A December 20th article by Associated Press medical writer Lauran Neergaard illustrated the difference between “watchful waiting” and “active surveillance” for men diagnosed with early-stage prostate cancer. Most of the 240,000 cases of prostate cancer diagnosed annually in the United States are in the “low-risk” category. Yet 90% of these men seek immediate treatment and its accompanying risks. For many of these men, “active surveillance” under the care of a urologist may have been a wiser choice. “Active surveillance” is much more aggressive than “watchful waiting”. It involves getting regular scans, blood tests and biopsies to monitor the tumor closely enough such that curative treatments could be administered if needed before symptoms would be observed. Men are urged to seek out treatment centers where such “active surveillance” is practiced. A panel from the National Institutes of Health (NIH) stated that men whose PSA level is less than ten (10) and whose Gleason score is six (6) or less would be candidates for such surveillance. A collaboration between two large active surveillance programs at Johns Hopkins University and Cedars Sinai Medical Center with the Prostate Cancer Foundation has been instituted to educate men about “active surveillance.” The program is entitled the National Proactive Surveillance Network- at http://www.npsn.net. Shortly an interactive section will be added to the site to link men with doctors who offer “active surveillance” and to track how these men fare over time. This represents an individualized approach to treatment as opposed to a one-size-fits-all approach.
1) The November 16th, 2011 issue of the Newsletter from Zero-The Project to End Prostate Cancer, published an interesting article from the New York Times entitled “A Watch-and-Wait Prostate Cancer Treatment.” The article focused on the PSA screening and subsequent actions that a man over the age of 70 can take to keep his prostate cancer from developing further and becoming problematic. Subjects such as cryosurgery, diet and nutrition, screenings and biopsies are discussed along with helpful advice from noted urologists.
2) The drug, TAK-700 (Ortoronel) and Phase 3 clinical trials have been described in a blog published on this website on June 3rd, 2011. TAK-700 is an oral, non-steroidal, androgen (e.g. testosterone) synthesis inhibitor. It is being developed by the Takeda Oncology Company affiliated with Millennium. They are sponsoring safety and efficacy clinical trials in men with metastatic prostate cancer who have not had previous chemotherapy or who have had chemotherapy more than two years earlier for early-stage prostate cancer (elm pc004) or metastatic cancer who have received chemotherapy (elm pc005). The trials are evaluating the safety and efficacy of TAK-700 when combined with prednisone as compared with prednisone alone. End points of the study are delay in disease progression and increased survival times. For details, see their website at http://elmpctrials.com/eligibilityAssessment.html?
3) The November 16th issue of Johns Hopkins Prostate Disorders Health Alerts (link) discusses the attractive option of using cryotherapy as a salvage procedure following failure of external beam radiation and/or brachytherapy to eradicate all the prostate cancer. Cryotherapy could minimize potential damage to the bladder and/or rectum which could occur if surgery or additional radiation therapy were used. See the full article for details.
Positive Phase 3 clinical trial results for the drug MDV3100 in men whose prostate cancers had progressed after failing hormonal therapy and chemotherapy have recently been reported in a special edition of the Prostate Cancer Foundation Newsletter, November 7th, 2011 (see http://www.pcf.org/site). Such positive results were observed that the trial was stopped early and the drug provided to men who had been previously receiving the placebo. MDV3100 was found to increase the median survival time by 4.8 months and provided a 37% reduction in the risk of death when compared to placebo. Some men had more durable remissions while some did not respond. Based on these results, the drug’s developers, Medivation Inc. and Astellas Pharma Inc., plan to submit MDV3100 to the Food and Drug Administration for approval in 2012. MDV3100 has been under clinical development in advanced prostate cancer patients who have already received chemotherapy with taxotere (docetaxel) as well as those who have not been treated with taxotere. MDV3100 works by blocking the androgen receptor (which is the engine that drives prostate cancer progression) at three distinct points in the cell-signaling pathway. The drug blocks testosterone (the fuel that drives the engine) from binding to the androgen receptor (the engine), impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation) and inhibits binding to DNA. MDV3100 has been described in an earlier blog (February 18th, 2011) on this website.
