Reprinted from PCRI Insights October 2000 vol. 3 no.3
By Stephen B. Strum, M.D.
The commonly adopted contemporary approach using androgen deprivation therapy (ADT) in advanced PC involves uninterrupted treatment. This assumes an ongoing response to therapy and the absence of significant adverse effects. Most men accept adverse effects from ADT if they achieve a meaningful remission from their disease, particularly for men with advanced disease.1 Patients with localized PC are candidates for local therapy that may include ADT.2,3 In such men, recent studies report a diminished quality of life during ADT.4-6 Symptoms attributable to ADT include loss of libido, impotence, loss of muscle bulk and strength, weight gain, cognitive dysfunction, and vasomotor instability. Additionally, acute and chronic complications such as anemia7,8 and osteoporosis9-12 may occur, the latter of which results in greater debility than is usually recognized.12 ADT has also been reported to exacerbate medical conditions such as hypertension, diabetes mellitus and hyperlipidemia.6,13
In 1989, we began to discontinue ADT in consenting patients who achieved and maintained an undetectable prostate-specific antigen (UDPSA). This approach was initiated due to favorable reports using intermittent androgen deprivation (IAD).4-6,14,15 Since then, Drs. Jonathan McDermed, Mark Scholz, and I have conducted an on-going study of IAD, and in February of this year The Oncologist published our paper which presented significant patient- and treatment-related factors associated with off-therapy duration in 52 assessable patients electing IAD using two agents: an luteinizing hormone-releasing hormone (LHRH) agonist and an anti-androgen.16
This article will present to you our early results and show you what we have observed. It will present clinical and laboratory findings that are associated with a long time-off ADT. It will also point out that the induction phase of ADT provides us with prognostic information relating to time-off therapy.
Figure 1 illustrates what we hypothesized both in this study and a follow-on study using a three drug IAD regimen, a study that will be published later this year. Our hypotheses are as follows:
(1) ADT would lead to apoptosis or programmed cell death. (2) A PSA drop to undetectable levels (<0.05) would indicate a sensitive tumor cell population. We considered this to be, in essence, an induction period. (3) Next, we attempted to maintain all patients at an undetectable PSA for an average of 12 months. This we considered to be a consolidation phase. (4) We hoped that in the context of intermittent androgen deprivation this approach would lead to a prolonged time-off therapy and improvement in the quality of life of our patients.
The definition of “response to ADT”, for the purposes of this IAD study, was the ability to achieve an undetectable PSA (UD-PSA) using a hypersensitive PSA assay to a level of <0.05 ng/ml and to maintain that level for a target duration of 12 months. We emphasize the need to use more stringent criteria insofar as the drop in PSA resulting from ADT to define a population of tumor cells exquisitely sensitive to apoptosis. For this reason, hypersensitive PSA assays such as the 3rd Generation Immulite Assay by DPC, Inc. or by Tosoh, Inc. are recommended.
Of the 336 patients meeting these criteria, 124 elected IAD (see Figure 2). Of those 124, 52 patients were involved in a two-drug IAD regimen (IAD2) using an LHRH agonist and an anti-androgen while 72 other patients were involved in a three-drug IAD regimen (IAD3) that added finasteride to the IAD2.
Prior therapy in the two-drug patient group indicated that over half of the patients, or 29 of 52 (56%), had received no prior therapy. Thirteen (25%) had undergone prior RP, while six (12%) had received RT and RP and four (8%) had received RT alone. A breakdown of the 29 untreated patients disclosed that six were stage T1c, 16 were T2a-c and seven were D0-D2.
The treatment roadmap is straightforward. Patients were begun on ADT2 with the antiandrogen given for one week prior to starting the LHRH agonist to prevent flare. Patients had to achieve and maintain an undetectable PSA at a level of <0.05 to be eligible for this study. The average time to an UD-PSA was four months. Patients were told that the overall study strategy had a target undetectable PSA (UD-PSA) for at least 12 months. The patients, however, determined when to stop ADT. The mean and median ADT times were 19 and 16 months, respectively.
