CAUTION: Some readers will find this protocol technically challenging. It is written for both the patient and the attending oncologist.

Introduction: Rationale to Diagnose PC Earlier

Not all PC is systemic, anymore than all breast cancer or other tumor types are systemic. If they were, we would never cure any man or woman of PC, breast cancer, or any other malignancy. Physicians claiming that every man with PC needs ADT as primary and sole therapy are blindly ignoring the growing numbers of men who present 8 to 15 years after RP or RT with a flat PSA graph. Emphasis on the use of routine PSA monitoring starting annually at the age of 40 with PSA velocity and doubling time determinations as a standard part of PSA reporting will increase the numbers of men diagnosed earlier, with a lower tumor burden, and cured with local modalities of treatment (Labrie et al., J. Clin. Endocrinol. Metab., 1995; Labrie et al., Urology, 1996). PSA testing with these enhancements should start earlier, at age 35, in men with a familial history of PC.

In addition, the use of routine free/total PSA levels should increase our ability to diagnose PC earlier since fractionation of PSA allows us to monitor the malignant-associated portion of PSA called complexed PSA. Evaluation of risk of PC using neural net technology as per the ProstaSure blood test also will enable an earlier diagnosis of PC (Babaian et al., Urology, 1998). As our standard and hopefully routine approach to monitoring PSA and other biological expressions of tumor cell activity increases, the percentage of men cured with PC should increase as well.

This is borne out in a recent report in which PC was detected in 22% (73/332) of men 50 years or older whose PSA reading was between 2.6 and 4. All cancers detected in this setting were clinically localized. This study indicates that PSA readings greater than 2.6 and less than 4.0 may represent a 22% risk of PC (Catalona et al., JAMA, 1997). The use of a free PSA test would help determine which of these men whose PSA readings were greater than 2.6 but less than 4.0 have a high probability of PC versus a low probability of PC. Such a test could reduce the number of unnecessary biopsies in the low-risk subset and focus a need for more comprehensive biopsing in the high-risk subset.

Another study involved 760 men with an initial PSA of 4.0 ng/ml or less, plus a normal or suspicious DRE and a benign prostate biopsy. These men were monitored with PSA testing every 4 months. Of 559 men with an initial PSA of 2.0 ng/ml or less, only three (0.5%) had a persistently abnormal PSA for 3 years; in this group, one cancer was detected (0.2%). Of 201 men with a PSA of 2.1 to 4.0, 37 had PSA levels that became and remained abnormal (defined as > 4.0). Of this group, 23 biopsies were performed, and 8 (35%) revealed PC. The study indicated that in men with an initial PSA of 2.1 to 4, the cancer detection rate was 4.5%. This was approximately 15-fold greater (p < 0.00001) than the cancer detection rate in the men with an initial PSA of 2.0 or less (Harris et al., J. Urol., 1997). Patients presenting with their first PSA at 2.1 or greater should therefore be the focus of more intense studies. This could include free/total PSA, PSA doubling time determination, and ProstaSure testing.

New biopsy techniques-such as 5-region biopsy of the prostate gland-have been shown to increase the diagnostic yield of PC by 35% (Eskew et al., 1997).

Despite these inroads, many men today are still being diagnosed with PC that is advanced, i.e., not organ-confined. What difference does this make?

The difference in treating early PC versus more advanced PC relates to the issue of cure as opposed to control. Early PC has the potential for cure via a local therapy combined with the use of ADT in situations where the tumor volume compromises the curative ability of local therapy such as RT (including seed implantation) or cryosurgery. This has been discussed in the section on Early PC.

The Biology of AIPC

When PC spreads to the capsular interface and leaves the prostate gland, it reflects a change in the biologic nature of the cancer. The PC now is expressing its more aggressive nature in its ability to spread and metastasize. Why?

The aggressiveness of these tumors appears to directly correlate with the proportion of higher Gleason grade cells. This frequently involves multiple clones of PC cells-some androgen-sensitive, but others androgen-insensitive, and/or possibly androgen-altered (Aihara et al., Urology, 1994; Brawn, Cancer, 1983). This heterogeneity appears related to tumor size or burden. As the tumor burden increases by cell division, the chances of gene mutation increase, which in turn may lead to androgen or drug-resistant tumors. Such mutations likely result from the activation of oncogenes or the inhibition of tumor suppressor genes.

In laboratory experiments, for example, expression of an activated H-ras oncogene in androgen- sensitive LNCaP PC cells allows these cells to grow independent of the presence of androgens. H-ras oncogene has also been shown to stimulate MDR-1, the multidrug resistance gene that is heavily implicated in chemotherapy drug resistance (Lehr et al., Cell. Mol. Biol., 1998; Yamazaki, Proc. Annu. Meet. Am. Assoc. Cancer. Res., 1993). Therefore, androgen independence and MDR-1 expression may go hand-in-hand. The sequence of events may be as follows:

It is now clear that more than one genetic aberration can lead to androgen independence. Mechanisms that have been identified include expression of the proto-oncogene bcl-2 and mutation of the genetic biomarker p53, a tumor suppressor gene (McDonnell et al., Cancer Res., 1992; Bookstein, Cancer Res., 1993).