Stopping of a clinical trial and offering the drug to patients taking the placebo had occurred earlier this year with the FDA-approved drug Zytiga (abiraterone acetate). Zytiga affects prostate cancer progression by shutting off the supply of testosterone, the fuel that drives the cancer engine. Using both MDV3100 and Zytiga together seems to be a very logical idea. A Phase 3 trial is already underway in hormone-resistant (refractory) prostate cancer patients who have never received chemotherapy. The results are not yet available but the trend will be to use both drugs earlier in the history of prostate cancer patients. They could possibly be used to potentially cure patients with high-risk cancer who had not yet been treated surgically.
I often consider my prostate cancer as “my problem.” I am focused on being maintained in a symptom-free condition for as long as possible, or potential treatments as needed and finally focused on not dying of the disease. But God sees my condition from a totally different viewpoint. From my personal perspective, it is often too easy for my trust to flounder and for my spiritual eyes to drift from God and Jesus to my disease. Once my focus shifts away from God, the problem becomes magnified. Such negative thinking can overwhelm faith and extinguish courage. We also tend to see obstacles such as prostate cancer in terms of our own strength and resources rather than God’s. Too often we miss God’s specific plan for us (which is always the best according to Romans 8:28 and Ephesians 2:10) because we view our disease as a problem instead of an opportunity.
God has a master plan for our good and it can even include a disease like prostate cancer. Had my cancer not recurred in 2002, I would not have launched this website (which I pray has been of some use to at least one person). When was the last time someone did something for you in a manner that was “exceedingly abundantly” more than you hoped for? To me, the word ‘abundantly’ means more than I need or want. ‘Exceedingly’ tells me it goes beyond what I perceive as needing or wanting. But the Bible states in Ephesians 3:20-21, “Now to Him who is able to do exceedingly abundantly beyond all that we ask or think, according to the power that works within us, to Him be the glory ………in Christ Jesus to all generations forever and ever, Amen.” (Ephesians 3:20-21.) God’s ability and love are unlimited. The apostle Paul clearly understood this when he wrote in Philippians 4:13, “I can do all things through Christ who strengthens me.” Everything I need, He will provide in His time. Problems and roadblocks are a way for God to demonstrate His awesome power and for our own faith to grow and mature. When our focus shifts to a Godly perspective, gloom turns to gladness and we experience joy.
God doesn’t always show us the entire picture; often He reveals it little by little. Why? So we will learn to rely on Him daily for all we need and trust Him for tomorrow. This would not be the case if I as an individual saw my entire future in one snapshot. As long as God has the entire picture of my present and eternal life in His view and under His control, I don’t need to see it all. HE SEES IT ALL.
Coming shortly, update on new promising drug, MDV 3100.
At the annual American Society of Clinical Oncology (ASCO) meeting in Chicago in June 2011, the Prostate Cancer Foundation September 30th newsletter reported on promising Phase III clinical trial results for radium-223 chloride (alpharadin), an agent specifically being developed for cancer patients with bone metastases. The drug works by emitting small doses of alpha particle radiation that damage the DNA of cancer cells, thereby killing them without harming healthy cells. [It should be noted that in comparison with other radioactive particles, alpha particles are quite heavy and do not penetrate surrounding tissues very far.] The data presented indicated that alpharadin significantly improves overall survival in patients with hormone-resistant prostate cancer that has metastasized to the bone. This conclusion was also cited in a report in the October 4th ZeroHour Newsletter. Thus, alpharadin may be the first drug to improve survival in men with cancer of the prostate that has spread to the bone, a worsening of the disease that occurs in 90 percent of men in the advanced stages of the disease.
Alpharadin was initially discovered by a Norwegian company Algeta ASA and was subsequently exclusively licensed to Bayer HealthCare Pharmaceuticals. On the basis of the results described above, alpharadin has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of castration-resistant (hormone-refractory) prostate cancer in patients with bone metastases. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious diseases and fill an unmet medical need, thereby hopefully leading to earlier drug approval and access by patients. Bayer plans to apply for regulatory approval in Europe and the U.S. by the middle of next year.
