Androgen Deprivation Therapy (ADT) Following Recurring Prostate Cancer Or When Androgen Deprivation Becomes The Necessary Therapy
By Prostate Cancer Patient and Advocate Charles C. Maack with editorial assistance from Bob Hustead, M.D. (Prostate Cancer survivors and active participants in the Wichita Chapter – Us TOO). Mr. Maack was diagnosed in 1992 with Gleason Score 3+4=7. After failure of radical prostatectomy and external beam radiation, he has been an androgen deprivation therapy patient and has maintained continuous research and study of this disease, focusing on appropriate androgen deprivation therapy, since 1996.
This “observation” is an attempt by this layman prostate cancer patient to provide a reasonable explanation of the controversies in Androgen Deprivation Therapy (ADT) for the treatment of recurrent prostate cancer. I am one of those patients. Herein are my personal conclusions; some readers may consider them as more confusing rhetoric.
It is obvious that many physicians administer ADT in different manners. The question by too many patients has become “what do I do?” Those who have researched ADT have found that there are several differing reasons as to why this physician or that physician has his or her “preference” and why they use different drugs in ADT treatment. Such patients may be left floundering and confused.
Testosterone (T) is the male hormone or androgen that comprises most of the androgens in a man’s body. Testosterone, by itself, plays a small part in driving prostate cancer (PC) growth. An enzyme in prostate cells converts T to as much as ten times a more potent metabolite, dihydrotestosterone (DHT), that profoundly stimulates cancer cell growth; that enzyme is 5-alpha reductase (5-AR).
Orchiectomy (surgical castration) removes the testicles that produce the majority of testosterone in men. T can also be reduced by chemical castration called Androgen Deprivation Therapy (ADT). Both methods reduce the production of testosterone in an attempt to starve or kill prostate cancer growth; neither method has the ability to stop the production of DHT nor to reduce the amount of androgens produced by the adrenal glands; in fact, both routes may stimulate adrenal androgen production which the prostate cells can convert to T and then to DHT. Both of these routes are called ADT, which was historically correct, but they should be called Testosterone Reducing Therapy (TRT).
Chemical castration is done by forcing the pituitary to over-stimulate the Leydig cells in the testicles to “wear them out” or to reduce the ability of the messenger to stimulate those cells; that messenger is LH or Luteinizing Hormone- Releasing Hormone of the hypothalamus. Such stimulators are called LHRH agonists (leuprolide acetate (Lupron), goserelin acetate (Zoladex), triptorelin acetate (Trelstar), leuprolide acetate in atrigel (Eligard) and two longer lasting agonists, leuprolide acetate implant (Viadur) and histrelin acetate implant (Vantas). The end product is a diminution of Leydig cell T. T production can also be slowed by newer agents that are LHRH antagonists called Abarelix and Centrilex. The loss or lowering of T effects most cells in the body, especially brain, bone, and muscle.
Prostate cell growth is stimulated by T or DHT attaching to androgen receptors in prostate cells. These receptors are also activated by many other androgenic substances. The androgen receptors in the prostate cell (and unfortunately elsewhere in the body) can be blocked by androgen receptor blockers or anti-androgen as bicalutamide (Casodex), flutamide (Eulexin), nilutamide (Nilandron), or cyproterone acetate (Androcur). Androcur also blocks LH. All these substances seem to act primarily on prostate cells.
The conversion of testosterone to DHT can be blocked by 5-AR inhibitor finasteride (Proscar) or even more completely by dutasteride (Avodart). When this conversion is blocked, T levels in the body usually rise to try to make up for the difference. Thus the rest of the body is not deprived of the effect of T. Of particular additional importance - it was reported at the February 2007 annual meeting of ASCO (the American Society of Clinical Oncology - the organization for physicians who treat cancer) that dutasteride (Avodart) had been found to upregulate the gene IGEBP3 and down regulate genes TMPRSS2 and TFF3, thus causing PC cell apoptosis and inhibiting cell proliferation. In my opinion, this is documented evidence that dutasteride (Avodart) should be prescribed in all androgen deprivation therapy.
