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IS IT NECESSARY TO CURE PROSTATE CANCER WHEN IT IS POSSIBLE? A REVIEW OF A PROSPECTIVE STUDY ON DIET AND NUTRITION

RONALD E. WHEELER, From the Prostatitis & Prostate Cancer Center, Sarasota, Fl

Prostate Cancer, arguably the most dominant disease of the 21st Century, is the most commonly diagnosed malignant neoplasm among men in North America.(1) Notwithstanding the strides that have been made related to diagnosis and treatment, prostate cancer poses the most significant health risk of modern times consistent with epidemic if not pandemic status. In 2004, the incidence of prostate cancer was noted to be in excess of 230,000 new cases while prostate cancer death currently ranks as the second most common male cancer death with approximately 32,000 men dying from the disease. (2) According to the SEER (Surveillance, Epidemiology & End Result) data and the age specific population projections in association with the United States Census Bureau, it is estimated that 99,000 men will die from prostate cancer in the year 2045. (3) Notwithstanding the enormity of the health risk posed, there is equal concern generated on how best to pay for the therapy moving forward. An aging population associated with a projected surge in prostate cancer detection promises to implode the most liberal health care budget without a novel change in treatment strategy. Current treatment strategy presents a veritable cornucopia of thought generally biased toward the educational background and training of the Professional rendering the opinion. (4) Despite the best efforts to cure, failure rates may be as high as 40-60%. (5) Regardless of the success or failure of a given procedure to cure the cancer, men tend to be living longer, while burdened with quality of life altering social change including incontinence and impotency. This group is not infrequently asked to take medications chronically that portend to restore what was lost at surgery or radiation.

From a point of fiscal responsibility associated with a lack of defined survival benefit with any therapy, there are many experts who question whether we are over treating prostate cancer. The poignant words of the late Willet Whitmore, M.D. may prove most prophetic. To paraphrase, his often quoted rhetorical question asks, "Is it possible to cure prostate cancer when it is necessary" and "Is it necessary to cure prostate cancer when it is possible"? Clearly, the query regarding the necessity to cure prostate cancer when it is possible had prompted the investigation germane to this study. Could it be that proper diet and appropriate nutrition could provide an acceptable alternative to expensive treatments that may represent more than the disease requires while avoiding loss of quality of life?

The goal of this prospective study was intended to evaluate the feasibility of treating prostate cancer conservatively yet effectively through dietary modification and a complex synergistic nutritional supplement patented to suppress and/or resolve non-bacterial prostatitis.

While there is no consensus on the best form of treatment for any stage of prostate cancer (3), this study concept provides a unique proactive strategic protocol that is more “hands on” and intellectually stimulating than Watchful Waiting but lacks the aggressiveness and defined side effect profile of definitive therapy.

METHODS AND MATERIALS:

Between 1998 and 2004, 22 men (mean age: 62 years) with biopsy proven prostate cancer were offered the opportunity to avoid an attempt at a curative cancer treatment in favor of a dietary and nutritionally oriented conservative protocol. The diet endorsed was the Modified Mediterranean Diet (Prostate Diet) while a patented prostatitis formula (Peenuts ®,) was the nutritional supplement common to all patients. By study design, none of the patients had ever been exposed to Anti-Androgen therapy, a Luteinizing Hormone-Releasing Hormone (LHRH) analogue, LHRH antagonist or definitive therapy with surgery, radiation, or cryosurgery. All men were followed at varying time intervals with a PSA (prostate specific antigen) blood test, while many of the men were followed with the International Prostate Symptom Score (IPSS) Index and the Expressed Prostatic Secretion (EPS). With the exception of two men with Gleason 6/7 components and two men with Gleason 5/6 components, all men exhibited either a Gleason 5 (n=6) or a Gleason 6 (n=12) pathological pattern. All men were clinically diagnosed as T1c (n=13), T2a (n=2), T2b (n=2), or T2c (n=5). 2 men described later, did not qualify for study data inclusion.

Interestingly, all men who met the entry criteria, outlined above, chose to treat their disease as a chronic disease through a dietary and nutritional supplementation protocol represented by the term Chronic Disease Management (CDM) rather than undergo definitive therapy. CDM therapy is a unique cancer concept, but not dissimilar to the treatment of Diabetes or Hypertension, whereby patients learn to live with the disease based on lifestyle changes consistent with diet, nutrition and exercise.

