a biopsy.

To date, most patients opting for watchful waiting have been older with more comorbidity or strongly averse to current treatment alternatives. Initial watchful waiting trials reported on study populations with higher clinical T stage, PSA and Gleason scores, and found that metastasis developed in several men during prolonged observation⁶. However, with the development of better monitoring algorithms, new trials are exploring the possibility of offering safe initial observation to greater numbers of patients⁷. Urologists either uncomfortable or unfamiliar with such studies should read this growing body of literature. Patients who have low risk tumor characteristics (as defined by serum PSA and its variations, cancer grade and extent of cancer on extended pattern biopsy), especially those of more advanced age, could pursue a trial of initial active monitoring at the time of diagnosis without sacrificing curative intent or exposure to undue risk of disease progression. Such an approach could preserve quality of life and achieve substantive cost savings without significantly impairing cure rates. Many have demonstrated the feasibility of “active surveillance.” Such patients, if well selected and monitored, do not appear to sacrifice the ability to be effectively treated at a later date. Clinicians and patients considering active surveillance should understand that under grading and under staging could occur and that the disease could be of a higher grade and volume. However, such risks are minimized with the use of a well performed extended pattern prostate biopsy, an essential component of initial and ongoing risk assessment. Under staging and significant under grading are not the problems today that they were 2 decades ago...

The field of urology will be judged on how we treat prostate cancer now and in the future. As a specialty we need to acknowledge that these problems exist and we, not another specialty or government agency, should deal with them primarily. We should begin by unlinking detection and treatment, as they are separate processes. Our zeal for immediate and aggressive treatment of such early cancers should be matched, if not exceeded, by an enthusiasm for identifying better markers of the need for treatment and carefully conducted trials of surveillance in well selected and monitored men. We should identify a future path that is evidenced based, focused on the issues that make a difference to patients, and results in better and longer lives of those with the disease and those who are at risk of getting it. If that path leads to an end where we treat fewer patients (although likely some more aggressively), we should pursue it with energy and confidence.

Overdiagnosis and Overtreatment
of Early Detected Prostate Cancer

C. H. Bangma, S. Roemeling & F. H. Schröder                                           
World J. Urology, v. 25 (2007), 3-9

In any population screened for cancer, four basic groups of patients exist: those diagnosed with cancer who would not have developed cancer symptoms during their lifetime (overdiagnosis); those diagnosed with cancer at an early stage that might otherwise have led to symptoms and/or the need for more aggressive curative treatment; those diagnosed with cancer at a curable stage with aggressive disease that might otherwise have progressed to metastatic disease at the time of diagnosis; and those whose cancer is diagnosed by screening at the same stage as it would have been diagnosed through clinical routines, and that involves cancers that are too late for curative therapy. Ideally, screening should reduce the number of patients in the fourth group (that cannot be cured), and increase those in the second and third group. The window of opportunity for decreasing cancer-mortality by screening for cancer lies with the second and third group. Randomized clinical trials, considered the gold standard for the evaluation of a screening test, have to show how sizeable the window of opportunity is. The difference between the first group and the second is however not always clear at the time of initial diagnosis. Any screening procedure carries a risk of overdiagnosis and overtreatment, which should be balanced against the benefits for those in which the cancers are diagnosed at a curative stage. Whether this balance is justifiable depends on more than mortality differences of randomized study groups only, but also on quality of life issues measured against the cultural background of the population studied…

Screening results in the more frequent detection of small volume, low grade and organ confined prostate cancers, which are diagnosed earlier in their course [6, 15]. Many of these tumors have the histological characteristic of autopsy tumors, that is, tumors that have not become symptomatic during life [16]. They have been called indolent or clinically insignificant cancers. Various definitions of clinically insignificant tumors have been designed based on the characteristics of the autopsy studies, of which the Epstein definition is widely known [17]. Detecting such tumors will increase the detection frequency of cancer, but it is unlikely that they will influence the prostate cancer specific mortality, as they do not alter the course of life…

The impact of overdiagnosis and unnecessary treatment and of its side effects on patient health is also unclear; however, application of a mathematical model (the Miscan model) on data from the ERSPC has shown that, in an annual screening program for men aged 55–67 years, 56% of diagnosed cases would constitute instances of overdiagnosis [22]. If this estimate proves to be realistic (as it appears to be the case), nationwide screening programs may not be acceptable using the present screening regimens, even if benefits in terms of mortality reduction were shown...