The off-ADT PSA was followed on a monthly basis along with serum testosterone levels. At an arbitrary PSA of 5.0, the patient was advised to restart the second cycle of ADT (2ADT2). Testosterone recovery was felt to be approaching physiologic levels at a serum testosterone of 150. The month that the testosterone reached this level was called T-150. The treatment roadmap is shown in Figure 3.
The three important clinical variables that were found to relate to time-off treatment were duration of UD-PSA, the presence of PSA recurrence (PSAR), and the time to testosterone recovery (see Figures 4–6.)
For the patients receiving IAD2, the duration of UD-PSA is a significant variable relating to the off-phase duration. Patients with an UD-PSA > 12 months had an off-phase duration three times longer than those with shorter UD-PSA durations. The average off-phase duration was 29 months in patients with an UD-PSA > 12 months vs. 8.5 months in patients with an UD-PSA <12 months.
In the subset of patients with only PSA recurrence (PSAR), off-phase duration was significantly extended and was two times greater than for patients not in this category, as shown in Figure 5.
The average off-phase duration of PSAR patients was 24 months vs. 12 months in the non-PSAR patients. Patients receiving IAD2 and having a testosterone recovery of longer than 4 months had an average off phase duration of 25 months vs. 10 months if testosterone recovery was shorter than 4 months. This is shown in Figure 6.
Our IAD2 study concluded that hormone-naïve patients who achieve and maintain a UD-PSA for at least one year during ADT may initiate IAD and anticipate a prolonged off-phase duration. Patients with PSAR and/or who require >= 4 months to reach a testosterone level >=150 ng/dl after ADT is stopped may not require a second cycle of IAD for years. Those with low volume disease requiring ADT in the future appear to have androgen-dependent PC (ADPC) and respond well to subsequent IAD cycles.
These are significant and very hopeful results for PC patients. However, not every patient is a candidate for IAD or can look forward to a long off-therapy duration. In our IAD2 study, 216 patients attained a UD-PSA, but only 52 have been in the off-phase of IAD for >= one year (or have restarted subsequent IAD cycles and are assessable for response). The selection process is complex and demands an understanding of the following:
- PC is an endocrine malignancy at diagnosis.
- PC treatment without evaluation of the endocrine axis is inappropriate.
- There are clues in the laboratory that optimize PC treatment.
- The response to ADT declares the extent (stage) and the composition of the PC (androgen-dependent vs. androgen-independent
Our approach with IAD has been to use the tumor cell population’s sensitivity to ADT to effectively select patients with ADPC, and to optimize apoptosis by prolonged exposure to ADT. The balance of this article details how understanding the endocrinology of prostate cancer and using the response to ADT leads to an optimum approach.
Understanding the Endocrinology of Prostate Cancer
Prostate cancer is the most endocrine-responsive malignancy and is incredibly sensitive to hormonal manipulations. Decades of clinical studies in men with advanced PC led to the award of the Nobel Prize in Medicine in 1966 to Charles Huggins, MD from the University of Chicago. He used testosterone-ablating therapies such as orchiectomy, DES, adrenalectomy and also hypophysectomy (pituitary removal) to successfully treat advanced PC. Huggins pioneered in demonstrating the dependency of PC growth on testosterone.17 In light of this unique biologic requirement, it is imperative that physicians and patients understand the endocrine aspects of PC since this will allow us to improve the quantity and quality of the lives of men diagnosed with PC.
