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We have not given details about item (2) above, the preparation of the patient. What is it all about?

Preparation of the patient refers to what we can do to increase the likelihood of success in any of the therapies of PC. Treatment with RT is limited by tumor volume. We can reduce tumor volume by using androgen deprivation therapy (ADT). ADT employs drugs that lower the tes-tosterone (T) level as well as other androgens such as dihydrotestosterone (DHT) and adrenal androgen precursors such as DHEA-S and androstenedione. Most commonly, ADT involves the use of anti-androgens (AA) coupled with LHRH agonists (LHRH-A). Examples of AA include flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron). Examples of LHRH-A include leuprolide (Lupron) or goserelin (Zoladex). AAs are oral agents given on a daily basis, while LHRH-A are given intramuscularly or subcutaneously as long-acting depot injections on a monthly, or every 3 to 4 month, basis. It is critical to the proper use of the LHRH-A that the AA is given for at least one week before initiating the LHRH-A to prevent flare. Flare is a paradoxical reaction that occurs during initial exposure to the LHRH-A. It is characterized by an increased release of LH from the LHRH receptor that is interacting with the LHRH-A. This is described in detail in the paper "Hormone Therapy" on the PCRI Web site and also in issue number three of our newsletter Insights.

Monitoring of ADT

Patients receiving combination hormone blockade using the above couplets of drugs need to be monitored with chemistry panels, complete blood count (CBC), and PSA levels on a monthly basis to detect signs of possible toxicity resulting from this treatment. Both Eulexin and Casodex can cause elevations in the liver enzymes SGOT and SGPT. With monthly monitoring, the risk of significant liver toxicity is minimized. In addition, the avoidance of alcohol and the use of silymarin (100 to 200 mg 3 times a day) will prevent toxicity to the liver cell or hepatocyte (Dehmlow et al., Hepatology, 1996). The CBC checks the hematocrit to monitor the anemia of androgen deprivation that occurs in 80% of men on ADT (Strum et al., J. Urol., 1997). In cases where the anemia is severe, the use of erythropoietin (Procrit) will correct this problem and alleviate symptoms of fatigue, shortness of breath, and possibly angina (Strum et al., J. Urol., 1997).

Rationale for ADT

The rationale for the use of ADT is to reduce tumor volume to allow RT to be more effective. The efficacy of RT is compromised when the PC volume is too great to allow RT to effectively eradicate the total tumor cell population. ADT reduces the tumor volume, synergizes with RT, and decreases angiogenesis to allow for a better outcome with RT. This has already been reported in the landmark paper by Bolla et al., which employed RT with 3 years of LHRH agonist therapy to treat high-grade Gleason score lesions (GS 8-10) or locally advanced PC (CS T3-4) (Bolla et al., N. Engl. J. Med., 1997). The literature on the use of ADT in patients with a lower clinical stage and lower GS is currently being written and appears to validate the use of ADT to allow RT to be more effective (Zelefsky et al., J. Clin. Oncol., 1998). Studies are being published that now show the equivalence of RT approaches such as external beam RT or seed implantation when compared to similarly selected patients who undergo RP (Keyser et al., Int. J. Radiat. Oncol. Biol. Phys., 1997). In such good-risk patients, the 10-year actuarial disease-free survival rates are about 80%. This means that there is no evidence of biochemical relapse as seen by a rising PSA in 80% of these patients at an actuarial time of 10 years. It is not surprising that this equivalence to RP is being seen with RT when the tumor volume is being controlled for by selecting patients with low levels of PSA and Gleason scores that reflect a lower tumor burden.

There are many fine points that relate to the above discussion. Limitations of space do not allow for all of these to be dealt with in this overview. We would suggest that the reader use the resources mentioned above along with those at the end of this section for a further understanding of the issues so far discussed. In addition, the PCRI newsletter Insights has examples of how a patient can proceed in a step-wise fashion in the evaluation of his disease; Insights can be printed off our homepage.

In lieu of RP, RT, or cryosurgery, PC patients may want to consider protocols that incorporate androgen deprivation therapy (ADT) for control of most prostate cancers. In essence, this is the primary use of hormone manipulations to control PC growth. Innovative natural adjunctive therapies are also implemented immediately upon the initiation of ADT or any anticancer therapy. Ideally, many of these adjunctive therapies should be utilized in a preventative fashion. This will be discussed in more detail later.

What is involved in using androgen deprivation therapy (ADT)?