During recent years, increased interest has risen to the possibility that increased detection of prostate cancer may lead to the diagnosis of cancers that rather should not have been diagnosed, and certainly should not have been treated, as their detection and subsequent treatment is unlikely to benefit patients, or even might harm them. Related to this, the terms ‘overdiagnosis’ and ‘overtreatment’ are being used. So, when is prostate cancer overdiagnosed? By using the clinical definition of overdiagnosis, that is diagnosing tumors that would otherwise remain clinically unrecognized until the individual died from other causes, it is clear that this definition can only be applied in retrospect in the evaluation of studies. There are currently no clinical or biological parameters that can identify such tumors 100% adequately at the time of diagnosis. By studying the natural course of prostate cancer, and comparing autopsy results with findings from screened populations, clinical and histological parameters can be identified that predict indolent tumors best. Those indolent tumors are likely to be only a subset of the tumors that are overdiagnosed in retrospect.

Overdiagnosis is predominantly being associated with early detection or screening programs. Overdiagnosis appears to be especially harmful when it results in invasive treatment of the tumors that would unlikely to be harmful. This is called overtreatment. Overdiagnosis occurs when screening detects small tumors that would otherwise remain clinically unrecognized until the individual dies from other causes. Such tumors are predominantly found in the low PSA ranges. Unfortunately, an unknown number of biologically more aggressive cancers may hide between the larger number of detectable tumors with favorable stages. Though some of the aggressive tumors can be diagnosed by adverse histological criteria such as high Gleason score in the biopsy, some of these features might be missed due to the heterogeneity of prostate cancers and their representation in the biopsy sampling. This might justify the amount of overtreatment that has been practiced in various areas of the world. Overtreatment is thus defined as unnecessary invasive treatment with respect to the outcome of the natural course of the tumor in combination with its host. One can wonder what number needed-to-treat to prevent one prostate cancer death we are prepared to accept. … approximately 73 patients will require radical treatment for each prostate cancer death averted [25]…

The incidence of erectile dysfunction ranges from 14 to 52%, depending on whether it is physician- or patient-reported. It is obvious that invasive treatment may influence the quality of life of men with prostate cancer and their families substantially. But so does a potential threat of prostate cancer that is not actively treated or not even diagnosed yet. It is unlikely that quality of life studies will be able to indicate the best balance between these points of view for management decisions on an individual patient level…

Because not all cancers diagnosed require treatment, one of the major challenges for the future is to determine which diagnosed cancers should be treated, and which can be managed by active surveillance. Active Surveillance manages selected men with prostate cancer expectantly with curative intent. This means men are carefully selected and subsequently actively observed in order to have the possibility to offer them deferred curative treatment once the tumor seems to progress. Active surveillance should be clearly differentiated from watchful waiting. Watchful waiting entails a strategy for all men who are managed expectantly, whereas active surveillance focuses on men for whom therapy is delayed until the tumor becomes progressive and curative treatment can be offered. This offers an attitude of active control over the cancer diagnosed for patients and their doctors. The stage migration that screening provides has resulted in an overrepresentation of low-risk cancers. Therefore, studies which validate monitoring algorithms in active surveillance regimens are ongoing [38].

Gleason grades ranging from least aggressive (1) to most aggressive (5);
the Gleason score consists of the sum of the two dominant grades

Klotz L: Urol Oncol. 2006 Jan-Feb;24(1):46-50... Our data suggest that in most patients, a determination that the patient has an aggressive phenotype can be made at approximately 2 years after surveillance has been initiated, based on 8−9 PSA data points (every 3 months) and 2 sets of 8−12 core biopsies. ...A PSA DT cutoff of 3 years would identify approximately 20% of cases as showing rapid PSA progression and is a reasonable threshold for intervention. ....Using this approach, approximately 20% of good risk patients will be treated for a rapid PSA DT and 5% to 10% for grade progression; 70% will remain stable or have very slow, nonclinically significant progression and will avoid the necessity for radical treatment.
          The risk assessment approach could be enhanced by incorporating a molecular profiling based evaluation of progression risk. Using currently available methods, including single nucleotide polymorphism chips and gene array, markers can undoubtedly be identified that individually or aggregately characterize more aggressive phenotypes in patients with favorable risk disease. This effect would readily translate from bench to bedside in patients who were surveillance candidates.
           One can easily envision a scenario in which patients with favorable risk disease based on Gleason score, PSA, and cancer volume are classified into further risk groupings based on clinical and genetic factors, including family history, race, body mass index, and a panel of genetic polymorphisms. Risk grouping assignment, based on high quality data, would permit accurate estimates of the risk of progression and death. This process would enhance the appeal of the surveillance approach. For example, a patient who is told that he had a 1% to 2% chance of prostate cancer death and a 5% to 10% chance of progression in 20 years would likely choose surveillance in most cases.