While the PSA is a recognized marker of disease activity, it is noted that PSA elevation may rise based on any combination of prostatitis (non-bacterial inflammation in ≥ 95% of cases), BPH (benign prostatic hyperplasia), and/or prostate cancer. The IPSS is a recognized marker associated primarily with BPH and prostatitis, while the EPS (expressed prostatic secretion), represents the diagnostic biologic marker for prostatitis. All men were evaluated at varying intervals of surveillance ranging from 5 months to 64 months (mean: 30 months).

With the exception of two patients, detailed later, a statistical analysis of 20 patients for a change in PSA was performed noting significance using the t-Test. The decision was to reject the Null Hypothesis that there was no change in PSA values. There was a significant decrease in PSA levels (ng/ml) after treatment with dietary encouragement and the herbal supplement taken at 2 capsules daily. The P value (T≤ t) one-tailed T test is 0.000880968. Two subjects, patient number 6 and patient number 20 had slight increases in their PSA levels.

The other 18 patients had decreased PSA levels. Therefore, 90% of the patients treated with diet and nutrition decreased their PSA values. Patient number 18 had the largest decrease in PSA from 14.4 ng/ml at diagnosis to 1.9 ng/ml at follow up in 14 months. Considering this subject to be an outlier, we re-evaluated the data using 19 patients. The results are as follows:

t-Test: Two-Sample Assuming Unequal Variances
	PSA at Diagnosis	PSA at Follow-Up
Mean	6.33684211	3.821053
Variance	7.45356725	5.653977
Observations	19	19
Hypothesized Mean Difference	0
Df	35
t Stat	3.02893837
P(T≤ t) one-tail	0.00229453
t Critical one-tail	1.68957285
P(T≤ t) two-tail	0.00458906
t Critical two-tail	2.03011041

At the significance level of Alpha = 0.05: The P (T≤ t) one-tailed test is 0.00229453. Thus, there was a significant decrease in PSA level with these 19 subjects. Statistical evaluation of the dietary and nutritional variables had a significant effect in reducing PSA levels in this subject group.

Descriptive Statistics:

PSA at Diagnosis Ø₀
Mean	6.74
Standard Error	0.718052923
Median	6.7
Mode	4.4
Standard Deviation	3.211230294
Sample Variance	10.312
Kurtosis	0.319273095
Skewness	0.720065776
Range	12.3
Minimum	2.1
Maximum	14.4
Sum	134.8
Count	20

PSA at Follow-Up Ø
	Mean	3.725
	Standard Error	0.526351644
	Median	3
	Mode	1.9
	Standard Deviation	2.35391611
	Sample Variance	5.540921053
	Kurtosis	3.59465374
	Skewness	1.668528589
	Range	10.1
	Minimum	0.8
	Maximum	10.9
	Sum	74.5
	Count	20

The null hypothesis: H0 that Ø = Ø0
The alternative hypothesis: H1 that Ø < Ø0
Level of significance: α = 0.05
Test statistic: T test

t-Test: Two-Sample Assuming Unequal Variances
	PSA at Diagnosis	PSA at Follow-up
Mean	6.74	3.725
Variance	10.312	5.540921053
Observations	20	20
Hypothesized Mean Difference	0	df 35
t Stat	3.386473378
P(T≤ t) one-tail	0.000880968
t Critical one-tail	1.689572855
P(T≤ t) two-tail	0.001761936
t Critical two-tail	2.030110409

RESULTS:

All men within an age range of 43-74 years with a diagnosis of prostate cancer (Gleason Score: 5, 5/6, 6, 6/7) were offered an opportunity to participate in a conservative quality of life protecting study with the understanding that diet and nutrition could play a significant role in disease proliferation or control. With the exception of the Gleason Score (excluding men with a primary Gleason Score: 7, 8, 9, or 10) as a qualifying category of prostate cancer, there was no bias inherent in the entrance process. Twenty men qualified for evaluation using the date of diagnosis (biopsy date) or the initial clinic appointment date with a reference PSA value as the starting point for data collection. 18 of 20 men experienced a positive response (decrease in PSA) to the conservative therapy while 2 men noted a mild increase in PSA value. Specifically, 90% of men (n=18) noted a 48% reduction (range of improvement: 4-87%) in PSA over an average of 30 months (range: 5-64 months). To state further, using a mean PSA starting point of 7.1 ng/ml, 90% of men experienced a mean reduction in PSA of 3.4 ng/ml (range: 0.5-12.5 ng/ml) over the identified time frame. The two men who experienced a mild elevation in PSA noted an increase of 0.9 ng/ml and 0.6 ng/ml over 34 months and 11 months, respectively. Overall, the effectiveness of Chronic Disease Management therapy to suppress prostate cancer was 90% when the PSA was used as the disease activity marker. A voiding symptom score (IPSS-Index) and prostatitis evaluation (EPS) were also conducted at the time of baseline and follow up evaluation on many of the participants. 11 men had completed an initial and secondary IPSS-Index while 9 men had undergone an initial and secondary EPS. All men reduced their voiding symptom score an average 5.1 points (range: 3-11) while noting an average starting score of 8.7 points (range: 4-19.5). The mean percentage reduction in IPSS-Index was 65% (range: 35-100). Men evaluated for EPS noted a mean reduction in the prostatitis marker of 227 white blood cells (range: 75-495) with a mean percentage improvement of 73% (range: 42-99).

