The PSA Controversy Part II

Part II of this article on PSA Screening shares detailed information on a young man who represents many thousands of men who have a father or brother with prostate cancer and who have undergone PSA screening despite the United States Preventive Services Task Force's recommendations not to use the PSA for screening—even in men with high-risk factors. Here Dr. Strum will point out how PSA screening and subsequent PSA testing can:

1. Facilitate an early diagnosis of prostate cancer,
2. Lead to a more informed assessment of a man's health status,
3. Use this information to correct many subclinical findings of ill health,
4. Ensure stability of the prostate cancer process, and
5. Allow, when indicated, a detour from the conventional response to a diagnosis of prostate cancer which typically mandates an invasive treatment, be it radical prostatectomy, radiation therapy in any form, cryosurgery or high intensity focused ultrasound.

This real-world case history shows how PSA screening can be used as a tool to diagnose and treat prostate cancer without resorting to the inappropriate use of side effect laden therapies.

This article provides highly technical details of a successful treatment involving a man named Andy who contracted prostate cancer at a young age.

Andy's first PSA was obtained in 1993 when he was 43 years of age. He was told that the result was normal because it was less than 4.0 ng/mL. Three years later it was slightly higher at 1.4 ng/mL, and approximately four more years later it had risen to 1.8 ng/mL. Andy's PSA's prior to his diagnosis of PC show a serial rise—not a saw-tooth or up and down pattern that is characteristic of inflammation of the prostate (prostatitis). Andy had been using the same laboratory for his PSA testing and almost all of his blood sampling was done in the morning. Andy was not aware of the effect of ejaculation on raising PSA test results1-4 since my involvement in his care did not occur until September 2007.

In Table 1 the PSA values of the son (Andy) of one of my patients (Dick) with established Prostate Cancer are shown.

Date	PSA	Date	PSA
3/8/93	1.2	12/8/08	5.1
7/19/96	1.4	1/6/09	4.3
4/14/00	1.8	2/17/09	3.9
7/30/01	2.0	6/12/09	4.0
3/10/04	2.4	10/26/09	3.6
9/19/05	2.5	4/9/10	3.8
10/17/06	2.9	7/8/10	3.7
9/5/07	2.92	10/5/10	3.6
9/27/07	Diagnosed with prostate cancer	2/8/11	3.8
TABLE 1: PSA Values for Andy. Recommendations for PSA testing were begun immediately after the patient's father was diagnosed with PC. In patients with a family history of PC, breast cancer or colorectal cancer, initial testing should begin at age 35 to establish a baseline.

An additional aspect of PSA testing that is important to communicate in the context of Andy's clinical course is how the PSA value relates to tumor (cancer) volume. All cells, including cancer cells make hundreds of products that include proteins, enzymes, etc. These are functional products and have relevance to the survivability, growth, and spread of cancer cells.

PSA functions to break down the extra-cellular tissue to allow spread of disease. Therefore, PSA is a detrimental enzyme when elevated because it can facilitate prostate cancer cell invasion.5 Each prostate cancer cell produces and secretes into the blood a certain amount of the biomarker—PSA, and this amount or leak of PSA into the blood relates to the aggressiveness of the individual patient's cancer cell population.

What is seen with Andy prior to his established diagnosis of PC on 9/27/07 is a slow but inexorable rise in PSA. Every new value is greater than the previous value. These values have been entered into a software program called PC Tools shown in Table 2. The change in PSA per year or PSA velocity (PSAV) is shown in the right column for each couplet of dates. The PSAVs look consistent with BPH (benign prostatic hypertrophy) since they are in the range of 0.1 ng/mL/yr. But then, between 2005 and 2006 the PSAV increases to a threshold of moderate concern or ≥ 0.3 ng/mL/yr.

An analysis of the PSA slope or trend (see Figure 1) from 1993 to 2007 shows increasing values of the natural log PSA value and a graph that again poses concern for prostate cancer (PC). If this were BPH there should be a more gradual slope.

Andy shared his concerns with his general practitioner and with the urologist that he was referred to. A DRE (digital rectal exam) indicated a T1c clinical stage (no pathological findings).6 Transrectal ultrasound guided biopsies were done and seven cores from both the right and left lobes were obtained.

Prostate cancer was found to involve three of seven cores of both the right and left lobes for a core percentage of 42.8%. The PC tissue involvement was 11mm of 161mm or 6.9%.7 The Gleason score evaluation by Helmut Bonkhoff, MD, an expert in PC pathology, was (3,3) or six.

A clear diagnosis of prostate cancer (PC) had been established. This was a young man with approximately 40 more years of estimated life expectancy. PC was found in almost half of the core biopsies. What should he do?