In essence, androgen independence is more likely to be present at the time patients are diagnosed with extensive disease, such as in the lymph nodes or bone, and possibly begins with the manifestation of capsular penetration. Since androgen deprivation therapy (ADT) primarily kills androgen-dependent and to a lesser extent androgen-sensitive cells, androgen-independent tumor cell populations will continue to grow and eventually emerge as the primary disease entity. It is therefore more likely that patients do not develop AIPC as a result of treatments such as ADT, but more likely that they already had AIPC at the time ADT was begun.

A mutation of the androgen receptor gene was hypothesized as one possible survival mechanism for AIPC during ADT. In an attempt to confirm the hypothesis that AIPC cell growth is mediated by gene mutation, Taplin et al. (N. Engl. J. Med., 1995) examined the androgen receptor genes in 10 patients with AIPC. The authors noted high levels of androgen receptor gene expression in all of the patient samples, supporting the hypothesis that tumor progression requires a functional androgen receptor gene. In five patients, point mutations in the androgen receptor gene were found, and all were located on the androgen-binding domain. When functional studies were done, progesterone and estrogen were capable of activating mutant androgen receptors in two patients. The authors concluded ADT selects AIPC cells whose mutated androgen receptors stimulate growth without the presence of usual androgen levels.

One of the point mutations found by Taplin et al. had been previously reported by Veldscholte et al. (Biochem. Biophys. Res. Commun., 1990) in LNCaP, a cell line used as an experimental model of androgen-sensitive human PC. This androgen receptor gene mutation resulted in an androgen receptor that could be activated by estrogen, progesterone, and the anti-androgen flutamide.

The critical issue for the patient with PC with evidence of disease progression is, Do I have AIPC or not? How can we logically explore this issue to more correctly guide such patients?

Defining AIPC and Excluding Other Causes of PSA Progression

The definition of AIPC is disease progression as evidenced by a progressively rising PSA (3 consecutive rises of at least 10% each, or 3 rises that involve an increase of 50% over the nadir PSA) or an increase in tumor mass on bone scan, x-ray, CT scan, or MRI despite a castrate level of testosterone (T<20 ng/dL). There are further issues that must be addressed, however, before such a patient is categorized as having AIPC. Understanding the endocrinology of PC is essential to accurately define the patient's status.

For example, if a patient's PSA stops falling and begins to rise on ADT2, the T level is castrate, and the adrenal androgen precursors are not low, then AIPC is presumed present until proven otherwise. If in the same setting above, the levels of the adrenal androgen precursors are suppressed, an androgen receptor mutation (ARM) should be excluded. The latter is confirmed by demonstrating a response to anti-androgen withdrawal with falling PSA levels.

If the testosterone is > 20 ng/dL, the patient's serum LH level should be checked. If LH is not completely suppressed (usually < 1.0), we believe it is reasonable to increase the dosage of the LHRH-A. If the LH level is suppressed, we measure the levels of adrenal androgen precursors dehydroepiandrosterone sulfate (DHEA-S) and androstenedione. These hormones can be converted to T and may account for T levels of > 20 ng/dL. If such levels were found, we would prescribe drugs to suppress adrenal androgen precursor production such as Nizoral (high-dose ketoconazole, or HDK) and hydrocortisone. The analysis involved in a patient on ADT with a rising PSA is shown below.

HDK = high-dose ketoconazole, HC = hydrocortisone,
LH = luteinizing hormone, ARM = androgen receptor mutation.

There are studies to support the concern that adrenal androgen precursors can increase in the setting of PC treatment and that this increase leads to higher T levels, which in turn effects a poor clinical outcome, if unrecognized. The elevation in androstenedione and T shown below in 10 of 27 men undergoing orchiectomy for PC supports our concerns (Sciarra et al., Clin. Endocrinol., 1993).

The Response to ADT as a Guide to the Presence of AIPC

The evaluation of the response of available bio-markers to ADT provides clues to the presence or absence of AIPC. In essence, it is an in vivo test of the tumor cell population. If the tumor cell population is predominantly that of ADPC (androgen-dependent PC), there is usually a brisk drop in PSA to very low levels that are maintained during the course of ADT. This assumes that an ARM has not developed over the course of time. The newly diagnosed patient with dramatic sensitivity to ADT, most likely has ADPC. We use an ultra-sensitive assay (3rd Generation Immulite from DPC International, Los Angeles) and define an undetectable PSA (UDPSA) as <0.05. If the patient achieves and maintains this level, it has been our experience that the development of AIPC is rare. On the other hand, if a UDPSA is not achieved or is achieved after a prolonged period of time, we are concerned about the presence of AIPC. In our experience, the biology of the tumor is manifested in its response to ADT. It therefore becomes significant to use a sensitive assay to monitor the response to ADT to confirm suspicions to the presence of AIPC.

