We also added the last link in this paragraph: Analogy to Mammograms. The pattern of lagging recommendations for testing appears to be following the path set with breast cancer in which twenty years ago breast cancer screening was questioned while today it is accepted practice. See link and for further comparison see link.
May 3. Added to the "Guidelines - Europe: ESMO" link (in the Links section to the right) a link to the May 2007 European Society for Medical Oncology prostate cancer guidelines marked: [EMSO]
May 3. In Lycopene, Selenium and Vitamin E in Combination we added: Resveratrol/Quercetin combo. Resveratrol [PMID: 18439064] [PMID: 18414053] has anti-cancer effects against prostate cancer but is made less bioavailable in the liver through sulfation. It was found that this can be counteracted making the Resveratrol more bioavailable if quercetin, mefenamic acid (a non-steroidal anti-inflammatory, NSAID, marketed by Pfizer as Ponstel in the US and Ponstan or Parkemed elsewhere) or salicyclic acid (aspirin, also an NSAID) were simultaneously administered. [PMID: 10923862. Longevinex, a maker of a resveratrol/quercetin combo pill also has information on their site [link]. Note that some caution here is in order with respect to drug interactions. (1) "Older persons who mix alcoholic beverages with large doses of aspirin to self-medicate for pain are therefore at particularly high risk for episodes of gastric bleeding (19). In addition, aspirin may increase the availability of alcohol (31), heightening the effects of a given dose of alcohol. Chronic alcohol ingestion activates enzymes that transform acetaminophen (Tylenol and others) into chemicals that can cause liver damage, even when acetaminophen is used in standard therapeutic amounts (32,33). These effects may occur with as little as 2.6 grams of acetaminophen in persons consuming widely varying amounts of alcohol (34)." according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA): [link]. (2) red wine has inhibitory effects on cytochrome P450 which can result in magnifying the effects of other drugs the user may be taking which may have undesirable effects. [PMID: 11125847]. At higher dosages even more serious drug interaction problems can appear.
May 4. In Choosing a Surgeon - Part I. Considerations, Choosing a Surgeon - Part I. Considerations we added:
May 12. In DCA we add: Although some of the comments from self medicating users on the web site are not encouraging some recent work at the University of Florida published in May 2008 supports the role of DCA as acting against bcl-2. As discussed in our post on Testosterone Metabolism bcl-2 protects cancer cells and therefore agents that act against bcl-2 might render the cancer defensiveless against attack by other drugs. Thus it might be that a more sophisticated approach could still work.
May 13. In Bradford Hill Criteria of Causation we added:
In the point about Coherence we add:
For an example from the literature, consider this May 2008 study [PMID: 18467718] that aims to compare laparascopic/robotic and open prostatectomy outcomes. As pointed out by Michael Blute in the same issue of the journal in which the study was published [PMID: 18467714] [Full Text]: "the data in this study indicate that the complication rates to open surgery may not be consistent with that reported for optimal open surgery."
In the point about Experimental evidence we add:
One particularly important feature to watch out for in assessing prostate cancer studies is to avoid relying on studies that fail to stratify, i.e. adjust, for differences in Gleason score or similar categorizations of disease severity. For example, let us again consider the May 2008 study [PMID: 18467718] that aims to compare laparascopic/robotic and open prostatectomy outcomes that was mentioned in the last point. The investigators "assessed the association between surgical approach and outcomes, adjusting for surgeon volume, age, race, comorbidity, and geographic region." However, as pointed out in [PMID: 18467714] [Full Text] the study also did not look at disease severity and "without clinical and pathologic data, one cannot reliably account for these differences". The same point is made in a May 10, 2008 Washington Post article [link] which says that the "study did not look at staging and scoring of the tumor, meaning that some of the differences seen might be due to differences in disease" rather than differences between laparoscopy and open surgery.
In the discussion of the Lycopene study we add:
In fact, in a 2005 review, Kristal and Schenk [PMID: 16046734] "do not find evidence to support a substantial association of lycopene or tomato products with reduced prostate cancer risk. Results of large cohort studies are mixed, and few serum-based or case-control studies were sufficiently large to detect modest effect sizes. Most of the studies published on lycopene and cancer have not been designed or analyzed to answer this question optimally, and key areas for advancing this research include a) improving assessments of lycopene exposure; b) incorporating information on cancer stage, grade, and screening into statistical analyses; and c) investigating interactions between oxidative stress or polymorphisms in genes affecting response to oxidative stress with lycopene intake." In a May 2008 news item [link] Kristal was further quoted as saying: "The excitement about lycopene (the pigment that puts the red in tomatoes) and prostate-cancer prevention is probably a mistake ... Most large and well-designed human studies, and most animal studies, have failed to find convincing associations between lycopene and reduced prostate-cancer risk."