Combination Hormone Blockade (ADT2 or ADT3)

There is currently controversy as to the value of ADT using combined modalities of blockade versus one modality of blockade. A recent article, for example, showed no benefit of Eulexin when given with orchiectomy compared to orchiectomy alone in men with advanced PC involving the bone (D2 disease) (Eisenberger et al., N. Engl. J. Med., 1998). In this study, the patients with minimal bone disease had a 5-year survival of ~ 50%. In contrast, Labrie et al. reported a 66% 5-year survival in D2 patients with 1 to 5 bone lesions receiving combination Eulexin and Lupron (Labrie et al., Clin. Invest. Med., 1993). Moreover, EORTC study 30853 showed improved survival in the group receiving combination Zoladex + Flutamide versus orchiectomy. In this 327-patient study, there was a 39% decrease in the death rate in good-prognosis patients in the combination-arm versus the orchiectomy-only arm (Denis et al., Eur. Urol., 1998). The different outcomes reported need to be resolved, since most men today are still receiving combined hormone blockade using an LHRH-A and an anti-androgen. In addition, clarification of other uses of hormone blockade remain relatively neglected. These include the use of ADT in earlier stages of PC, inhibition of dihydrotestosterone (DHT) production, and the use of prolactin inhibitors. These are discussed in the PCRI paper called "Hormone Therapy." In this paper, clinical detailed studies using agents that block additional areas in the hormonal axis are cited. Some of these issues are worth discussing here.

The use of finasteride (Proscar) to block 5-alpha-reductase, to prevent conversion of T into DHT (which is five to ten times as potent), appears reasonable. When we employ three drugs as part of ADT, we indicate this by the designation ADT3. We are striving for terminology that allows us to communicate more clearly. ADT3-LEP indicates three-drug ADT with Lupron, Eulexin, and Proscar. These are studies using Proscar in post-radical prostatectomy patients to delay the rise in PSA, as well as studies that have combined Proscar with an anti-androgen (AA) (Andriole et al., Urology, 1995; Brufsky et al., Urology, 1997). The latter approach is called sequential androgen blockade (SAB) since it involves blocking DHT production along with preventing both T and DHT from interacting with the nuclear androgen receptors. The SAB approach maintains a high level of T. In some men, this results in fewer problems with erectile dysfunction, muscle loss, and other signs and symptoms associated with androgen deficiency. We have used Proscar as part of ADT since 1990, employing a dose of 5 mg twice a day. To date, there are no randomized studies comparing two-drug ADT (ADT2) versus three-drug ADT (ADT3). We have published preliminary findings using three-drug therapy in the setting of intermittent androgen deprivation (IAD). When such patients are taken off the LHRH-A and the anti- androgen, they are left on Proscar as maintenance therapy. Patients treated in this fashion had an extra 13 months "off time" from IAD compared to those who received ADT2 and no Proscar maintenance (Scholz et al., J. Urol., 1999).

The use of prolactin inhibitors in PC patients is based on work showing that prolactin increases the number and sensitivity of androgen receptors. Rana et al. used the prolactin-suppressing drug bromocriptine along with orchiectomy and hydrocortisone (regimen A) in treating advanced PC. Regimen A was compared to orchiectomy plus Eulexin and to orchiectomy alone. Regimen A resulted in a 61% suppression of primary prostate growth, compared with only a 48% reduction with orchiectomy and Eulexin alone. After 36 months, 40% of the group receiving Regimen A experienced disease progression, compared with 60% in the orchiectomy-only group (Rana et al., Eur. J. Cancer, 1995).

PC patients should have their prolactin levels checked via a blood test drawn in the morning. If your prolactin levels are elevated, you should consider one of the following prescription drugs:

• Bromocriptine, 5 mg 1 to 2 times a day
  
• Dostinex, 0.5 mg twice a week

Check your prolactin levels again in 30 days to make sure the drug you choose is, in fact, suppressing prolactin released into your blood from the pituitary gland. Dostinex is the newest and easiest drug to use since it has fewer side effects than the older drugs, is more effective in suppressing prolactin, and requires dosing only twice a week.

Many patients use ADT to prepare themselves for local therapies such as RP, RT, or cryosurgery. Others use ADT as a means to extend time before decisions on local therapy, hoping for a new breakthrough that preserves prostatic integrity. Still others are using ADT as primary therapy of PC. It is important that we inform patients that approaches like IAD are still considered investigational. When ADT is used in conjunction with local therapies such as RP, RT (including seed implantation), or cryosurgery, it is important to stress the need for baseline studies to assess the stage of disease before starting ADT, as well as to coordinate the goals of ADT with the team involved with the local prostate treatment. For example, the choice of external beam radiation therapy (EBRT) with seed implantation is based on evaluations that include Gleason score, PSA, local extent of disease, and gland volume. Studies that involve the latter two items should be done as baseline before ADT is begun. The gland volume should be monitored by digital rectal exam with the goal of lowering the prostate size for optimal implantation. For many brachytherapists, this is in the 15 to 30 cubic centimeter (cc) range.