Androgen Receptor Mutation (ARM) and
Anti-androgen Withdrawal (AAW)

We now know that an ARM can result in the antiandrogen paradoxically stimulating tumor growth. Antiandrogen withdrawal in such patients has been shown to result in tumor regression in approximately 20% of patients. This phenomenon is referred to as an anti-androgen withdrawal response (AAWR).

If androgen blockade included an anti-androgen- e.g. Eulexin, Casodex, or Nilandron-these agents must be stopped in order to monitor for a possible AAWR. Failure to recognize an AAWR is one of the problems encountered when we attempt to interpret results of studies of PC treatments published in the past. If a patient stopped anti-androgen therapy at the same time a different therapy was started, an AAWR, if it occurred, could affect the assessment of response to the second therapy. PC treatment studies should require withdrawal of anti-androgens for at least 2 to 6 weeks (the longer time in patients being withdrawn from Casodex) to assess whether or not the PSA decline is due to an AAWR.

Another reason for supporting measurement of adrenal androgen precursor levels was reported in a 1994 abstract. In that study, Herrada et al. (Proc. Am. Soc. Clin. Oncol., 1994) measured serum levels of dehydroepiandrosterone (DHEA) in 10 patients with PSA progression on ADT. After antiandrogen therapy was stopped, patients were observed for an AAWR. None of the patients with DHEA levels > 75 ng/ml had an AAWR, while 3 of 5 patients (60%) with DHEA levels < 75 ng/ml achieved an AAWR. Therefore, DHEA levels at the time of PSA progression may be used to identify patients who may or may not benefit from anti-androgen withdrawal.

We have used the DHEA-S, a more stable blood level, to assess the presence of an AAWR. If the androgen receptor is regarding the anti-androgen as a growth stimulator (agonist), then the brain (hypothalamus) will sense adequate androgen levels and down-regulate the stimulatory hormones that are involved with T production. Such hormones would include LH and ACTH. LH stimulates the Leydig cells in the testicles to make T. This mechanism is already blocked by the LHRH-A. ACTH stimulates the adrenal cortex to make adrenal androgen precursors such as DHEA-S and androstenedione. Both of these are converted within prostate cells, be they benign or malignant, to T and then to DHT. If an ARM is operative, ACTH will be turned down and so will the levels of DHEA-S and androstenedione. Therefore, when we find suppressed levels of these two adrenal androgen precursors, we are suspicious of an ARM and proceed with anti-androgen withdrawal.

A PSA decline with flutamide withdrawal was first reported in 1993 by Scher and Kelly (J. Clin. Oncol., 1993). Defining an AAWR by a greater than 50% decline from baseline PSA, the authors reported an AAWR in 10 of 36 (28%) patients after 3 months of Eulexin withdrawal. Twenty-five of these patients received ADT as initial treatment, of whom 10 (40%) had an AAWR. In this study, none of the 11 patients who received Eulexin after PSA relapse on "monotherapy" (orchiectomy or LHRH-A treatment alone) showed an AAWR.

Figg et al. (Am. J. Med., 1995) and Small et al. (Cancer, 1995) subsequently published two other studies of Eulexin withdrawal responses, the latter of which evaluated a large cohort of advanced disease patients. In contrast to Scher et al., Small et al. showed similar rates of response regardless of when Eulexin was begun. Eight (14%) of 57 patients who received concomitant Eulexin with ADT had an AAWR, while 4 (16%) of 25 patients who received Eulexin after PSA progression on monotherapy had an AAWR. Patients who responded were treated with Eulexin for a longer time than nonresponding patients (median duration 21 months versus 12 months, respectively, p = 0.2).

Withdrawal of Casodex has also been reported to result in an AAWR (Small and Carroll, Urology, 1994; Small et al., Proc. Am. Soc. Clin. Oncol., 1996). The time until PSA begins to decline after anti- androgen withdrawal is shorter with Eulexin than with Casodex, reflecting the longer half-life of elimination from the body with Casodex (7 days) versus Eulexin (5.2 hours) (Small et al., Proc. Am. Soc. Clin. Oncol., 1996).

Withdrawal responses do not appear to be limited to nonsteroidal anti-androgens. A withdrawal response was reported in a patient receiving the progestin, megestrol acetate (Megace), which also binds to androgen receptors (Dawson and McLeod, J. Urol., 1995) and in patients withdrawn from Diethylstilbestrol (Bissach and Kaczmaiek, J. Urol., 1995).

