By Stephen B. Strum, M.D., and
Jonathan E. McDermed, Pharm.D.

Dr. Strum is on the Life Extension Medical Advisory Board, and Dr. McDermed is from the Prostate Cancer Research Institute (PCRI) in Los Angeles, California. Drs. Strum and McDermed are proponents of a holistic medical strategy that combines peer-reviewed conventional scientific publications with new findings in the areas of nutrition and supportive care of the patient. Dr. Strum and his partner Mark C. Scholz, M.D., have a medical practice (Healing Touch Oncology) in Marina del Rey, California, that cares for patients with prostate cancer (PC) or who are at high risk of having PC.

Emphasis on the use of routine prostate-specific antigen (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 number 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 will also enable an earlier diagnosis of PC (Babaian et al., Urology, 1998). As our standard, and ideally routine, approach to monitoring PSA and other biological expressions of tumor cell activity increases in use, 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 3, or 0.5%, had a persistently abnormal PSA for 3 years; in this group, 1 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 greater than 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 androgen deprivation therapy (ADT) in situations where the tumor volume compromises the curative ability of local therapy, such as radiation therapy (including seed implantation) or cryosurgery. (Refer to the Prostate Cancer [Early-Stage] protocol for specific treatment information.)

Heredity Factors in the Development of PC

PC is now being linked to genetic abnormalities that explain the familial occurrence of PC that we frequently see. An understanding of why PC affects certain populations of men more than others is now becoming better understood. We know that PC is equally as prevalent in Asian men as in Western men, but that the frequency of biologically aggressive PC is significantly greater in the non-Asian population. This finding is felt to be possibly related to the lower amount of dietary fat in the Asian diet as well as the frequent use of soy products and a higher intake of green tea polyphenols (Aldercreutz et al., Proc. Annu. Meet. Cancer Res.). In the United States, 74% of men with PC are considered to have "sporadic" PC, while the remaining 26% demonstrate evidence of genetic clustering. Within the 26%, 19% are cases of hereditary PC (HPC) versus 81% designated as familial PC (FPC) (Bastacky et al., J. Urol., 1995). Familial prostate cancer is defined as the simple clustering of the cancer in families, whereas hereditary prostate cancer requires any of the following three criteria: a family with three generations affected, three first-degree (brother[s] or father) relatives affected, or three relatives affected before the age of 55 years (Carter et al., J. Urol., 1993). Men with either FPC or HPC are prime candidates for preventive approaches involving nutritional adjuncts.

HPC is a subtype of FPC with a Mendelian pattern of inheritance linked to a single gene that is transmitted as an autosomal dominant of high penetrance. In simpler terms, this gene is passed along from father to son, and from father to daughter and then to grandson. With HPC, due to the high penetrance of the gene, nearly half of the male offspring will have prostate cancer; many of these will develop PC at an early age, i.e., less than 55. Because the gene is passed along via female offspring, the family history should include questioning about maternal grandfather, maternal uncles, and maternal cousins. HPC accounts for 43% of early onset disease (age 55 years or younger) (Carter et al., J. Urol., 1993; Carter et al., Cancer Surv., 1991; Carter et al., Proc. Natl. Acad. Sci. USA, 1992). Extensive family studies of PC indicate that PC shows a stronger familial aggregation, even more than colon or breast cancer, but less than that of ovarian cancer (Cannon et al., Cancer Surv., 1982).

Studies at Johns Hopkins indicated that HPC occurs in the general population at the rare frequency of 0.36% (Carter et al., J. Urol., 1993). Men who carry this dominant gene will develop PC at the rate of 88% of the carriers that live to the age of 85 compared to 5% of the noncarriers (Carter et al., J. Urol., 1993). The rarity of this gene will result in 9% of all PC occurrences by age 85 years being related to HPC (Carter et al., J. Urol., 1993). Important aspects of HPC and FPC are shown in Table 1.

Early detection approaches have been recommended for men with a history of familial or hereditary PC (Spitz et al., J. Urol., 1991). Such diagnostic measures could include yearly DRE, PSA, Free/ Total PSA, ProstaSure, and tracking of PSA velocity and PSA doubling time. In my opinion, this should begin at age 35 to 40 in men with FPC or HPC. Men with a family history of breast cancer in the maternal line are also at greater risk for developing PC. Women with brothers and/or fathers with PC are also at higher risk for breast cancer, since breast cancer and PC share some common genes (Sellers et al., Proc. Annu. Meet. Am. Assoc. Cancer. Res., 1994). Early nutritional intervention should be a major consideration to alter the natural history in such high-risk patients.

Table 1:
Characteristics of Hereditary and Familial Prostate Cancer

Feature	HPC	FPC	Senior Authors
Definition	3 generations or 3 first degree relatives or 2 relatives with PC < 55 years of age	Clustering in families	Carter et al., J. Urol., 1993
Frequency	~20% of clustered PC	~80% of clustered PC	Bastacky et al., J. Urol., 1995
Early Onset PC	Accounts for 43% of early onset PC		Carter et al., J. Urol., 1993 Carter et al., Proc. Natl. Acad. Sci. USA, 1992 Carter et al., Cancer Surv., 1991
Number of 1st-Degree Affected Relatives vs. Risk	Increased Risk-Odds Ratio	95% Confidence Intervals	Steinberg et al., Prostate, 1990
1	2.2	1.4-3.5
2	4.9	2.0-12.3
3 or more	10.9	2.7-43.1
Number 1st- or 2nd- Degree Affected Relatives vs. Riska	Increased Risk-Odds Ratio	95% Confidence Interval	Steinberg et al., Prostate, 1990
1	1.5	1.3-1.8
2	2.3	1.7-3.3
3 or more	3.6	2.2-5.9
Type of Relative with PC vs. Risk of Getting PC	Increased Risk-Odds Ratio	95% Confidence Intervals	Steinberg et al., Prostate, 1990
2nd degree: uncle or grandfather	1.7 (Steinberg) 2.1 (Spitz)	1.0-2.9 0.8-5.7	Spitz et al., J. Urol., 1991
1st degree: brother or father	2.0 (Steinberg) 2.4 (Spitz)	1.2-3.3 1.3-4.5	Steinberg et al., Prostate, 1990
1st and 2nd degree	8.8 (Steinberg)	2.8-28.1	Spitz et al., J. Urol., 1991 Steinberg et al., Prostate, 1990
Age of PC Onset in Patient vs. Riskb	No Additional Relatives Affected	1 or More 1st Degree Relatives Affected	Carter et al., J. Urol., 1993
50	1.9 ( 1.2-2.8)	7.1 ( 3.7-13.6)
60	1.4 ( 1.1-1.7 )	5.2 ( 3.1-8.7 )
70	1.0 (reference group)	3.8 (2.4-6.0)

     ^a This number does not include the patient.
     ^b This relates to risk in first-degree relative(s) of the patient with PC; For example, a 50-year-old patient who has a father or brother(s) with PC would confer a 7.1-fold greater risk to an additional first-degree relative.