PCRI has been involved in major inroads in prostate cancer therapy, inroads that have a direct effect on the quality as well as the length of life for men with prostate cancer. Areas of involvement include:
BONE INTEGRITY AFFECTS THE NATURAL HISTORY OF PROSTATE CANCER
While the initial observation of bone loss secondary to ADT was not made by PCRI, recognition of the severity of this finding and the potential effect on the course of disease was emphasized by Dr. Strum in the 1997 Seattle Conference on prostate cancer and again in the 1999 Phoenix Conference on prostate cancer. During those meetings, other physicians heard this presentation and began writing and discussing the importance of bone integrity in PC.
In addition, Drs. Strum and Scholz championed the use of pamidronate (Aredia) in the setting of bone metastases from PC. They were the first doctors to routinely use this medication in such circumstances although no Medicare reimbursement was forthcoming for years. Medicare now approves the use of Aredia in the setting of bone metastases in PC thanks to the efforts of these co-founders of PCRI. PCRI Insights dedicated almost an entire issue to Bone Integrity in January 1999 (Vol 2, no. 1). The following Insights issue (vol2, no. 2) pointed out that the baseline level of Pyrilinks-D (Dpd), a simple urine test, is likely to be a clue to systemic bone metastases if above-normal values were noted prior to the institution of ADT. The importance of bone integrity is becoming more and more obvious with the increasing number of publications on this subject. Most recently, Novartis has had its new drug, Zometa, approved for problems with bone resorption
ANDROGEN DEPRIVATION SYNDROME (ADS)
During the years of observation of hundreds of patients on ADT (androgen deprivation therapy), it became apparent that a spectrum of complaints was being heard from patients that related to lack of male hormone. The spectrum ranged from virtually no symptoms due to ADT to a complete intolerance from the lowering of testosterone. Symptoms included the obvious loss of libido but also muscle and bone loss, anemia, hot flashes, emotional lability with easy crying, changes in hair growth, brittle nails, memory and calculating difficulties, weight gain, frequent aggravation of hypertension, diabetes, nipple hypersensitivity and breast enlargement. These findings were described for the first time as the Androgen Deprivation Syndrome or ADS at the American Society of Clinical Oncology (ASCO) in Los Angeles in 1998. ADS was the topic presented in PCRI Insights in the January 1999 issue. In that issue, Tables 3a & 3b detailed recommendations for the treatment or prevention of symptoms of acute ADS and chronic ADS. The recognition of ADS as a clinical entity and the need for correction of any of these problems if they become significant remains an area needing more attention and education. If we are to be successful in the use of ADT, then we need to know the downsides of such treatment and institute corrective measures. This is how optimal patient outcome is achieved: accentuate the positive, minimize the negative.
ANEMIA ASSOCIATED WITH ANDROGEN DEPRIVATION (AAAD)
AAAD was described for the first time in abstract form in 1994 by Dr. Strum and was published in full in 1997 in the British Journal of Urology by Drs. Strum, Scholz and others. It is the first description of a new type of anemia commonly found in men undergoing androgen deprivation therapy (ADT). This is related to the known importance of androgens in the development of red blood cell formation and accounts for the differences in the blood count (hemoglobin and hematocrit) seen between men and women. In men with significant AAAD, symptoms such as severe lethargy and weakness, shortness of breath, and development of angina or aggravation of angina may occur. A fall in hematocrit of at least 10% is seen in 88% of men on ADT2 (Two drug androgen deprivation involving an LHRH-agonist and an anti-androgen). This supports the contention that two agents have a more profound effect on lowering androgen levels than one agent. A fall in hematocrit of ( 25% was seen in 11.5% of all men with 12.8% having severe symptoms of angina, shortness of breath or severe weakness.
PROCRIT (ERYTHROPOIETIN) CORRECTS THE ANEMIA OF ANDROGEN DEPRIVATION
It is one thing to describe a new anemia and its clinical significance but another level of medicine is needed to define its resolution with a new therapy. AAAD is extremely sensitive to the use of human recombinant erythropoietin (Brand names Procrit, Epogen). We presented this at the AUA meeting in 1997 and received the best poster of the day award. We have not had time to prepare the definitive paper on this but our work has already impacted many patients since many physicians are now using Procrit to correct AAAD in patients with symptomatology. Most recently, Procrit is being advertised on television as a way to correct fatigue due to anemia of many causes.
VIAGRA (SILDENAFIL) RESTORES ERECTILE ABILITY IN MEN ON ADT
This conclusion was presented as a Letter to the Editor in the Journal of Urology in 1999. In a study of 21 patients, it was found that erectile function was dramatically restored in the majority of men using Viagra. This is another example of the resolution of one of the ADS findings by continued efforts of PCRI founders. The use of Viagra in this setting is important not only for achieving erectile function but also for preventing penile atrophy that is so common in men on long-term ADT. The Jane Fonda statement "Use it or lose it" applies to this situation as it does to the need for interval exercise of skeletal muscles to prevent muscle loss as well as ongoing use of brain activity to prevent cognitive dysfunction.