In an article published in the International Journal of Paleopathology, a research team in Portugal has recently diagnosed the oldest known case of prostate cancer in ancient Egypt and the second oldest documented case in the world. The earliest diagnosis came from a 2,700 year-old skeleton of a Scythian king in Russia. The tumors were detected by performing high-resolution computerized tomography (CT) scans on three Egyptian mummies in which small, 1-2 mm diameter tumors were detected in the pelvis, lumbar spine and upper arm and leg bones. While it has been thought that exposure to carcinogens during the industrial age led to a general increase in cancers, this disease could have been prevalent in ancient peoples as well. This information was adapted from ScienceNOW, an on-line daily news service of the journal Science.
As discussed in this website blog posted on October 15th, a government medical panel, the United States Preventive Services Task Force, recently recommended that routine PSA testing in healthy men under the age of 75 be discontinued unless they have symptoms that are highly suspicious for prostate cancer. The panel claimed that such routine screening did not result in the overall saving of lives but instead led to an increase of potentially harmful side effects. This controversial recommendation has produced considerable comment. The Johns Hopkins Health Alerts posted an excellent review of this issue in their October 26th edition. I recommend reading the Johns Hopkins review of the current situation and the government panel’s rationale for their recommendation. Johns Hopkins’ advice was as follows. “Many leading cancer and patient groups and doctors agree that there is harm with PSA screening and the treatment that follows diagnosis. But a more targeted screening approach focusing on those at greatest risk of developing prostate cancer and active surveillance for those who don’t need immediate treatment, could shift the balance of benefit and harm toward benefit. PSA screening is the best test available for the detection of cancer cells in the prostate. Rather than discontinuing use of the only test available to detect the disease early and treat it successfully, efforts should focus on reducing harm.”
In addition, the November 1st edition of the ZeroHour Newsletter from the Project to End Prostate Cancer, cited an article published on October 28th in U.S. News and World Report, disclosing the results of a survey of urologists and internal medicine specialists’ responses to the government recommendation. “Virtually all responding urologists and more than 60 percent of internal-medicine specialists rejected the recent proposal by a high-level government advisory committee to end routine PSA testing.” About 95 percent of the responding urologists felt that doctors should continue to advise men starting at age 50, when testing typically begins, to have PSA screenings as part of a routine physical exam, contrary to the task force’s recommendation. There was however agreement that too many patients are encouraged to seek radical prostatectomy or radiation treatments and too few are informed about “watchful waiting”, in which periodic PSA tests, frequent physical exams, and biopsies are used to track a tumor’s growth and decide when, if ever, to pursue aggressive treatment.
The United States Preventive Services Task Force (USPSTF), an independent panel appointed by the Federal cabinet-level Department of Health and Human Services (DHHS), is preparing a recommendation which would eliminate prostate cancer testing (PSA) for all men. The rationale cited by the government panel is that there is moderate or high certainty that PSA testing has no net benefit or that its harms outweigh its benefits. (It should be noted that the panel did not include a urologist nor a medical oncologist.) The basic question involved in this recommendation is whether or not routine PSA testing saves men’s lives. Prostate cancer patients, survivors and advocates are being urged to voice their opinion about this recommendation to their Senators and members of Congress. Additionally, the USPSTF is accepting public comments on the new recommendations for the next four weeks. Links to communicate your opinions can be found in the October 7th and October 12th ZeroHour Newsletter from Zero-the Project to End Prostate Cancer.