All of the preceding foundational research led to the emergence of landmark developments in PC that began appearing in the 1980s. FDA approval of Lupron® and Flutamide®, plus the concepts of the intracrinology of PC were part of this renewed awareness about PC. This recognition of the importance of the hormonal axis in patients with PC also tied in with the discovery of PSA – the most sensitive biomarker available for a common malignancy. The pioneering efforts of Schally, Wang, Labrie and others accounts for the refocusing of attention on the endo- and intra-crinology of PC.18-21 Since it was Huggins who pointed out that men failing primary endocrine manipulation with orchiectomy or DES could obtain an additional response with adrenalectomy, he should be given credit for pointing out the importance of the adrenal axis in PC growth.
“Endocrine therapy” in the treatment of PC is essentially androgen deprivation therapy or ADT. ADT is what we are doing with most hormonal manipulations—we are depriving the tumor cell of a necessary growth substance—androgen. Traditionally, endocrine therapy has been used most commonly in the treatment of advanced or systemic PC. The controversy as to when to start ADT in systemic PC appears to have been laid to rest with the work of Messing et al.22 ADT finds utility in earlier stages of disease such as high Gleason score lesions (8-10) or high locally advanced clinical stages (T3-4) as seen with the work of Bolla et al.23
Today, ADT is routinely used in preparation for various forms of radiation therapy (RT) such as seed implant (SI), high dose rate (HDR), external beam RT with 3D Conformal (3DCRT), Proton Beam or Intensity Modulated RT (IMRT), or combinations of these. We are also using ADT in preparation for cryosurgery. RT and cryosurgery are tumor volume-dependent modalities and the use of ADT enhances their ability to eradicate PC. Most approaches using ADT in these settings employ ADT prior to, during and/or after RT or cryosurgery. Studies are needed to optimize the scheduling of ADT in these settings. ADT used in this manner is for local, regional and high-risk probability systemic disease. What is not clear is the full impact of ADT as the sole therapy in the setting of PC treatment of clinically localized PC. This is the essence of this article.
Primary and Backup Systems in the Endocrinology of PC
Figure 7 portrays at least two of the pathways that try to maintain a testosterone balance within man. The primary pathway is via production of luteinizing hormone (LH) from the pituitary. LH stimulates the testicles to manufacture testosterone (T). T is carried into the prostate cell and interacts with the androgen receptor (AR) within the nucleus of the cell. T is also converted to dihydrotestosterone (DHT), a metabolite that is five times as potent as T in its effects on prostate cell growth. Figure 7 also shows the additional pathway to the prostate cell via the adrenal androgen precursors DHEA-S and androstenedione. These are also converted within the prostate cell to T and thence to DHT. This is part of the intracrinology of the prostate cell.24
What role does DHT play in prostate cancer growth? Most clinical studies in PC have ignored the role of the pathway from T to DHT and the enzymes (5 alpha reductase Type II, and perhaps Type I). We hope our research on IAD-3 will refocus an interest in the major contribution of DHT and its inhibition as it relates to PC treatment.25
The principles of BALANCE and COMMUNICATION are inherent in the endocrine pathways of PC. The principle of balance or homeostasis is manifested in the pituitary-testicular axis and its main backup system, the pituitary-adrenal axis. The preponderant strengths of the primary axis and the backup axis may vary among individual patients. (This has relevance to the success or failure of ADT; it will be discussed later in this article.) These pathways, and others, exist to maintain the organism (you) in a state of balance and to provide your cellular environment with a key substance: androgen. When we disrupt this balance, the body tries to compensate. When T is diminished or absent, feedback loops to the hypothalamus and/or pituitary try to achieve homeostasis by stimulating more LH to “turn on” the testicles. This attempt to restore androgen homeostasis occurs in men who have undergone an orchiectomy. These men have very high LH levels e.g. 20s, 30s and higher (the LH normal range is 1.4-7.7). This stimulation of the hypothalamic-pituitary tract appears to effect a spillover into the production of adrenocorticotrophic hormone or ACTH. This pituitary hormone in turn stimulates the production of the adrenal androgen precursor DHEA which is metabolized to androstenedione. Within the prostate cell (malignant or benign), DHEA and androstenedione are converted to testosterone and from there to DHT.
