ADT 101 (My opinion as to appropriate and most efficient Androgen Deprivation Therapy for Prostate Cancer with advanced or recurring disease):
By Charles Maack (Prostate Cancer survivor and active participant in the Wichita Chapter – Us TOO)
I DO NOT advocate immediate total androgen blockade as soon as one's PSA begins a rise, and particularly for patients not considered to have advanced prostate cancer. For patients diagnosed with possible advanced prostate cancer (Gleason Scores of 8, 9, or 10) there are several tests (among which should be PAP, CEA, CGA, and NSE) that should come into play at that time to determine the extent of and possible aggressiveness of the disease. Androgen deprivation medications could hamper those tests. However, once tests do determine that prostate cancer is present and a staging level and a Gleason Score have been assigned, many men choose (as they should) to research and study their options before jumping to a suggested treatment option. If, during that research/study time their PSA is showing a continuing rise, it is at that time that I would encourage androgen deprivation to rein in the PC development if the patient prefers continuing his research/study. It should be noted that for those men who are averse to surgery and radiation, androgen deprivation therapy can be their option. Androgen Deprivation Therapy also comes into play with recurring PC development after prior treatment options.
Prior to the administration of an LHRH agonist like Lupron, Zoladex, Eligard, etc. it is important to first prescribe an anti-androgen like Casodex, Eulexin, Nilandron at least a week prior and up to time of injection for the LHRH agonist as well as to a month beyond to preclude the possibility of "flare" that can result in medical emergencies such as spinal cord compression, ureteral blockade or severe increase in bone pain that can otherwise occur with the surge of testosterone/androgen production that occurs during the first two weeks following the injection of an LHRH agonist that could otherwise stimulate PC cell growth.
Since the aim of androgen deprivation is to block the stimulation by testosterone/androgen of PC cell growth in order to rein in the cancer as well as kill the cancer cells, then triple hormonal/androgen blockade serves that purpose more thoroughly than simply cutting down testosterone/androgen production with an LHRH agonist. Though the LHRH agonist overworks the leydig cells in the testicles by causing them to initially over-produce testosterone and subsequently wear down, it may not entirely shut off all testosterone from that source. And, the LHRH agonist has no effect on the adrenal glands that also produce, albeit much less, testosterone (however, with androgen/testosterone production from the testicles dropping, the adrenal glands tend to increase production in an attempt to compensate). Thus, some testosterone can still access and feed prostate cancer cells. Testosterone in and of itself is not a strong stimulant to PC cell growth; it is when enzymes in the PC cells convert the incoming testosterone to dihydrotestosterone that an up-to-ten-times more powerful stimulation to those cells occurs. So, it becomes necessary to prevent that conversion from occurring. And that is where 5Alfa Reductase (5AR) Inhibitors Avodart or Proscar enter the process to prevent that conversion. They inhibit the ability of those enzymes to function. Avodart, in particular is known to up-regulate/increase the effectiveness of the IGEBP3 gene known to cause apoptosis/cell death while at the same time down-regulate/decrease the effectiveness of the TMPRSS2 gene that otherwise stimulates cell growth, and also down-regulate//decrease the effectiveness of the TFF3 gene that otherwise blocks PC cell apoptosis (for more information in this regard, view http://www.medpagetoday.com:80/MeetingCoverage/ASCOProstate/tb/5119. Since testosterone/androgen from either the testicles or adrenal glands have to access the prostate cancer cells by way of androgen receptors on those cells, the method to prohibit that access is, obviously, by blocking those receptors. And that is where the non-steroidal anti-androgens Casodex, Eulexin, and Nilandron come into play since that is the job they accomplish. Anti-androgens can also ease severe bone pain in advanced prostate cancer.
I hope that explains why triple androgen blockade is much more successful not only in reining in PC growth but also killing off PC cells by starving them.
Now, you often read of the anti-androgens, over a period of time, failing and PC cells mutating and those same anti-androgens now changing their role to actually be providing a form of fuel to the PC cells. When this is suspected, the anti-androgen is withdrawn to see if once again the PSA stops rising. When the PSA does NOT stop rising, it is an indication that the androgen deprivation is beginning to fail, so High Dose Ketoconazole (HDK) comes into play since HDK blocks the adrenal glands as well as, to some degree, the testicles from androgen production. Some PC experts consider it important to begin HDK as soon as it is noted that an anti-androgen appears to be failing and a PSA rise is occurring while on ADT. The more toxic HDK is not used early on in androgen deprivation therapy and only comes into the treatment process when absolutely necessary and as a precursor to having to move to yet the higher level of attacking PC cells with chemotherapy. When HDK does enter the process, an LHRH agonist is continued to avoid sudden production of testosterone by the testicles, the anti-androgen is sometimes also continued, and the 5AR inhibitor should also continue. Important also to note, according to Mark Scholz, a Medical Oncologist with specific expertise in androgen deprivation and the use of HDK, since HDK also blocks adrenal production of hydrocortisone, administration of hydrocortisone 20mg at breakfast and 10mg at dinner is prescribed to prevent side effects that could occur with the loss of too much cortisone because of HDK. HDK is most often initially administered at 200mg three times per day the first week, then increased to 400mg three times per day thereafter. HDK should be taken on an empty stomach at least 30-60 minutes before any food or 2 hours after. Hydrocortisone should be taken with food. The use of estradiol patches should be stopped when on HDK since there are a number of bad side effect reactions that can occur when used in combination.
This should answer any questions how I come to support when to use and why to use triple hormonal blockade, as well as why and when HDK becomes part of the preventive process. During all these processes regular monitoring/laboratory testing should be maintained by your Medical Oncologist (who should be the one monitoring your treatment once these medications become required therapy).
To review the article regarding "When Should You Start Treatment With Ketoconazole" by Mark Scholz, Richard Lam, Brad Guess, and Ralph Blum, please click onto the URL below then scroll down to page 5.
http://www.paactusa.org/newsletters/2005/cc_vol_21-4.pdf
BELOW IS URL REGARDING ASCO RECOMMENDATIONS WRITTEN IN 2004:
http://jco.ascopubs.org/cgi/content/full/22/14/2927
HOWEVER, BELOW IS URL OF REPORT TO ASCO REGARDING IMPORTANCE OF AVODART TO PC APOPTOSIS ALONG WITH AN ARTICLE FROM "MEDICAL NEWS TODAY":
http://www.medpagetoday.com:80/MeetingCoverage/ASCOProstate/tb/5119
http://www.medicalnewstoday.com:80/medicalnews.php?newsid=45741