Two major conflicting medical studies, one American and the other a European study, are being cited as evidence for/against this recommendation. These studies and their conclusions have been summarized by Dr. Patrick Walsh from the James Buchanan Brady Urological Institute – Johns Hopkins University on its website. (It should be noted that this institute at Johns Hopkins has been named the #1 choice for urology for the last 21 years consecutively by the annual survey in U.S. News and World Report. Dr. Walsh pioneered the development of the surgical nerve-sparing techniques whereby nerves controlling erections and urination are spared from damage during radical prostatectomies.) The European study was carried out in seven European countries involving 162,000 men who were randomized to PSA screening every four years versus no screening. After fourteen years of follow-up, “there was a 20% decrease in deaths from prostate cancer in the group of men assigned to screening.” Further examination of the data leads to a conclusion that the decrease in prostate cancer deaths could be as high as 27%. According to Dr. Walsh, “this reduction in death from prostate cancer is similar to the 30% reduction in mortality from breast cancer in women who undergo mammography and the 33% reduction in prostate cancer mortality that occurred in the United States between 1994 and 2003 following the introduction of PSA screening. Thus, the results from the European study support other findings and unequivocally demonstrate that PSA testing can save lives.” The second trial was carried out in the United States and was half the size of the European trial. “It compared screening with PSA every year for six years with no screening thereafter versus no planned screening. It showed no improvement in prostate cancer mortality at 7 years.” The reader is encouraged to review Dr. Walsh’s comments on these trials at the Brady Urological Institute website. He concludes that “if you are a healthy man age 55-69 who does not want to die from prostate cancer, the European trial provides conclusive evidence that PSA testing can save your life.”
What could occur if PSA screening was less accessible? What would be the options for a middle-aged man? A physician and close friend commented as follows. There are no specific symptoms whatsoever of the early stages of prostate cancer. The signs of early prostate cancer are indistinguishable from the signs of benign prostatic enlargement that commonly occurs as we age–namely, a weak or intermittent urinary stream, hesitancy (difficulty starting the flow of urine), straining, dribbling, having to get up at night to urinate, and the need to strain during urination. More serious signs–that increase the odds of a cancer being present–include blood in the urine and bone pain especially in the pelvis, ribs, or back. Any of the symptoms mentioned above in a man over 40 years old should prompt a visit to a physician. If cancer were present, blood in the urine and bone pain would seem to indicate the disease had advanced considerably by this point if more routine PSA screening had not been available.
As with any treatment, there are both benefits and risks. In the pre-PSA era, approximately 80% of patients who were diagnosed with prostate cancer, were already in advanced stages of the disease with metastatic cancer. Today, the number of patients who are diagnosed with metastatic disease at the time of initial diagnosis is around 20%. In the past 15 years, the prostate cancer death rate has been reduced from 42,000 annually to 33,000. On the other hand, according to the Prostate Cancer Foundation’s NewsPulse, PSA screening leads to biopsies wherein less than half of the patients who are biopsied each year are subsequently diagnosed with cancer. In addition, recent studies show that approximately 7% of men over 65 who have prostate biopsies are hospitalized within 30 days of the procedure, primarily due to infections according to the October 4th issue of the National Cancer Institute Bulletin.
Treating men over 70 aggressively for prostate cancer when instead their cancers might never become life-threatening is a practice that needs to be reduced. Instead, concentrating treatment on younger prostate cancer patients should be encouraged.
Personally, at the age of 54, my own cancer was discovered by a biopsy which was dictated by a moderately-consistent PSA of 4-5 ng/ml. I underwent a radical prostatectomy in 1995 at Johns Hopkins which resulted in virtually none of the side effects such as incontinence and impotence. This is indicative of the Johns Hopkins surgical nerve-sparing skills. (This website tells my entire story and lessons learned.)
There are more positive recommendations that could be made in the case of prostate cancer screening. PSA screening in patients should be more selectively targeted thus reducing over-testing and risks from over-treatment. Annual PSA screening may be better utilized as a baseline test and a series of tests over time to determine the rate of change of the PSA values with time (PSA velocity). Another useful test is prostate density, which refers to the PSA divided by the estimated weight of the prostate. A PSA of 5 ng/ml in a small prostate is more likely to indicate a cancer than a PSA of 8 ng/ml in a very large prostate. Also, through joint public-private research partnerships, government scientists such as those at the National Cancer Institute (NCI) of the National Institutes of Health (NIH) could focus stronger efforts on better early detection tests of lethal prostate cancers. Above all, validated biomarkers that are prevalent in most prostate cancers and could be detectible in urine or blood tests are sorely needed in order to detect and determine the aggressiveness of prostate cancers. For example, the DNA markers TMPRSS2:ERG gene fusion and PCA3 (prostate cancer antigen DNA) are expressed at high levels in 95 percent of prostate cancers. The gene fusion TMPRSS2:ERG occurs in 50 percent of prostate cancer patients. This two-gene DNA urine test is ultra-specific to prostate cancer and prostate cancer only.
