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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, any more than all breast cancer or other tumor types are systemic. If they were, we would never cure 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 radical prostatectomy (RP) or radiation therapy (RT) with a flat prostate specific antigen (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 biopsying 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

Continuation of PROSTATE CANCER: LATE STAGE