High-dose Casodex after Eulexin Withdrawal

As described earlier, Veldscholte et al. (Biochem. Biophys. Res. Commun., 1990) described an androgen receptor gene mutation in a LNCaP human PC cell line that could be activated by estrogen, progesterone, and Eulexin. This same point mutation and growth stimulating effect by Eulexin was noted by other investigators (Culig et al., Mol. Endocrinol., 1993; Taplin, et al., N. Engl. J. Med., 1995; Fenton et al., Clin. Cancer Res., 1997). However, some mutant androgen receptors were found to be paradoxically antagonized by the structurally different anti-androgen, Casodex. Similarly, LNCaP cell growth was inhibited by Casodex (Olea et al., Endocrinology, 1990). Based upon these observations, Joyce et al. (J. Urol., 1998) conducted a pilot study of high-dose Casodex (150 mg/day) in 30 patients who failed ADT that included Eulexin. Fourteen (48%) received Eulexin as part of the primary ADT, whereas the other 16 received Eulexin after PSA progression on monotherapy. Although 70% of patients had received at least one nonhormonal therapy prior to study entry, all patients had a rising PSA after Eulexin withdrawal and were progressing on their last treatment. Using a response criteria defined as a > 50% decline from baseline PSA maintained at least 2 months, 7 (23%) patients responded to high-dose Casodex. Six (43%) of the 14 patients receiving Eulexin as part of primary ADT were responders, whereas only 1 (6%) of 16 patients receiving Eulexin at PSA progression on monotherapy were responders (p = 0.03). There was no correlation between patients having a response to high-dose Casodex and those having had a prior anti-androgen response. Therefore, in this study, it appears that patients progressing on ADT that includes Eulexin as part of combination hormone blockade are candidates to receive high-dose Casodex at 150 mg a day, regardless of whether or not they had an AAWR upon discontinuing Eulexin. Treatment was generally well tolerated. The primary side effects reported included exacerbation of hot flushes (40%), nausea (10%), fatigue (10%) and gynecomastia (5%). There were no liver function abnormalities seen. The authors concluded that Casodex at this dose is modestly effective for patients with AIPC, particularly for those treated with long-term Eulexin.

In the setting of PSA progression, the above evaluations should be undertaken to properly diagnose the patient's situation. If such an analysis is not done, the patient may be inappropriately labeled as having "hormone refractory disease" when in fact he may have an ARM, or perhaps excessive production of adrenal androgen precursors, or perhaps insufficient suppression of LH. Once this analysis is complete and the above causes of PSA progression have been excluded, the physician and patient can focus on therapies used in the treatment of AIPC.

I have divided these therapies into two major categories that reflect ease of treatment administration. This is a separation based on quality of life issues and not on the magnitude of response to treatment. As we improve in our treatments of AIPC, this separation may disappear. The treatment strategy is shown below.

Table 2

The Treatment of AIPC

Nizoral or High-dose Ketoconazole (HDK) with Hydrocortisone (HC)

Nizoral plus hydrocortisone (HC) is an excellent treatment approach for men with AIPC. In fact, Nizoral has so many outstanding effects against both ADPC and AIPC that it is surprising not to see this agent as a mainstay in the initial treatment of PC. Nizoral rapidly lowers serum testosterone to castrate levels by 48 hours by mechanisms that are different than LHRH agonists and antiandrogens (see figure below after Trachtenberg et al.).

After Trachtenberg, et al. (J. Urol., 1983)

Nizoral blocks the production of testosterone produced by the testicles and blocks the production of androgen precursors (DHEA, DHEA-S, and androstenedione) that are metabolized to T and DHT within the prostate cell. Since Nizoral also may reduce cortisol production by approximately 25%, a small percentage of patients may develop symptoms consistent with adrenal mineralocorticoid deficiency. Patients therefore are usually given HC (hydrocortisone) along with Nizoral to prevent this potential side effect and also because of the known antitumor effect of HC against AIPC. The standard dose of HC advised is 20 mg with breakfast and 20 mg with dinner. Patients may have their dose of HC titrated down using the results of ACTH and cortisol levels.

Other Anticancer Effects of Nizoral

Nizoral possesses other anti-cancer properties independent of its testosterone-lowering effects. In laboratory studies, Nizoral showed synergistic (more than additive) cell-killing effects when used with the chemotherapy drugs vinblastine (Velban) and etoposide (VePesid) in cancer cell cultures (Eichenberger et al., Clin. Invest. Med., 1989).

Nizoral acts on cytochrome P-450-dependent 14-demethylation, and decreases conversion of lanosterol to cholesterol, and blocks 17,20-desmolase (or lyase), resulting in a decrease in serum T, androstenedione, and dehydroepiandrosterone (DHEA). Twenty-four-hour urinary free cortisol is reduced 25% but still remains within the range of normal, as mentioned above. Recent studies indicate that Nizoral also blocks 17a-hydroxylase.

Velban is an active agent in AIPC and is used with Nizoral, doxorubicin (Adriamycin), and estramustine (Emcyt) in the "Logothetis protocol." Nizoral also has a direct cytotoxic effect on the PC cell (see figure below). In two human cell lines of AIPC, PC-3, and DU-145, Nizoral had direct cell-killing effects at serum values that were attainable with oral doses used clinically, as shown on the following page (1.1 to 10.0 mcg/ml) (Eichenberger et al., J. Urol., 1989).