INTERMITTENT ANDROGEN DEPRIVATION (IAD)
Due to the importance of ADS and the critical role that physiologic levels of testosterone play in the health of man, a visionary approach to ADT was begun in 1990. This was styled after the approach taken by the pioneers in this field from the Cancer Control Agency of British Columbia- Bruchovsky, Gleave, Goldenberg et al. The approach used by Dr. Strum differed, in that the target PSA on ADT had to reach an undetectable value (<0.05 ng/ml) using an ultra-sensitive assay. The hypothesis here was: "A low level PSA reached on ADT would reflect a sensitive PC cell population that was most likely uniform in nature (homogeneous) and truly androgen dependent." It makes no scientific sense to be critical of androgen deprivation therapy in men presenting with findings indicative of androgen independent PC? ADT can show tremendous efficacy in populations of androgen dependent tumors but not with androgen independent populations. This is the very nature of ADT_(androgen deprivation therapy) yet most physicians treating men with PC ignore this basic principle.
The most recent publication on the use of two-drug ADT (ADT2) was published in February 2000 in the medical journal The Oncologist and the October 2000 issue of PCRI Insights. The use of IAD3 or three-drug combination therapy (finasteride or Proscar was the third drug added) has been presented at the American Urologic Association in 2000 and at the PCRI-US TOO Conference 2000, but has not yet been submitted for full publication. The results of this approach are striking and should influence current intermittent approaches. The key concept here is to use a therapy that invokes principles of tumor sensitivity as manifested by a sensitive biomarker such as the ultra-sensitive PSA (DPC 3rd Generation Immulite or Tosoh Hypersensitive Assay). Moreover, the IAD3 data indicate that Proscar, in the setting of additional agents such as an anti-androgen (Eulexin, Casodex, Nilandron) combined with an LHRH agonist (Lupron, Zoladex), has profound activity in allowing men to discontinue conventional ADT while remaining only on Proscar. In fact, the average time off ADT in the setting of PSA recurrences following RP or RT is in excess of five years and the average time off ADT has not yet been reached! All of this progress has emanated from the ongoing research at PCRI.
EARLY USE OF NIZORAL PROLONGS RESPONSE TIME
A landmark paper by Messing et al (Urol Oncol. 2003 Jul-Aug; 21(4):245-54) on the early use of ADT in men with lymph node disease at radical prostatectomy has been discussed at many conferences. One of the concepts underlying this appears to be that earlier use of therapies is more effective. In our study of Nizoral in men progressing after ADT, we also have found a greater response to this treatment if it is initiated before the disease becomes bulky and mutates to resistant cell clones. If Nizoral (High-Dose Ketoconazole or HDK) was begun at PSA levels of 10 or less, the average duration of response was 25 months vs. four months if the baseline PSA (bPSA) was greater than 10. We also demonstrated that the nadir PSA (the lowest PSA) has a bearing on reflecting the sensitivity of the tumor cell population that is being treated. In the Nizoral study, if the PSA nadir was <0.2, the average duration of response was 40 months. If it was 0.2 to 4.0, the average duration of response was 18 months but if it was 4.0-10.0, the response duration dropped to eight months and if > 10, to only four months. Overall, the study points out the efficacy of Nizoral when used early and the excellent response duration seen if the PSA nadir achieved is very low. This is another of the many advances to the quantity and quality of life that PCRI and its staff have made on behalf of the man with PC and his family.
IMPORTANCE OF BONE MARROW SUPPORT IN PATIENTS ON CHEMOTHERAPY FOR PC
This was discussed both at the San Diego PC Conference in 1998 and at the PCRI-US TOO Conference 2000 as well as in the December 1999 issue of PCRI Insights. If we are to achieve inroads in the treatment of advanced PC, we cannot lose men to complications such as infections secondary to bone marrow suppression that result from chemotherapy. Agents like Neupogen or Leukine, used in a preventative fashion, can protect patients from overwhelming infection that can be fatal. Unfortunately, we are seeing too many men on chemotherapy for PC who are not receiving the benefit of modern scientific advances such as the use of these agents. Bone marrow stimulants also include Procrit or Epogen (to correct the anemia secondary to chemotherapy and ADT) and Numega (to correct low platelet counts (thrombocytopenia) secondary to chemotherapy or due to radioactive isotopes like Strontium 89 [Metastron] and Samarium 153 [Quadramet]). PCRI will continue to stress the importance of such measures to physicians and patients alike. In the new millennium, we should not lose any men secondary to overwhelming infections due to marrow suppression.