In a study of 37 men undergoing orchiectomy, Sciarra et al showed that almost 40% of the patients had a reflex increase in androstenedione that led to significant testosterone levels (see Figure 8).26 This can easily account for clinical failure occurring in some men undergoing orchiectomy, and it demonstrates the crucial need to obtain baseline and follow-up testosterone levels in men undergoing hormonal manipulation of any kind. In the setting of having performed an orchiectomy, knowing baseline DHEA-S, androstenedione and T levels would be essential to intelligently manage such patients.
Diagnostics Products Corporation (310- 645-8200) in Los Angeles manufactures the Immulite 1 that has allowed me to properly evaluate the endocrine status of patients via measurements of testosterone, sex hormone binding globulin (SHBG), DHEA-S, LH, as well as PSA (using a hypersensitive PSA assay down to <0.003) and PAP. The tests shown in Table 1 are part of my routine evaluation of a man on ADT. Other endocrinologic measurements such as LH and prolactin are used in special circumstances as part of differential testing. Prolactin will be discussed in a later issue of Insights.
Critical Endocrine Assessments
During ADT, the first significant crossroad that must be crossed is whether or not a castrate testosterone level has been reached. We determine this as part of the routine evaluation of a man on ADT. We check the T level monthly until a castrate level (<20 ng/dl) has been reached. Most commonly this occurs after 2-3 months of ADT.
What if a castrate level of T is not obtained? If the testosterone is >20 and the PSA is rising or not falling to desirable levels, we check to see if the LHRH agonist (Lupron® or Zoladex) is working. To do this, we check LH to see if it is suppressed to <1. If it is, the LHRH agonist is effecting its desired goal.
An LH level <= 1, however, indicates an inadequate suppression of LH. This could be remedied by increasing the dose of the LHRH agonist (Lupron® or Zoladex), by decreasing the dosing interval between LHRH injections, or by switching the LHRH agonists, i.e. substituting Zoladex for Lupron® or vice versa. In addition, we have seen the four-month depot injections wearing off before four months. Therefore, going back to monthly injections may be tried. It is also of value to point out that three-month or four-month intervals for dosing with an LHRH agonist are actually 28 days x 3 (84 days) or 28 x 4 (112 days) and not three or four calendar months from the previous injection.
If the T is >20 and the LH is <1, we check to see if the adrenal androgen (AA) levels are normal or elevated. If so, then these precursors are being transformed within the prostate cell to T to account for the non-castrate T levels found. If T is < 20, we check to see if the AA levels are diminished. If so, then an androgen receptor mutation (ARM) may have developed. The androgen receptor, if mutated, may regard an antiandrogen such as Flutamide®, Casodex® or Nilutamide as an androgen. If this is operative, positive feedback at the hypothalamic-pituitary level results in a drop in AA. Lastly, if the testosterone is <20, and the AA are not decreased, AIPC is likely.
Table 2 is an excellent roadmap for PC treatment. It shows the essence of what I have learned in the last 16 years treating thousands of men with PC. Once castrate levels (< 20 ng/dl) of testosterone are reached, there is no need to keep rechecking the testosterone level. If the patient is receiving finasteride (Proscar®) as part of ADT, the baseline DHT level should drop to levels < 30. Once that is documented, there is no need to keep rechecking the DHT level. However, if there is evidence of a deteriorating clinical situation, a repeat check of critical baseline levels may clarify issues.