Nizoral has additional anticancer effects. It has been proven to block the multidrug resistance (MDR) gene that is largely responsible for cancer cells developing resistance to many types of chemotherapy drugs. In a 1994 paper by Siegsmund et al., Nizoral added to in vitro cancer cell cultures was effective in overcoming MDR to Velban and Adriamycin (Siegsmund et al., J. Urol., 1987).

Nizoral and HC in AIPC

Published clinical trials of Nizoral involved studies in the pre-PSA era. In the current era, PSA is used as a surrogate biomarker of disease response. In the pre-PSA era, Pont et al. (J. Urol., 1987) reported an 88% decrease or disappearance in pain in 17 previously untreated men with metastatic PC. Two of these patients remained in complete remission with no evidence of disease after 30 months of treatment.

Muscato et al. (Proc. Am. Soc. Clin. Oncol., 1994) reported results with Nizoral + HC in 21 patients considered hormone-refractory. Seven (33%) of 21 patients had a greater than 90% fall in PSA, with six of these seven maintaining remissions lasting longer than 12 months (range 14 to 35+ months). Muscato et al. emphasized the importance of an acid environment for proper absorption, the avoidance of taking Nizoral with food, as well as the importance of making sure patients are not taking H2-blockers, Carafate, and/or antacids. Muscato et al. pointed out that H2-blockers (Zantac, Tagamet, Axid, Pepcid) or proton pump inhibitors (such as Prilosec or Prevacid) can decrease the absorption of Nizoral by as much as 75%. Therefore, Nizoral plus HC may be one of the most active regimens for AIPC.

In a recent paper, Small et al. (J. Urol., 1997) reported the results of Nizoral plus HC therapy in men with progressive disease on ADT and after anti-androgen withdrawal. Of 48 evaluable patients, 30 (63%) had a PSA decrease of greater than 50% for at least 8 weeks, while 23 of these (48%) had a decrease in PSA of greater than 80% for at least 8 weeks. For all patients, the median PSA decrease was 79% (range 0 to 99%). The median duration of response was 3.5 months, with 23 of the 48patients having ongoing responses (range 3.3+ months to 12.8+ months). No difference was seen in response rates despite the presence or absence of an AAWR. The median survival of all patients had not been reached at 6+ months.

In another report, Small et al. (Cancer, 1997) treated 20 consecutive patients with simultaneous antiandrogen withdrawal and Nizoral + HC. The median PSA at entry was 13 ng/mL (range 1.9 to 1000 ng/mL). Eleven of 20 patients (55%) met their criteria for response, i.e., a greater than 50% decline from baseline PSA. The median duration of response was 8.5 months (95% confidence interval 7 to 17 months), and the median overall survival was 19 months. Due to its effects on the MDR gene, Nizoral has been studied in combination with chemotherapy.

HDK in Regimens Combined with Chemotherapy

It is not clear whether HDK should be used in combination with HC versus a chemotherapy combination-in light of its synergism with Adriamycin and Velban-along with its ability to prevent MDR (multidrug resistance). There are two regimens that use HDK in combination with chemotherapy. The first regimen was a combination of Adriamycin and Ketoconazole (Sella et al., J. Clin. Oncol., 1994).

The Sella regimen with its effectiveness was employed in a multidrug regimen that we have termed the Logothetis regimen (Ellerhorst et al., Clin. Cancer Res., 1997). Dr. Christopher Logothetis has combined two most active chemotherapy regimens into one protocol of alternating regimens. Our modifications of this regimen are italicized.

• Chemotherapy Cycle length = 56 days (8 weeks)
  Adriamycin 20 mg/m2 IV day 1, 15, 29
  Ketoconazole 400 mg orally 3 times a day for days 1-7, 15-21,
  29-35
  Vinblastine 4 mg/m2 IV day 8, 22, 36
  Estramustine 140 mg orally 3 times a day for days 8-14, 22-28,
  36-42
  Rest period from day 43 to 56, then restart next cycle

• Supportive Medications
  Hydrocortisone, 20 mg orally in A.M. and 10 mg in P.M. (take with food)
  Coumadin dosed to maintain an INR between 1.75 and 2.25
  Neupogen 300 mcg s.q. twice a week except during the rest period
  Epogen, 10,000 units s.q. 3 times a week as needed to avert anemia
  Kytril, 0.7 mg with each dose of Velban or Adriamycin
  Decadron, 10 mg with each dose of Adriamycin

• Laboratory Tests
  CBC blood test on the day of each injection and day #10 of the first cycle
  Chemistry panel once a month and day #14 of the first cycle
  PSA and PAP once a month
  Prothrombin time weekly

  Information that We Also Discuss with the Patient
  Nonspecific lassitude and tiredness may occur.Hair loss to some degree is common. Temporary mouth sores and/or diarrhea is unusual but can occur.