Thus there are three levels at which it is possible to interfere with the prostate cell growth (and androgen dependent prostate cancer growth), viz., at the hypothalamus in the brain, in the Leydig cell of the testicles, or within the substance of prostate cells where T is converted to DHT. DHT powers the prostate cells with energy to divide.
Surgical or chemical castration was called ADT or androgen deprivation therapy when little was known about the two other levels. Today any two or three levels can be blocked to sequentially or concurrently slow down prostate cancer growth.
Some of the above drugs seem to kill old prostate cells or to cause what is called Apoptosis. Apoptosis seems to occur best with a combination of drugs. To just slow down PC growth is buying time, but causing Apoptosis can kill cancer. When cancer is slowed down, it seeks another source of feeding materials by mutating or forming new clones. Some of the new clones are Androgen Independent Prostate Cancer (AIPC) and some are just more aggressive prostate cancer.
The accepted treatment of metastatic PC (invasive and growing by itself away from the prostate) has been to block PC by starting with surgical or chemical castration (ADT) and reserving Casodex or Androcur (ADT2) and Avodart or Proscar (ADT3) for future use should PSA and/or testosterone levels rise to indicate continued growth of PC, despite the ADT.
This fails to make sense to me based on much recent evidence. Experts are becoming more knowledgeable about the need to stop or kill cancer as quickly as we can and before it has had time to multiply and form more invasive clones. Thus, I believe that when it is obvious that ANY prostate cancer is present, it appears logical and rational that ADT3 – a full blockade against the growth of prostate cancer cells – should be initiated. My reasoning is why wait for a change to occur, which would mean you held back a therapy that may have served to kill cancer cells in their earlier stages and could have prevented that change or made them stay dormant for many years? This reasoning has been shown to be extremely important in Breast Cancer.
Modern thinking physicians who have followed many persons on LH-RH agonists (Lupron and Zoladex) have determined how detrimental it is for many patients to be on continuous Testosterone Deprivation; they have determined that Intermittent ADT (IAD) (stopping use of the agonist) can be as beneficial as continuous therapy as long as the individual has been able to obtain and maintain for 1 year a PSA level that is “undetectable” or <0.05 ng/ml and a “castrate” testosterone level <20ng/dl before considering IAD. During any IAD interval, a continued “maintenance” with Avodart or Proscar should be considered. This allows T to slowly recover but still inhibits the conversion of T to DHT so as to interfere least with the good effects of T on the rest of the body and probably to delay the onset of Androgen Insensitive PC clones.
The National Comprehensive Cancer Network (NCCN) statement indicates there is currently no clinical data to support the addition of antiandrogen blockade and 5-AR blockade additions to ADT. This is because clinical trials were not presented to the Federal Drug Administration (FDA). Largely because the drugs were already in use and their patents about to expire. Clinical trials require huge financial support of the pharmaceutical firms to get the studies into the pipeline. Now that newer drugs like Androcur and Avodart are available, and their patents have many years of protection, it is likely that such studies of them might get underway. But it will still be years before this information gets to NCCN or guys like us; in the meantime the older drugs will be ignored.
However, data in peer reviewed literature has been validated and there is a nucleus of physicians specializing in prostate cancer treatment (those at the annual National Prostate Cancer Conferences like Strum, Scholz, Myers, Lam, Tucker, Leibowitz, et al) who have applied this combination therapy with the older drugs and published results. They have established its effectiveness in blocking the androgen receptors and inhibiting the conversion of T to DHT, and in so doing, increasing the effectiveness of ADT. The important report to ASCO noted previously regarding dutasterinde (Avodart) playing a role in PC cell apoptosis and inhibiting PC cell proliferation should no longer be ignored.