Tumor Cell Population
The next step is to assess the tumor cell population and test the tumor cell population by evaluating its sensitivity to ADT. Excellent results using ADT will not be obtained if the tumor population is not primarily androgen-dependent. ADT causes apoptosis (programmed cell death) in androgendependent PC (ADPC). With ADT, such populations of PC cells should demonstrate their sensitivity and their homogeneity by dropping the PSA to very low levels (<0.05 ng/ml) such as those obtained using a hypersensitive assay (DPC or Tosoh). In addition, these levels should be able to be maintained. The response to treatment, therefore, gives clues to the nature of the tumor cell population, just as the response to an antibiotic gives clues to the nature of an infection. In Figure 9, a relative homogeneous tumor population is shown. ADT results in rapid cell kill which is manifested by a plummeting of the PSA to undetectable levels. Our arbitrary definition of undetectable at <0.05 ng/ml appears to have been sufficiently sensitive to allow us to discriminate between androgen-dependent and independent cell populations. This hypersensitive assay is available as either the Tosoh assay or as the DPC 3rd Generation Immulite assay.
On the other hand, with a heterogeneous population of PC cells, ADT results in a drop in PSA, a flattening, and then a rise in PSA. This biomarker profile represents a partial cell killing effect of ADT on a mixed population of tumor cells; some are androgen dependent while others are androgen independent.
We are seeing less and less androgen-independent prostate cancer (AIPC) as we make the diagnosis of PC earlier. In our IAD studies, we have rarely encountered AIPC (one out of 120 patients). I do not believe we induce AIPC with ADT if it is not already present. We can, however, induce an androgen receptor mutation (ARM) as discussed below.
I do not believe that ADPC progresses to AIPC unless there is a significant component of AIPC already present. AIPC appears to be highly correlated with tumor volume and with extra-prostatic disease, but not always. Therefore, it never hurts to first test the tumor cell population by using ADT to see if an UD-PSA can be achieved.
Androgen Receptor Mutation (ARM)
Patients who have an initial response to ADT may, however, go on to show a PSA rise that relates to development of an ARM. This is a result of mutation of the androgen receptor (AR).
The strategy shown in Figure 10 is a way to approach a rising PSA on ADT to exclude an ARM. Since we are treating the patient by stopping the anti-androgen, it is important to realize that the anti-androgens have different pharmacologic profiles with different half-lives. Flutamide® has a half-life of < 8 hours vs. Casodex® with a half-life of six days. A steady-state or equilibrium for Flutamide® is reached after four half-lives or 32 hours vs. six half-lives or 37 days for Casodex®. Anti-androgen withdrawal response (AAWR) for Flutamide® may be evaluated after one week off Flutamide® by rechecking the PSA. In the setting of Casodex® withdrawal, however, the PSA should not be rechecked for six weeks due to the much longer half-life of Casodex® .
These same concerns regarding half-lives or steady-state equilibrium must also be applied insofar as the issue of starting an anti-androgen for the purposes of preventing flare from the LHRH agonist. That is why we routinely use Flutamide® when starting ADT and pre-treat the patient for one week prior to starting the LHRH agonist (Lupron® or Zoladex). Later, if the patient or physician wishes, we can switch from Flutamide® to Casodex®. We also employ Proscar® at 5 mg twice a day along with Flutamide® as part of this induction regimen to prevent flare and cause greater cell kill.
Heterogeneity of the tumor cell population relates to the differentiation of the cells.
Figure 11 depicts the tumor cell populations and the markers more likely to be seen with poorly or de-differentiated tumor cells. This is in keeping with the finding that high Gleason score lesions (GS 8-10) often do not secrete much PSA because there is a decrease in PSA leak as the GS increases. A GS (5,5) lesion secretes four times less PSA into the blood than a GS (3,3) lesion.
Tumor cell populations are often heterogeneous, especially in disease that has been diagnosed late and allowed to mutate. To know what we are dealing with, it is important to assess these other markers of tumor de-differentiation. The PAP is a forgotten tumor marker of significance.