  Adriamycin and Velban can cause low blood counts, which can increase the risk for serious infection. It is critical that weekly CBC tests are obtained to guide chemotherapy and Neupogen dosing.

  Any fever greater than 100.5 should be called to your M.D. immediately, day or night.
  Velban can cause numbness and tingling in the hands and feet.

  Velban has caused temporary malfunction of the intestines, resulting in bloating (ileus). We recommend a small dose of milk of magnesia on the day of Velban therapy.

  Ketoconazole and Estramustine can cause nausea and upset stomach, but with use of antinausea drugs this should not occur.

  Estrogen in Estramustine can cause blood clots, thus the need for Coumadin.
  Adriamycin, if it is used for more than 1 year, can occasionally cause weakening of the heart muscle.

  Adriamycin and Velban, if they are improperly injected into the skin (outside of the vein), can cause severe skin reactions and ulcers.

  Ketoconazole can cause hepatitis, thus the need to do monthly chemistry.

  Hydrocortisone can cause adrenal atrophy, so when the protocol is stopped, the hydrocortisone must be tapered off over a 4 to 8 week period.

The results with the Logothetis regimen for AIPC indicate a median survival of 19 months. In responding patients, the median survival has not yet been reached.

Patient Guidelines for Nizoral and HC

We start Nizoral at a dose of 200 mg every 8 hours for 1 week, then increase the dose to 400 mg (2 tablets) every 8 hours thereafter. HC should be given at a dose of 20 mg with breakfast and 20 mg with dinner. If symptoms suggest HC excess (ankle swelling or diabetes in poor control), we decrease the dose to 20 mg with breakfast and 10 mg with dinner.

Stomach acid is needed to enhance Nizoral absorption. We advise patients to take Nizoral on an empty stomach since food reduces acid. As stated above, histamine-2 blockers (Zantac, Tagamet, Pepcid, and Axid) decrease Nizoral absorption by 75%. Prescription proton-pump inhibitors such as omeprazole (Prilosec) and lansoprazole (Prevacid) reduce stomach acid even more. Antacids and the prescription anti-ulcer agent sucralfate (Carafate) will also interfere with Nizoral absorption.

We recommend taking Nizoral with Coca-Cola, Pepsi, 1000 mg of chewable vitamin C, lemonade, or orange juice. In a recent study done in AIDS patients receiving acid-reducing drugs, the oral absorption (bioavailability) of Nizoral was increased by 50% by the concurrent intake of Coca-Cola or Pepsi (Chin et al., Antimicrob. Agents Chemother., 1995).

It is now possible to measure Nizoral levels in the serum using a new assay method. We recommend monitoring serum drug levels at the onset and periodically on Nizoral therapy. A blood level between 3 and 5 mcg/mL is considered therapeutic when drawn 4 hours after the usual dose of Nizoral. Serum Nizoral values can also be obtained 1 hour post Nizoral ingestion (peak level) and just before the next dose of Nizoral (trough level).

Other drugs that have the potential to interfere with Nizoral absorption by decreasing stomach acid through anticholinergic mechanisms are listed below. Drugs commonly used in PC patients appear in boldface type.

The main side effects of Nizoral are nausea and loss of appetite in approximately 10% of patients. Concurrent administration of HC may reduce the frequency of this side effect. A number of skin changes-including rash; dry, cracked lips; and an unusual "sticky skin" syndrome-have also been reported in approximately 5% of patients. This can usually respond to topical application of vitamin E. The peeling of the lips is very responsive to the use of Carmex topical ointment. Photophobia (sensitivity to light) is rarely seen in patients taking Nizoral for fungal infections, but may be more common with chronic use. Liver function tests (LFTs) include elevations in SGOT, SGPT, and/or alkaline phosphatase. These are generally mild and usually return to normal without intervention. Patients on Nizoral must have LFTs checked monthly. Although rare, a rise in serum bilirubin indicates that Nizoral must be discontinued. Intolerance of nausea, fatigue, or abnormal liver function tests is the most common reason patients stop Nizoral treatment.

Side-effects of Nizoral +HC

Potential Drug Interactions with Nizoral

Drugs that may need dose changes if Nizoral is taken concurrently

Warning: Nizoral should not be taken with alcohol. Concurrent use of Nizoral and alcohol-containing beverages may cause an "antabuse reaction" (skin flushing, rash, swollen legs, nausea, vomiting, and headache).

Corticosteroid Therapy in AIPC

Corticosteroids are a family of semisynthetic and synthetic compounds that mimic the anti-inflammatory effects of cortisol. Corticosteroids are produced naturally by the adrenal glands. The most commonly prescribed agents include cortisone acetate (Cortef), hydrocortisone (Hydrocortone), prednisone (Deltasone), and dexamethasone (Decadron or Hexadrol). It has been recognized for many years that corticosteroids have a definite palliative (symptom improving) and sometimes objectively beneficial effect on the clinical course of patients with AIPC.