Thank you for reading this most urgent blog. Please express your opinions on PSA screening to your senators and congressional representatives as well as to the USPSTF government panel.
For years, the general practice used in the initial screening for prostate cancer is a blood test for prostate-specific antigen (PSA) in conjunction with a digital rectal examination. These tests are then used to determine whether or not to subject the patient to a prostate biopsy, inherent with its own side effects and hopefully negative results. If the biopsy reveals cancer, then the questions of whether or not to treat the cancer, what treatment(s) would be most effective while minimizing potential side effects, and the possibility of no treatment or “watchful waiting” must be addressed. It would be extremely useful if a blood or urine test could identify genetic biomarkers (genes and their products such as proteins) whereby physicians could determine not only the presence or absence of prostate cancer but be able to predict whether or not the cancer would require treatment and if so, should aggressive treatment be necessary. For the many cases of prostate cancer which are identified, ‘no one size of treatment fits all.’ Methods are sorely needed to determine the appropriate level of treatment, if any.
More than 25 genetic subtypes of prostate cancer have been already identified. Some of these cancers might never require treatment and a man could die of other causes while other cancers require immediate, aggressive treatment. A team of researchers from Seattle and Sweden have recently identified a set of variations in five (5) genes which may be signatures for lethal prostate cancer thereby requiring aggressive treatment. These genetic variants might serve as the basis for a new blood test that could be given on initial diagnosis in order to determine which patients need aggressive treatment versus “watchful waiting.” To discover the five “disease genes” implicated in lethal prostate cancers, researchers looked for genetic variants that prostate cancer patients share in common. These variants in genes are called single-nucleotide polymorphisms, or SNPs (pronounced “snips”). Genes can be depicted as chains of thousands of beads comprised of four-five basic colors all arranged in a specific sequence. An example of a SNP would be the substitution of one blue bead in a gene by a red bead at a specific location along the chain of thousands of colored beads. These inherited genetic variants are certain genes that may signal the development of fatal varieties of prostate cancer. The five SNPs that were identified were linked to five genes that may affect prostate cancer progression, namely LEPR, RNASEL, IL4, CRY1, and ARVCF. It was of special interest to note that two of the five genes studied (IL4 and RNASEL) were associated with inflammation of the prostate, thereby suggesting a possible link between chronic inflammation of the prostate and the triggering of prostate cancer. The state of this research requires much more validation and development before it could be used as a diagostic test for aggressive prostate cancer. But it is a significant finding and indicative of the type of biomarker which would eventually relieve the uncertainties associated with PSA tests.
The research findings were published in the September issue of Cancer Epidemiology, Biomarkers and Prevention, and summarized in the September 2011 issue of NewsPulse from the Prostate Cancer Foundation.
It has been known for over 60 years that in general, prostate cancer cells respond to androgen deprivation (hormonal) therapy. At some point however, the prostate cells no longer respond (they become hormone-refractory) and levels of prostate-specific antigen (PSA) begin to rise. Treating this hormone-refractory prostate cancer remains a major challenge. There is now evidence that the resulting hormone-refractory solid tumors originate from undifferentiated (less-specialized) stem cell-like cells which are thought to only comprise 0.1 percent of the original prostate tumors. Metastasis also arises from these stem cell-like cells. [Stem cells are found in all multicellular organisms; they can divide and change from being less-specialized into more-specialized cell types as well as producing more stem cells.] These cancer stem cell-like cells often do not respond to chemotherapy or hormonal therapy, so a different approach that attacks these cells in advanced prostate cancer is needed.
In a recent report on Prostate.net and in the September 20th, 2011 ZeroHour Newsletter, a Swedish research team has found that a protein called STAT3 is active in the stem cell-like cells. In addition, a natural compound called galiellalactone was found to have an effect on STAT3 and inhibits prostate cancer growth. This research represents only the initial stages of the process of developing a drug that will attack the stem cell-like cells. Using the known compound galiellalactone as a model, other better drug-like substances will hopefully be identified that will inhibit STAT3 and become new therapies that attack the stem cell-like cancer cells in men who have prostate cancer and prevent growth and spread of the disease.