PAP is one of the biomarkers that many physicians have discarded. PAP expression is associated with biochemical relapse after radical prostatectomy. A PAP of 3.0 or higher at diagnosis is associated with a four times greater likelihood of failure after an RP.27,28 Other investigators use PAP as a high risk factor for ECE (extra-capsular extension) and risk for systemic disease. Tarle et al believe that the ratio of PSA/PAP tells a lot about the tumor cell population and its lack of response to ADT.29
Since PAP hydrolyzes phosphate esters that occur in bone, and since PAP elevation is associated with bone metastases, it may be that tumor cells producing PAP are using this enzyme to digest bone and to secure a foothold in the skeleton.
PAP, and other markers, including PSA, are not just laboratory tests. They represent active biologic substances produced from cell populations whose function is to maintain tumor cell growth and spread.
Assessing the tumor cell population by identifying markers other than PSA therefore identifies other populations that need to be evaluated to define the degree of response to any kind of treatment. In other words, if we identify elevations in PSA, PAP and CEA prior to treatment, then we need to assess these biomarkers as part of our response criteria. Are all three falling, or only one or two?
Until proven otherwise, it seems reasonable to assume that normalizing or eliminating all aspects of tumor manifestation can only result in better survival. The response to treatment of more than one marker is called “concordance”. Focusing on concordance reflects the potential heterogeneity of tumor cell growth. Our goals in PC management are durable remissions achieved by obtaining concordant drops in all markers known to be elevated at baseline (see The Importance of Concordance in PC Management).
The importance of concordance was demonstrated by a study by Steineck et al.30 This study showed a doubling of mean survival when concordance in marker response to both PSA and PAP (> 50% decline from baseline) was achieved. This concept of concordance is found throughout medicine. It relates to a consolidation of findings, be they tumor marker responses or diagnostic characteristics. When we confirm our findings we get a fuller measure of what the situation really is. If it looks like a horse, smells like a horse, and sounds like a horse, it probably is a horse.
The degree of response to a challenge with ADT provides clues to the presence of AIPC. Other investigators have reported on the degree of response to ADT as it relates to prognosis31,32 and also the response to other modalities of treatment such as RT.33
Other markers are not as easily understood. NSE is often seen elevated especially when there is locally invasive disease. NSE elevations in conjunction with CEA are found in patients with an aggressive course of disease. CEA, a fetal antigen, is also found associated with AIPC. Elevations in NSE and CEA or NSE and CGA are associated with more virulent manifestations of PC characterized by low PSA production, lytic bone lesions, and the frequent occurrence of PC spread to the liver and lungs. Isolated progressive elevations of CGA are also associated with low PSA producing aggressive tumors. Elevated, but not progressively increasing levels of CGA, are frequently seen in patients with excessive bone resorption as measured by the Pyrilinks-D test (see Insights, Jan. 1999 issue, vol. 2, no. 1, p. 5).
Figure 12 depicts a reasonable approach to assessing ADT and distinguishing ADPC (androgen-dependent PC) from AIPC (androgen-independent PC).
We are using the products of cell proliferation such as hormone levels (T) (dehydropiandrosterone sulfate (DHEA-S), androstenedione, and luteinizing hormones) to assess the dynamics of the endocrine system. We are using ADT, a treatment, as a functional way to assess the tumor cell population. We are using biomarkers from the tumor cell population to more comprehensively evaluate our response to therapy and to give us insights into tumor cell mechanisms that we might be able to exploit with innovative therapies. This laboratory-to-the-bedside approach has been utilized in my care of PC patients for decades with excellent results. This is summarized in Table 3.
All of this leads up to our work with IAD. We have used the criteria detailed above to choose patients with androgen-dependent PC as candidates for IAD. Moreover, we have intentionally chosen patients who have the highest probability of a homogeneous population of PC cells that are androgen-dependent by virtue of their exquisite response to ADT by achieving and maintaining an undetectable PSA at <0.05 ng/ml for at least 12 months. For those patients, IAD can be initiated with a high probability of prolonged off-treatment duration.
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3. Zelefsky MJ, Lyass O, Fuks Z et al. Predictors for improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy. J Clin Oncol 16:3380- 3385, 1998.
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