Obviously, by this writing, I support the importance of what is called three level ADT (ADT3). It should be noted that the NCCN recognizes that patient preference is to be included as a part of the treatment decision. Every patient should study and understand their treatment options in order to be able to validate their treatment preference. Here is the specific "Summary" statement in the National Comprehensive Cancer Network Prostate Cancer Guidelines:
"SUMMARY The intention of these NCCN Prostate Cancer Guidelines is to provide a framework on which to base treatment decisions. Prostate cancer is a complex disease, with many controversial aspects of management and with a dearth of sound data to support treatment recommendations. Several variables (including life expectancy, disease characteristics, predicted outcomes, AND PATIENT PREFERENCES (my highlighting)) must be considered by the patient and physician in tailoring prostate cancer therapy to the individual patient."
The use of 5AR (Alpha Reductase) inhibitors such as dutasteride/Avodart or finasteride/Proscar is NOT UNETHICAL. Despite many physicians commenting that their use "has not been proven," if the patient chooses to have the medication prescribed as part of his androgen/hormonal deprivation therapy (ADT), it should be honored by the physician. The NCCN guidelines even question the necessity of antiandrogens if the LHRH agonist effectively brings down the testosterone and PSA levels, despite the knowledge that antiandrogens block prostate cancer (PC) cell androgen receptors, thus hopefully blocking all such receptors from testosterone accessing the prostate cancer cell. They apparently choose to ignore that the adrenal glands can still produce testosterone and thus access prostate cancer cells, or they hold off these necessary medications "until they become necessary;" a somewhat ridiculous reason when one considers that if they become important and appropriate when "they become necessary," then they certainly should be important and appropriate in any event. And since any testosterone accessing the prostate cancer cell (that can occur even with antiandrogens since it is unlikely that every single prostate cancer cell is blocked) can then be converted to the much more powerful stimulant to prostate cancer cell growth, dihydrotestosterone (DHT), a 5AR inhibitor becomes a necessary safeguard to inhibit that conversion.
And, despite the remark by many physicians that androgen deprivation therapy is not a "curative" therapy, ADT can cause PC cell apoptosis as well as inhibit PC cell proliferation. There are no therapies that can definitely be claimed to be "curative." My personal opinion is that the word "cure" should not be part of the vocabulary of cancer. We hope for "cure," but once diagnosed with any cancer, we must ever more be vigilant.
I recognize that the choice of therapy can be driven by the cost of that therapy. All ADT drugs are expensive. Medicare, as do most insurers, pays for injectible drugs like Lupron that must be injected in a medical setting. Medicare only pays for drugs taken orally like Casodex, Eulexin, Avodart, Proscar, Androcur, etcetera to the limits of its Plan D . Those moved to pursue this therapy should be prepared to pay for the added medications or to find out if their physicians or the drug companies are able to obtain these drugs in clinical trials, samples, or a price reduction for those with financial need. Many medications are available to military veterans at a Veteran’s Administration medical facility.
When physicians are ready to insist and support their reasoning to insurers the necessity of providing coverage for these drugs that are available to save lives, and when pharmaceutical companies can afford to make them available at reasonable cost, we may begin to see patients extending their lives in immeasurable years rather than in numbered months.
The foregoing described my research, study, and personal experience with over eleven years as a patient with androgen deprivation therapy. However, I would be remiss if I did not make mention of an alternative androgen deprivation therapy - the use of estradiol patches. Estradiol patches are less expensive than conventional LHRH agonists and anti-androgens. My understanding is that estradiol patches do not cause osteoporosis and are less risky than oral estrogen that has been known to cause blood clots. Many physicians will not prescribe estradiol therapy because of their awareness of oral estrogen side effects. Of importance if seeking this form of androgen deprivation is doing your own personal research and study, then finding a physician with understanding and experience in its administration as to proper dosage and close monitoring.
(I did not go into side effects and drug interactions/reactions of ADT treatment that can include hot flashes, breast enlargement, muscle weakness, fatigue, osteoporosis, and others that require regular physician/laboratory monitoring; they are separate but very important issues that every patient should research and be aware to discuss with as well as question their physician)