Tannock et al. (J. Clin. Oncol., 1989) studied the clinical benefit of Deltasone given at a dose of 7.5 to 10 mg a day in 13 patients with AIPC. Results of this study showed objective responses in 5 (38%) patients lasting a median of 3 months. The authors attempted to correlate patient response with suppression of the adrenal androgens DHEA-S and androstenedione. Twelve (92%) of 13 patients had significant suppression of either one or both hormones, with levels of < 1 mM/L and < 1 nM/L for DHEA-S and androstenedione, respectively. The authors concluded that low-dose Deltasone provided excellent suppression of adrenal androgen levels, which results in good palliative benefits for patients with AIPC. In a subsequent randomized trial by the same principal investigator, the response rate to Deltasone alone was lower, but still significant at 13.5%. The median duration of response to single, agent Deltasone in this trial was 4.5 months (Tannock et al., J. Clin. Oncol., 1996).

Harvey et al. (Proc. Am. Soc. Clin. Oncol., 1994) studied Decadron at a weekly dose of 10 mg intravenously in six patients with advanced-stage PC who had failed at least two prior hormone maneuvers and who also had received chemotherapy. Using a response criteria of a > 50% decline of PSA from baseline, 5 of 6 (83%) of patients responded. They also demonstrated a decrease in pain and an improved performance status. The median duration of survival was 9 months (range of 4 to 20+ months) with 5 patients still responding at the time of the report.

Storlie et al. (Proc. Am. Soc. Clin. Oncol., 1994) evaluated the effectiveness of oral Decadron in 38 patients with progressive disease after orchiectomy. The Decadron dose was 0.75 mg twice a day. Responses were seen in 23 of 38 (61%) of patients evidenced by a greater than 50% PSA decline. Thirteen of 38 (34%) of patients had a greater than 80% decline in PSA. In two of 23 responding patients, the possibility of an AAWR could not be excluded. However, 21 (55%) of 38 patients still had a greater than 50% decline in PSA if these two patients are excluded from analysis. The authors unfortunately did not mention the duration of response in this abstract.

Kelly et al. (Cancer, 1973) conducted a prospective study in which patients with AIPC were initially treated with Hydrocortisone alone, and then were progressively given suramin. Patients treated with suramin require Hydrocortisone to replace the loss of adrenal cortisol production caused by suramin. In that report, only 10% of patients derived an independent benefit from suramin, suggesting that the use of Hydrocortisone may have accounted for the high rates of antitumor response previously reported in suramin trials for AIPC.

In our opinion, all of these studies should have measured DHEA-S and androstenedione levels at baseline and during steroid treatment. If the observations of Tannock et al. were correct in their initial study, the suppression of these hormone levels values may possibly identify which patients may respond best to corticosteroid therapy.

Estrogen Therapy for AIPC: Diethylstilbestrol (DES)

Estrogens have significant effects on the PC cell. Estradiol has been shown to localize irreversibly to the nuclear membrane of the tumor cell within 2 hours of exposure (Sinha et al., Cancer, 1973). Diethylstilbestrol, a nonsteroidal estrogen, has been shown to inhibit RNA polymerase activity in prostatic tissue and inhibit DNA synthesis in both benign and malignant prostate tissue (Davies and Griffiths, J. Endocrinol., 1973; Lasnitzki, J. Steroid Biochem., 1979). All estrogens also exert a competitive inhibitory effect on androgen-dependent cancers by suppressing LH secretion at the level of the pituitary-testicular axis.

Until the advent of LHRH agonists, estrogens and Diethylstilbestrol were extensively used in the treatment of advanced PC. In the initial Veterans Administration Cooperative Urologic Research Group (VACURG) studies, Diethylstilbestrol was found to be as effective as orchiectomy for PC, but at a dose of 5 mg/day, carried a significant risk of cardiovascular morbidity (Byer, Cancer, 1973).

More recently, single and cooperative group studies have evaluated the effectiveness of Diethylstilbestrol at dosages of 3 and 1 mg a day (Blackard, Cancer Chemother. Rep., 1975; Pavone-Macaluso et al., J. Urol., 1986; Emtage et al., Eur. J. Cancer, 1990).

Both dosages were found to be as effective as the 5 mg/day dosage with considerably fewer cardiovascular toxicities. Although serum T levels were not consistently suppressed to castrate levels using the 1 mg/day dose, this dosage showed an equivalent anticancer effect compared to the 5mg/day dosage (Byer and Corle, NCI Monogr., 1988). It should be noted that the regression of metastatic disease can occur without maximal suppression of serum T levels (Scott et al., Cancer, 1990).