Andy's status relating to many of the co-related health issues associated with PC was examined. These associations include, but are not limited, to bone loss, elevated LDL, abnormal fatty acid indicators of excessive inflammation, low vitamin D metabolite levels, and glucose intolerance. For example, because of the significant correlation of osteoporosis and osteopenia with newly diagnosed men with PC,8 a quantitative computerized tomography (QCT) bone density (not to be confused with a bone scan, or with a DEXA bone density) was obtained. This revealed a bone mineral density (BMD) of 121 grams/cc for a T score of –2.03 involving the L1 to L3 lumbar vertebrae; this indicated significant osteopenia. The BMD at the left hip femoral neck revealed a T score of –1.58 consistent with osteopenia of a milder degree.

Emphasizing the association of PC, and all cancers, with other health conditions, an understanding of the biology of cancer makes such associations easily understandable. Cancer cells require energy or fuel to enable proliferation, growth, invasion, and metastasis. These fuels include glucose, omega-6 fatty acids, low density lipoprotein (LDL), and glutamine.9-11 Andy was advised to obtain an NMR LipoProfile, which unlike the standard "cholesterol panel" or "lipid panel" quantitates the various lipid particles. The results of this study showed an LDL of 122 mg/dL (optimal <100 mg/dL), and a total particle LDL value of 1,115 nmol/L (optimal <1,000 nmol/L) and a small particle LDL of 702 nmol/L (optimal <600 nmol/L). A metabolite of vitamin D-3 named (25-OH)-D3 has been shown to be an anti-proliferative vitamin and some studies show (25-OH)-D3 supplementation has an anti-PC effect.12 Andy's 25-hydroxyvitamin D blood level was very low at 23.5 ng/mL with a desired threshold level of at least 60 ng/mL, and an optimal level of 80 ng/mL.13 Andy was placed on vitamin D-3 dose of 5,000 IU per day, with advised to recheck 25-hydroxyvitamin D level after 1-2 months.

Andy's homocysteine (Hcy) level was 4.5 µmol/L, with optimal values being less than 7 µmol/L.14,15 Hcy is an inflammatory substance and has been shown to be elevated proportionally to the amount (volume) of prostate cancer.16,17 A serum testosterone level was 509 ng/dL, which was considered acceptable, but not at the optimal level of at least 550 ng/dL.18 The serum prolactin of 9.4 ng/mL was not optimal and given that prolactin stimulates angiogenesis19-23 and also sensitizes the androgen receptor to the effects of male hormones testosterone and dihydrotestosterone (DHT),24-26 treatment with cabergoline (Dostinex®) to lower prolactin was recommended. A serum PAP (prostatic acid phosphatase) was normal at 1.5 ng/mL indicating a lower risk for PC spreading beyond the capsule of the prostate.27-31 All of the above investigations fine tune the care of any man with PC, and detects abnormalities that if uncorrected could lead to serious medical conditions that are then attributed to the treatment of PC. This is part of the Paul Harvey "and now for the rest of the story." A few more examples of investigating the whole patient to understand his unique biology are given below. Indeed, MD should stand for medical detective.

A Comprehensive Fatty Acid (CFA) profile panel was obtained from the Mayo Medical Labs to evaluate various omega-3 and omega-6 fatty acids. Arachidonic acid (AA) and linoleic acid are two omega-6 fatty acids which are pro-inflammatory and act as growth stimulants for PC. The key omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) act to balance out the negative effects of the omega-6 fatty acids. The ratio of AA to EPA (AA/EPA) for Andy was optimal at 1.2. His omega-6 to omega-3 ratio was close to optimal at 2.44.32 But we learned that Andy had already begun supplementing his diet with fish oil containing 1,400 mg of EPA and 1,000 mg of DHA per day prior to any baseline testing.

Further analysis of the PC tissue obtained at biopsy was obtained using the services of Dr. Helmut Bonkhoff, an international expert in PC pathology. He performed IHC (immunohistochemistry) analyses on the PC tissue to determine if Andy's PC relied on specific enzyme pathways (gene products) to enhance oncogenic signaling crucial to cancer growth and spread. Abnormal PC tissue expressions of cyclooxygenase-2 (COX-2), fatty acid synthase (FAS), heat shock protein (HSP) and vascular endothelial growth factor (VEGF) were found. Based on peer-reviewed medical publications about dietary, supplement and drug therapies to reduce (down-regulate) the effects of these gene products, recommendations were made to Andy (see Table 3).

With this more complete evaluation of Andy's status, "refined imaging" was next advised to obtain a more comprehensive sense of the PC volume and to establish Andy's baseline profile (see http://bit.ly/LYerzy).67 An endorectal MRI and MR spectroscopy (MRS) was done at UCSF. It showed MRI abnormalities in the left apex and left base and in the central gland. MRS was abnormal in the central gland and left base. No extracapsular extension (ECE) nor seminal vesicle or regional lymph node involvement were seen. A repeat 25-hydroxyvitamin D blood test after one month of 5,000 IU of vitamin D-3 showed a doubling to 52 ng/mL. A further dose increase to 7,000 IU per day was recommended.