Biomarkers to Assess Tumor-cell Sensitivity

If tumor cells that make substances such as PSA and prolactin (as well as other biological markers such as PAP, NSE, CGA) are destroyed by anti-cancer therapy of any kind, then the biomarker levels drop to low or undetectable levels. The more sensitive the tumor cell population is to the therapy used, the more quickly and more sustained the biomarker(s) drop. It has been our practice to use ADT with the goal of achieving and maintaining an undetectable PSA (UD-PSA) level for at least 1 year in the setting of men using ADT as primary therapy for newly diagnosed PC. When we are able to achieve this, we feel comfortable that we are not dealing with other mutated tumor cell populations (clones). We believe that these mutated clones, with continued growth, lead to the clinical expression of androgen-independent PC (AIPC). Therefore, our goal is to assess the tumor cell population comprehensively with various biomarkers, treat the tumor cell population with a combination approach to ADT, achieve a UD-PSA, and maintain it for approximately one year. We are routinely using the 3- drug combination of anti-androgen (Flutamide or Casodex), LHRH agonist (Lupron or Zoladex), and Proscar in our patients. In patients with elevated or high-normal prolactin levels, we suggest entry into a trial using Dostinex to see if this effects a change in PSA that correlates with prolactin suppression. Our results using Dostinex are too preliminary to report at this time. However, the results with our intermittent androgen deprivation (IAD) approach are mature enough to state that our average duration of time off therapy with an UD-PSA (ADT2 for approximately 13 months), achieved and maintained, is currently 19 months. We can also state that the use of Proscar during induction ADT and maintenance off ADT extends this time to an average of 32 months. Discontinuation of ADT allows normal T recovery and prevents the man on ADT from having chronic debilitation due to lack of male hormones. Work is needed to refine optimal drug combinations and duration of therapy.

The Androgen Deprivation Syndrome (ADS)

Signs and symptoms resulting from ADT are called the androgen deprivation syndrome, or ADS (Strum et al., Proc. Amer. Soc. Clin. Oncol., 1998). Androgens are vital to the proper function of most organ systems. For example, blocking androgen in the nervous tissue of the brain may be associated with short-term memory loss, while blocking androgen receptors in the bone marrow often leads to the anemia of androgen deprivation. Many men on ADT report joint symptoms characterized by aches and pains in their feet, knees, and hips and stiffness in their hands. It is believed that the latter represents the effects of androgen deprivation leading to excessive bone resorption. If unchecked, this eventually leads to osteoporosis. How does this happen? Androgen receptors have been found on osteoblasts. Perhaps the androgen blockade that occurs as a result of ADT causes diminished osteoblast growth, leading to an uncoupling of osteoblast-osteoclast function with excessive osteoclastic activity and bone resorption. The signs and symptoms relating to the ADS are highly variable from man to man. Some men have few complaints from withdrawal of androgens, while others have multiple problems and are miserable. It is our goal to kill as many PC cells as possible while allowing a high quality of life. The second issue of Insights and the PCRI Web site have articles on ADS and how symptoms can be ameliorated to improve the quality of life of men experiencing such adverse effects from ADT.

Summary of Recommendations for Treatment
of Apparent Early Prostate Cancer

The optimal treatment of apparently organ-confined PC requires the proper selection of the patient based on a careful risk assessment of known prognostic factors. This means that the patient should have an expert Gleason score obtained as well as a careful evaluation of all known factors that are involved in a thorough risk assessment of extent of disease. These include, at least, baseline PSA, PAP, clinical stage, gland volume, number of cores involved, ploidy, and pathological stage. Using this information and applying known algorithms to calculate PC risk outside the prostate, the clinician-patient team can exclude such extraprostatic involvement with appropriate tests and increase the chance of treating localized PC with a greater probability of cure. This approach to patient selection for localized treatment of PC is further enhanced by using ADT to reduce tumor and gland volume to increase the chances of cure with local therapy modalities such as external beam RT and/or seed implantation, or cryosurgery. To date, there is no data to suggest that ADT enhances the cure rate of RP. Perhaps the 3 months of neoadjuvant therapy used in most studies is insufficient time to achieve this goal. Finally, the choice of a physician(s) to deliver these therapies is critical to the successful treatment of PC.

Cancerfacts.com

Cancerfacts.com is a new Internet service that employs the philosophy and take-home lessons shown above. Patients are asked for essential data that are used to compile multiple algorithmic assessments. This is presented using a wizard to guide the patient while educating the patient with references, glossary, and abstracts. This leads to treatment options that are personalized to the patient depending on preferences that the patient has indicated and the results of the algorithmic assessment. The Internet URL for this service is [http://www.cancerfacts.com].