In a more recent study, Jazieh et al. (Proc. Am. Assoc. Cancer Res., 1994) reported results using oral Diethylstilbestrol treatment in 14 patients with progressive AIPC. Diethylstilbestrol was given at a dose of 1 mg, 3 times a day along with routine anticoagulation with warfarin (Coumadin). In this study, 9 (64%) of 14 patients responded with a greater than 75% decline in baseline PSA. PSA levels normalized in 5 of 14 (36%) of patients. Two of these patients, however, may have had an anti-androgen withdrawal response. In patients with symptomatic disease, 50% showed improvement with Diethylstilbestrol treatment. The median duration of response was 8 months (range 2 to 24 months), and the median time to reach PSA nadir was 3 months (range 1 to 10 months). There were no cardiovascular or thrombotic (blood clotting) events reported.

More recently, Smith et al. (Urology, 1998) reported results of a phase II study of Diethylstilbestrol at a dose of 1 mg/day in 21 patients failing ADT. All patients were withdrawn from anti-androgen therapy and started Diethylstilbestrol at PSA progression. LHRH agonist therapy was stopped simultaneously. Response in this study was defined as a > 50% decline from baseline PSA. This was seen in 9 of 21 (43%) patients. In 13 patients who failed only one hormonal therapy, responses were seen in 8 (62%) patients. In the 13 patients who failed more than one prior hormone treatment, a response was seen in only 1 (13%) of 8 patients. Duration of response was not reported. Sixteen patients remained alive after a median follow-up of 82 weeks with a 2-year survival rate of 63%. Therapy was generally tolerated well. Nineteen (90%) patients complained of nipple tenderness, but none discontinued therapy because of this side effect. Three (14%) patients developed gynecomastia (breast enlargement), and one (5%) patient developed deep venous thrombosis.

Intravenous Estrogens (Fosfestrol or Stilbestrol Diphosphate)

Stilbestrol diphosphate (Stilphosterol) is a water-soluble formulation of nonsteroidal estrogen that can be injected intravenously. High-dose intravenous estrogens are thought to have a direct cytotoxic effect on the PC cell. In theory, Stilphosterol enters the cell, and free stilbestrol is liberated by an enzymatic action within the cancer. This enzyme, acid phosphatase, is abundant in malignant prostatic tissue and releases free stilbestrol via dephosphorylation. Within the cell, stilbestrol destroys the cell by inducing apoptosis (programmed cell suicide) (Colapino and Aberhart, Br. J. Urol., 1961).

Selenomethionine is a radioactive isotope that is used as a marker for protein synthesis by the cell. At DES plasma levels of 1 mcg/ml, incorporation of this isotope into PC cells was inhibited 20%. At DES levels of 5 mcg/ml, isotope incorporation was inhibited by 69.6% (Ferro et al., Br. J. Urol., 1988). DES blood levels of this magnitude can easily be achieved in the clinical setting. Using high- pressure liquid chromatography, a 1-gram intravenous injection of Stilphosterol resulted in a mean plasma DES level of 3.6 mcg/ml 30 minutes after injection (Abramson and Miller, J. Urol., 1982).

Ferro et al. (Urology, 1989) conducted a prospective trial of high-dose intravenous Stilphosterol in 29 patients with symptomatic AIPC metastatic to bone. At baseline, all patients had elevated PSA levels, 24 (83%) had elevated PAP levels, and 28 (97%) had elevated alkaline phosphatase levels. Stilphosterol was administered as a dose of 1104 mg intravenously over 5 minutes daily for 7 days. A subjective response was seen in 22 (76%) patients as evidenced by improvement in bone pain, mobility, and/or decreased analgesic requirements. Significant decreases in serum PSA were noted in 13 (45%) patients, with PSA reductions ranging from 44 to 93%. Duration of patient response or survival were not reported. Side effects consisted of perineal discomfort, nausea, vomiting, and bone pain in some patients, with widespread bony metastases. No cardiovascular or thrombotic complications were reported.

Fosfestrol is a European formulation similar to stilbestrol diphosphate and is known by the names of Honvan, Fosfostilben, Honvol, and ST-52. In a study by Droz et al. (Cancer, 1993) 16 AIPC patients received fosfestrol, 4 grams a day intravenously over 3.5 hours for 5 consecutive days. For the remainder of the month, patients received an unspecified oral dose of fosfestrol, with intravenous therapy repeated once a month. Response, defined as a > 50% decline in baseline PSA, was seen in seven (43%) patients. The median duration of survival was longer in responding patients (10 months versus 5 months, respectively). Cardiovascular complications occurred in 6% of patients.

A slower rate of intravenous administration appears to reduce the risk for perineal discomfort, nausea, and vomiting. Intravenous Stilphosterol has not been reported to cause cardiovascular or thrombotic complications when the duration of treatment is limited to 7 days (Ferro, Urol. Clin. N. Am., 1991). Since we use Stilphosterol over many weeks' duration, routine anticoagulation with Coumadin is advised.

Further studies with oral and intravenous estrogens are needed. The activity of both oral and high-dose intravenous therapy in AIPC patients who already have castrate testosterone levels clearly indicates their mechanism of action is different from simply effects upon the pituitary-testicular axis.