Andy adjusted his supplements in response to the findings in Table 3 by adding EGCG at 472 mg/day, silibinin at 85 mg/day, ginger at 10 mg/day, rosemary extract at 800 mcg/day and also increased his total EPA + DHA dose to 3,600 mg/day. He also began a natural COX-2 inhibitor product called Zyflamend® containing rosemary, turmeric, ginger, holy basil, green tea, and other agents.68-71 In May of 2008 the (25-OH)-D3 level had risen to 67.9 ng/mL. In October of 2008, Andy began Dostinex® at 2.5 mg three times a week to lower serum prolactin. He also began a resistance exercise program to improve his bone density. In December 2008 his fasting morning prolactin level had dropped to 1.1 ng/mL and he was told to reduce the Dostinex® dose to only twice a week. In early 2009, a repeat MRI at UCSF showed improvement with only a slight area of T-2 abnormality in the left aspect of the central gland remaining. No other pathology was apparent.

Since 2009, Andy has had dose adjustments of various supplements and medications based on periodically assessing BEPs (Biological End Points). BEPs are the test results that are objective data relating to diet, lifestyle or medication interventions. BEPs are identical to the LEDs on the dashboard of your car—they are status indicators. Andy has had additional BEPs that include a normal HbA1c of 5.6% to assess his handling of carbohydrates and a Cystatin C of 0.62 mg/dL which assesses renal function and inflammation.

In July 2010, an additional MRI and MRS was done at UCSF and showed no abnormal findings. However, a repeat QCT bone density showed the BMD to have decreased to 106.7 gm/cc at the lumbar spine with an associated T score of -2.6 indicating osteoporosis. Bone resorption markers (additional BEPs) that included urine testing for DpD (deoxypyridinoline) was 2.7 nmol Dpd/mmol creatinine, a normal result. A serum b-CTX (C-Terminal Telopeptide, b-Crosslaps) was slightly elevated at 375 pg/mL (normal 87-345 pg/mL). However, a repeat CTx to confirm the abnormal finding was normal at 266 pg/mL in March 2011. A follow-up NMR LipoProfile indicated small particle LDL to be <90 nmol/L and total LDL particles to be 646 nmol/L, both entirely normal.

Andy's PSA levels since his diagnosis of PC in September 2007 are shown below (Table 4). These findings show no serial increase in PSA and coupled with normal imaging studies indicate no progression of PC, and perhaps regression. Repeat prostate biopsies are being considered.

Andy is now 62 years of age. He was not pushed into any form of invasive treatment for his PC but instead he was given the various options that included RP (radical prostatectomy), RT (radiation therapy) using IMRT (intensity modulating radiation therapy), cryosurgery and HIFU (high intensity focused ultrasound). Andy has become an empowered patient that understands the value of obtaining baseline studies, follow-up BEPs, and determining strategy based on his personal status. The diagnosis of PC and the realization of the co-relationships with other areas of his health has resulted in major improvements in Andy's health (see Figure 2 on the next page).

But Andy clearly understands that he still needs to focus on issues where abnormal findings have not been resolved. In this use of PSA screening for a man with a family history of PC, all of the principles discussed in the beginning sections of this article were employed. For Andy, he has not needed an invasive treatment to control his PC. The use of the PSA facilitated an early diagnosis of PC when tumor volume was low and the PC remained confined to the prostate. Understanding the patient's context, employing various medical artists to enhance an understanding of his status, educating the patient as to foundational concepts involved in optimizing health has evolved Andy's health status compared to his state of ignorance prior to his diagnosis of PC.

PSA screening for this man has been a blessing. Not only was the message understood, but the messengers used worked together with Andy as a cohesive medical team in the spirit of collaboration and collegiality. Whether or not this can be done with the vast majority of other men who have PC are determined by the knowledge of physicians and other health care practitioners involved in the diagnosis and management of the most common malignancy affecting mankind.

Summary

If Andy had followed the recommendations of the United States Preventative Services Task Force to not screen for PSA, he may have already undergone debilitating conventional therapies (surgery, radiation, hormone ablation, and/or chemotherapy) without the cancer being eradicated. Unlike many other cancers, certain PC patients may exert a tremendous amount of control over their disease with the appropriate use of non-toxic treatments.

This article provides highly technical details of a treatment program not only for Andy's prostate cancer, but also one that corrected risk factors for vascular disease, osteoporosis, and malignancies that may have developed at other sites in Andy's body.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

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