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March 2007

Local Therapy vs Watchful Waiting

A man, diagnosed with prostate cancer, is pondering what to do. Local therapy such as radical prostatectomy (RP) or radiation therapy (RT)? Watchful waiting (WW)? —What is the best choice? It is not a simple choice, in particular for those who have a cancer that does not appear aggressive: the Gleason score is 6 or a ‘good’ 7 (3,4).
In the medical world decisions are preferably based on a clinical trial in which patients are randomly divided in two groups. Our interest would be in a trial in which the men in one group were treated with local therapy and the men in the other group not treated at all. Only one such trial (RP vs WW) has been completed (A Bill-Axelson et al.: N Engl J Med. 2005): men with RP lived longer than men with WW. Most of the survival benefits, however, were experienced by men younger than 65 years.
What should a man older than 65 years do? He could look at a recent publication by Dr. YN Wong et al (JAMA, 2006 Dec 13), presenting a comparison of two groups of men aged 65-80 years. The men in these groups had been diagnosed with localized prostate cancer. One group (32,022) had been treated and the other group (12,608) had not been treated. After 12 years or until death 4,663 men (37%) in the observational group and 7,639 men (23.8%) in the treatment group had died: 314 (6.8%) of the 4,663 and 612 (8.0%) of the 7,639 men in the observational and treatment groups, respectively, had died of prostate cancer. Many more men die with prostate cancer (as long as it is localized cancer) than of it!
The difference between the two groups as far as the overall survival is concerned, is remarkable. One lives longer when treated – see figure. But if one dies in the treatment group, it is more likely of prostate cancer.
The authors of this study did their best to make the men in the two groups comparable, and they look very similar indeed as far as age, tumor grade, and co-morbidity are concerned. More subtle differences, however, may explain the differences in survival:
“Most urologists and radiation oncologists will attest that older men who receive active treatment are inherently different from those managed expectantly. A patient who is judged likely to live for more than 10 years is offered aggressive treatment, whereas a man expected to die of other causes in fewer than 10 years is counseled that his best option is watchful waiting. Therefore, despite the authors’ methodological rigor, it is difficult in a nonrandomized, claims-based analysis to account fully for this implicit clinical assessment” (Litwin MS & Miller DC, Editorial Comment).
With other words: stay tuned. Don’t attach too much significance to Dr. Wong’s analysis. Randomized trials will eventually answer questions about overall survival and prostate cancer-specific survival. Two such trials (PIVOT in the USA, and PROTECT in the UK) will be completed in 2008 and 2009 respectively. In the mean time a man newly diagnosed with prostate cancer can consider the results of the Swedish trial (A Bill-Axelson et al.: N Engl J Med. 2005).
The two groups in this study consisted of 347 men in the RP group and 348 men in the WW group. The prostate-specific mortality and over-all mortality were 30 and 83, and 50 and 106, respectively. Surgery did yield a survival benefit but at a price: 17 cancers had to be removed to prevent one prostate cancer-specific death over 10 years. Men with surgery had also more ED than men on WW: 88% vs 45%, and more urinary leakage: 49 vs 21 %.
What are the conclusions? The only clinical trial on local therapy vs WW demonstrates that surgery results in less deaths than watchful waiting but that there was a price to be paid. Today, as a result of improved techniques (robotic surgery!), ED and incontinence have been reduced in prostatectomy patients. Watchful waiting has also changed, and the term Active Surveillance is better. Patients are carefully monitored and local treatment will be advised when necessary.
Can not make up your mind? According to an article authored by urologists from Johns Hopkins (#1 in urology in the USA) MA Khan et al.: J Urol. 2004 Nov: “Delays of up to several months from prostate cancer diagnosis to RP do not appear to impact long-term biochemical cancer control rates. Therefore, patients can be reassured that there is no immediate urgency to perform RP after prostate cancer diagnosis, especially in those with T1c disease and biopsy Gleason scores less than 7.” Postponement has, however, a psychological burden.
Good luck!