For more detailed information on lycopenes see the US FDA site and their explanation of why they found the evidence insufficient to allow health claims for lycopenes: [link]
May 13. In Yananow Case History Links and Depth of Presentation we regenerated the table based on data revisions in Yananow.
May 13. In Yananow Place Name Table we regenerated the table based on data revisions in Yananow.
May 15. In Biochemical PSA Recurrence we added: The d'Amico risk category (discussed in the Favorable Outlook section of this post and the subject of an April 2008 validation study at the Mayo Clinic [PMID: 18289596] specifically within the context of biochemical recurrence) can also been used for assessing progression risk.
May 18. In Choosing a Surgeon - Part I. Considerations, Choosing a Surgeon - Part I. Considerations we added: This summary of the Whitmore Lecture at the 2008 AUA meeting by Dr. Patrick Walsh (pioneer of nerve sparing prostatectomy, e.g. see Nerve Sparing Turns 25) briefly discusses the evolution of surgical techniques involved in prostatectomy.
May 2/08. Reworked and expanded the description in PSA Doubling Time (PSADT) - Part 4. Online Calculators of the Sunnybrook calculator: Sunnybrook. This calculator is intended to be used for determining when to exit active surveillance and is based on a model of such patients. The model may not be applicable to other applications. The model is different than the prior ones discussed in that it posits that log(PSA) is quadratic, rather than linear, in time and further depends on both age and Gleason Score so it differs in key respects from the models discussed here previously. It is described further at this page. The online calculator lets one enter a series of PSA values and also allows one to easily calculate the PSADT and PSAV on various subsets without re-entering the numbers. On the same graph as the data it shows typical progression for a high risk group as a line and a low risk group as a second line (both assuming the same baseline PSA as the data entered). If the data entered more closely resembles the high risk group or lies above it then active surveillance would not be advisable according to this model. Jon Nowlin has re-implemented in Excel this calculator and improved on it by using a semilog scale.
May 21/08. Added this reference to treating stress incontinence with stem cells in the Urinary Incontinence post: [Urotoday, 2008]
May 21/08. In Testosterone Metabolism and Prostate Cancer we add: Individuals with a certain genetic defect in 5AR exhibit pseudohermaphroditism and produce high levels of testosterone with low levels of DHT and have never been known to exhibit prostate cancer. "The expression of 5a-reductase-2 gene in prostate cells is regulated by various factors. A high dietary fat intake, a risk factor of prostate cancer, induces prostate 5a-reductase-2 gene expression and subsequently stimulates prostate growth, which is blocked by genistein, a phytoestrogen. Inhibition of 5a-reductase activity by medication is used in the treatment of BPH and male-pattern baldness, while its use in prostate cancer prevention is still controversial although it can decrease the incidence of prostate cancer. " [PMID: 18483578] Also see this figure from the same paper which illustrates the use of our Model 2 to describe a hypothesized model of fat and genistein effects.
May 22/08. In PSA Screening and Early Detection - Part 3. Current Environment we added: There was a presentation on the 2008 AUA PSA guidelines at the 2008 AUA meeting summarized here.
May 22/08. Under Advice to the Newly Diagnosed we add:
Also radiation as a treatment, as opposed to using it as a diagnostic, was also reported to lead to higher rates of bladder, colorectal and lung cancer in [link] although from the same link the investigator stated that: "the absolute risk associated with the development of secondary malignancies in patients exposed to external beam radiation therapy is quite small".
May 23. In Testosterone Metabolism and Prostate Cancer we added:
Histone Deacetylase Inhibitors. Referred to as simply HDAC or HDI, there is some evidence that these inhibit the detrimental ER-alpha without also inhibiting the beneficial ER-beta and therefore may form a new class of anti-cancer drug in the future. See [PMID: 16158045] [full text]
May 24. In Testosterone Metabolism and Prostate Cancer we added these links: Estrogen receptors, ER-alpha and ER-beta.
May 24.
In Advice to the Newly Diagnosed we add:
Treat or Not. Paul Mathew, M.D., (papers) an assistant professor in the Department of Genitourinary Medical Oncology at M. D. Anderson, cited “a very apt aphorism” by the late Willet Whitmore, Jr., M.D., (papers) of Memorial Sloan-Kettering Cancer Center in New York: “If cure is necessary, is it feasible? And if cure is feasible, is it necessary?” Dr. Mathew said that dichotomy frames the current view of localized prostate cancer. A 50-year-old patient with an aggressive type of prostate cancer is almost certain to die of his disease unless it is cured. “It’s clearly necessary,” he said, “but is it feasible? Do we have clear evidence that radical prostatectomy offers cure in a high-grade prostate cancer? Surprisingly, this is still a controversial area.” On the other hand, in an 80-year-old patient with a low-grade cancer, “If you remove his prostate, he’d be cured. But is it really necessary?” Such a patient might well live the rest of his life without experiencing significant problems related to the cancer.