Watchful Waiting and Watchful Waiting

Watchful Waiting, as a choice after a man has been diagnosed with prostate cancer, is well known, but there is another type of Watchful Waiting that is fortunately less familiar to most of us.
After local treatment, whether by surgery of radiation, the cancer can come back: recurrent prostate cancer. The cancer is ‘out of control biochemically’ (see the citation on the previous page). To say this in terms easier to understand: the PSA begins to rise. PSA failure!
A few PSA measurements are made, and depending on how fast the PSA doubles (can be calculated with the PSA Doubling Time calculator on our website) and the length of the time span between the local therapy and the recurrence) some action is taken. It can be hormonal therapy, radiation, or doing nothing but keeping track of the PSA regularly: Watchful Waiting, the other Watchful Waiting.
During ASCO’s Prostate Cancer Symposium last February an abstract (#158) was presented by AO Sartor, P Scardino, D McLeod, P Schellhammer, A D'Amico, and S Halabi. “Contemporary management of PSA recurrence after initial definitive local therapy for prostate cancer: Results from the COMPARE Registry.”
The COMPARE Registry is an observational registry of prostate cancer patients with rising PSA after definitive local therapy. “As of August 2006, 1,120 men have been enrolled in the COMPARE Registry, primarily by urologists (91%) and radiation oncologists (5%). The most common initial definitive treatments were radical prostatectomy (RP) 45%, external beam radiation therapy (EBRT) 33%, brachytherapy (BT) 11%, RP+EBRT 7%, EBRT+BT 4%, and other <1%. Of 1,120 enrolled patients with PSA failure, the management choice was watchful waiting (WW) for 829 (74%), HT for 246 (22%), and data was missing for 45 (4%)”.
“Of the 246 patients receiving HT .. the following therapies were used ..: LHRH agonist alone (50%), antiandrogen alone (7%), LHRH agonist+antiandrogen (21%), other (4%), LHRH agonist+other (1%), LHRH agonist+anti- androgens+other (2%), and unspecified (16%).”…
”WW is the predominant management choice for a rising PSA after definitive local therapy. This applies across all PSA levels, Gleason scores, and age categories.”

What do the French do about ED (Erectile Dysfunction)?

We thought that the following abstract may provide some insight how prostate cancer patients’ sexuality is managed in France: “Nowadays, taking into account the sexuality is an essential component of the management of prostate cancer patients. This implies the necessity for providing accurate, clear and transparent information about the potential adverse effects on the sexual functioning for each proposed treatment. This information is not only given to the patient, but also to his female partner. The association of extended radical prostatectomy (without preservation of neurovascular bundles) and androgen suppression therapy will be proposed for men with locally advanced prostate cancer at high-risk for recurrence. The impact of such combined management regarding sexual functioning is high in terms of erection and sexual interest. Early pharmacological treatment of erectile dysfunction (within the three months following surgical treatment) with <Viagra, Levitra, or Cialis> or intracavernous injections <with Caverject, Edex, or Muse> will allow an optimal recovery of a certain quality of erection. Moreover, monotherapy with <Casodex> will be associated with significant advantage in terms of sexual interest. The sexuality after treatment will certainly be different but will be accomplished.” (D Chevallier & J. Amiel: Ann Urol (Paris). 2006 Dec)

Snippets

“At baseline 28% of <268> patients <treated with EBRT radiation of 68-78 Gy> had erectile dysfunction (ED). After 1 year, 27% of the pretreatment potent patients had developed ED. After 2 years this percentage had increased to 36%. After 3 years it almost stabilized at 38%.” (GJ van der Wielen et al.: Int J Radiat Oncol Biol Phys. Feb 2007)
A total of 2652 patients with localized carcinoma prostate underwent VIP <=Vattikuti Institute prostatectomy= robotic RP>. ..Complete follow-up information was obtained in 1142 patients with a minimum follow-up of 12 months (range: 12-66 mo; median: 36 mo). .. Median duration of incontinence was 4 wk; 0.8% patients had total incontinence at 12 mo. The intercourse rate was 93% in men with no preoperative erectile dysfunction undergoing veil nerve-sparing surgery, although only 51% returned to baseline function.” (M Menon et al.: Eur Urol. March 2007)
"...423 patients who underwent radical retropu