To evaluate those options, a patient’s risk of treatment failure is assessed on the basis of his PSA level, tumor stage, and combined Gleason score. Patients with a PSA level less than 10, a tumor stage of T2a (a small, palpable tumor confined to the gland) or lower, and a Gleason score of 6 or less are in the low-risk category, with an 80% or greater chance of long-term control. Those with a PSA level higher than 20, a tumor stage of T3 (outside of the gland) or higher, and a Gleason score of 8 or higher are in the high-risk category with less than a 50% chance of long-term control. All those in between are in the intermediate-risk group.
For patients whose life expectancy and comorbidities suggest that they are likely to die of something other than prostate cancer, cure is not considered necessary, so a strategy of watchful waiting is typically chosen. The patient’s PSA level is checked every four to six months and, as long as the cancer remains minimal, treatment remains unnecessary.
For younger patients or for those with more aggressive cancers, though, treatment is necessary, and several options are available. "And because, in many patients, we can’t truly say that one option is better than the others, it comes down to the patient’s decision," Dr. Kuban (papers) said. (paragraphs from From OncoLog, December 2004, Vol. 49, No. 12)
May 25. In Prostate Cancer Calculators we added: a significant caveat is that "Chun et al. [6, 7, 33] demonstrated recently that nomograms developed in the sextant biopsy era may not be able to predict the probability of PCa on needle biopsy in the extended biopsy era, equally accurate as they used to in the sextant biopsy era. In consequence, many clinicians are reluctant to use tools that were developed in the sextant biopsy era [46]." [PMID: 17333203]
May 25. In
PSA Screening and Early Detection - Part 5. More Diagnostic Testing Concepts we added another example:
Example 7. Power Doppler.
Power doppler is a type of color doppler that uses the amplitude of the echo rather than its frequency shift and is believed to be better at detecting cancer.
In a 1998 investigation reported in [PMID: 9586699] there were 23 patients with prostate cancer and 19 of them were successfully detected with power Doppler sonography. Also there were 17 who did not have prostate cancer and 4 of them had positive tests anyways. Thus we have this table:
| PCa | No PCa | ||
| Test +ve | 19 | 4 | 23 |
| Test -ve | 4 | 13 | 17 |
| 23 | 17 | 40 |
The diagonal elements divided by their column totals give the sensitivity, 19/23 = 82.6%, and specificity, 13/17 = 76.5% and the upper diagonal element divided by its row total gives the positive predictive value, PPV, which is 19/23 = 82.6% -- in this case is coincidentally the same as the sensitivity. The prevalence is the ratio of the first column total to the grand total which is 23/40 = 57.5% . This is much higher than the prevalence of prostate cancer in the general population but such imaging would likely only be done on patients who already had some positive indication from a PSA test or DRE. At any rate the PPV but not the sensitivity and specificity depend on the prevalence.
A second 1998 power doppler investigation was described like this: [PMID: 9772875]
OBJECTIVE: To determine the role of transrectal power Doppler ultrasonography (PDU) in the diagnosis of prostate cancer. PATIENTS AND METHODS: Thirty-six patients (mean age 66.4 years, SD 7.7, range 59-82) with possible prostate cancer, suspected from an abnormal digital rectal examination or elevated prostate specific antigen level, underwent transrectal ultrasonography, transrectal PDU and biopsy. The vascularity on PDU was graded on a scale of 0-2, where grade 1-2 was considered positive and grade 0 negative. RESULTS: The vascularity was grade 2 in 11 patients, grade 1 in 11 and grade 0 in 14; 20 of the 36 (56%) patients had prostate cancer. Of the 22 patients positive on PDU, 18 had malignant disease and four benign; two of 20 patients with histopathologically confirmed malignancy had a normal PDU. The sensitivity of PDU was 90%, the specificity 75% and the positive predictive value 82%. CONCLUSION: Focal hypervascularity on PDU was associated with an increased likelihood of prostate cancer. Although ultrasonography alone cannot detect all cancers, even using PDU, the technique appears to increase the sensitivity and to help identify appropriate sites for biopsy.
The reader may wish to try filling out the table prior to looking:
| PCa | No PCa | ||
| Test +ve | 18 | 4 | 22 |
| Test -ve | 2 | 12 | 14 |
| 20 | 16 | 36 |
and then calculating the sensitivity, specificity, PPV and prevalence which should be 18/20 = 90%, 12/16 = 75%, 18/22 = 81.8% and and 20/36 = 56% .
These numbers are reasonably close to the first investigation so their consistency seems favorable.
A third study found that targeting biopsies at areas of high blood flow resulted in higher detection rates: [Science Daily].
More information on power Doppler sonography is summarized on the web site of Dr. Bard here: [here].
May 27. In How Healthy Men Can Reduce Their Risk we added: At the 2008 AUA meeting, presenters pointed out that for PSA screening to be effective it must be done regularly. In a study of PSA screening of over 34,000 men, the majority of prostate cancers and the majority of more serious cancers were only detected after multiple screening visits. See [link] or [link] for details.
May 27. In How Healthy Men Can Reduce Their Risk we add: If PSA is elevated (the cutoff was once considered to be 4.0 but is now considered to be 2.5 by many as discussed in last section) or PSA velocity is high (greater than 0.75 ng/ml per year although some feel that the cutoff should be lowered to 0.3 as discussed in last section) or if PSA doubling time is less than 10 years it is important to eliminate the possibility that it was caused by nonmalignant conditions rather than cancer (see Factors affecting PSA section of indicated link for non-cancer factors that can raise PSA). Usually Cipro or other antibiotic is prescribed and then a retest is taken. A Free PSA Test (described in the Free PSA section of this page) is less sensitive to inflammation and is often also given on the retest. In addition a new genetic-based test, based on the PCA3 gene, available from these labs has greater specificity (i.e. its more likely to be negative when you don't have cancer) than the PSA test. Ultrasound, color doppler ultrasound and power doppler ultrasound (in increasing order of ability to assess the risk of cancer) are other test methods that are used. Ultimately if the risk is assessed to be sufficient high a biopsy is performed.
May 28. In Testosterone Metabolism and Prostate Cancer we added: It is believed that ER-alpha and ER-beta have a relationship to TMPRSS2-ETS gene fusions. These gene fusions are associated with more aggressive cancers and future diagnostics may use their presence as a marker to distinguish between indolent and aggressive prostate cancer.
May 30. Added to Bradford Hill Criteria of Causation: One potential explanation is that the way lycopene is combined with other ingredients is key to whether or not it is effective. A news item reporting an upcoming study to be published in Cancer Research found that working with certain rats that 10% of rats fed dehydrated tomato paste had prostate tumors vs. 30% for regular tomato paste and 60% with no tomato paste. Human trials would be required to determine if this result continues to hold. The researchers believe that FruHis in dehydrated tomato paste may be a key element. See [link]. In animal studies and small short term human studies Fleshner found improved response from combining lycopene with other antioxidants relative to lycopene itself. See this post. Thus it may be that lycopene must be administered in a certain way or in conjunction with certain other ingredients in order to find a beneficial effect.
For more detailed information on lycopenes see the US FDA site and their explanation of why they found the evidence insufficient to allow health claims for lycopenes: [link]
May 31. Updated the estradiol info in Free Downloadable Materials: For advanced prostate cancer this article advances the viewpoint that Transdermal Estradiol can provide similar benefits to more expensive androgen suppression drugs and with less side effects (except as discussed) and cost. It is written by Dr. Richard Wassersug of the Department of Anatomy & Neurobiology, Dalhousie University, Halifax. Also see one patient's experience [here] and the warnings in Wassersug's article as well as this more recent [warning] which may or may not apply.
May 31. Updated the information on Our Voice magazine in Free Downloadable Materials:
Our Voice
Patient-oriented articles by Canadian urologists and medical personnel.
http://www.cpcn.org/02_other_news.htm. Copies of Our Voice are available at the cited link. Also Our Voice has its own web site but as of this writing seems to be still under construction. As examples of content, we point out that we have cited an article by Emmi Champion, a urodynamic nurse, from issue 3(2), in our Urinary Incontinence post and issue 4(1) contains an interesting article by Dr. Tom Pickles on prevention of prostate cancer. There is also a French language version of the magazine at the same link. In addition to the back issues [here] there is also an archive of some of the notable back articles here.
May 31. Added to Free Downloadable Brochures/Flyers/Pamphlets: A 2005 pamphlet on prevention from the Canadian Prostate Health Council summarizes prevention steps in Table 1 and provides 20 brief pages of patient-oriented advice on prevention.
May 31. In Free Downloadable Brochures/Flyers/Pamphlets added: Canadian Prostate Health. The Canadian Prostate Health Council has pamphlets and articles on a variety of prostate cancer topics [here] and [here]. Some are patient-oriented pamphlets intended to be used by urologists to provide information to their patients whereas others are past articles from Our Voice magazine (also discussed in Free Downloadable Materials).
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