STUDY ANALYSIS AND DISCUSSION:

The appeal to treat prostate cancer more conservatively has always been intriguing to the patient and a concern for the clinician. Prior to this study, previous studies have commonly grouped Gleason 7 scores with Gleason 5 and 6 scores within the designation of moderately well differentiated cancers. Ostensibly, this would give patients with Gleason 7 scores improved odds for cure while decreasing the chance for success in the patients with Gleason 5 and 6 scores. This assumes the higher the Gleason score, the lower the chance for cure. (5,6)
Increasing evidence through analyses now suggests that Gleason 7 prostate cancer responds better than a Gleason 8-10 but not as well as a Gleason 5 or 6. (5) Additionally, it is believed that Gleason scores of 5-7 may comprise almost 90% of all cancers encountered. (5) To be sure, 35-62% of men in most study groups analyzed are identified in the Gleason 6 Category (5).

Qualification for this study included men with the diagnosis of prostate cancer who had not been exposed previously to anti-androgen therapy, LHRH therapy or any other definitive process of prostate disease manipulation. Of the twenty two patients evaluated, 12 men were diagnosed with a Gleason 6 score, 6 men had a Gleason 5 score, 2 men had a Gleason 5-6 score while 2 men were noted with a Gleason 6-7 score. The clinical stage assessment noted 13 men with a T1c, 5 men with a T2c, 2 men with a T2b and 2 men with a T2a stage classification. Pathologically, the diagnosis ranged from T1a – T2c. (Refer to Patient Performance chart) While the number of biopsy cores positive for cancer and the percentage of cancer per core varied widely, the percentage of cores positive for cancer (identified at the biopsy procedure) ranged from 17%-73% (mean: 36%) associated with a range of biopsy samples from 2-12. Minimally, this speaks to the presence of significant disease.

In an effort to improve the understanding for the role of diet to prostate cancer, reference is made to a study performed by Dean Ornish. In a unique study, Ornish and colleagues evaluated the ability of the Vegan Diet (n=44) to alter the PSA in a comparative analysis with a non-restrictive diet (n=43) in men documented with a Gleason 6 prostate cancer. (7) While the merits of the Vegan Diet cannot be disputed as a benefit to heart disease prevention, it was less clear what effect this diet would have on men with known cancer. While an average decrease in PSA of 0.25 ng/ml identified in the Vegan group was statistically significant, the difference was modest when the result was compared to the 0.38 ng/ml rise in the control group at one year. This study result does not suggest a lack of benefit to the Vegan Diet, but rather demonstrates the impact of diet on prostate cancer appears to be less than clinically significant.

In our prospective study, we evaluated the benefit of a modified Mediterranean diet on known prostate cancer patients with Gleason scores of 5-7. The Mediterranean diet is recognized worldwide for its health benefits systemically but more specifically its heart healthy and prostate healthy characteristics. (8) By design, men were asked to avoid red meat and dairy products including eggs in an effort to decrease saturated fat. It is commonly recognized that animal fat and dairy fat may play a role in prostate cancer proliferation. (9) Unlike the Ornish cohort, men did not use soy in their diets. Fresh fruits and cruciferous vegetables belonging to the brassica classification were highlighted while the oil of choice was olive.

Germane to our study group, beyond the type of diet, was the use of a nutritional supplement patented versus Prostatitis. This formula represents a unique, synergistic blend of vitamins, minerals, amino acids and herbs. Functionally, these ingredients have been shown individually to affect profoundly cellular oxidation, inflammation and immune function, while offering additional potential, albeit, less clear, benefits from beta-sitosterols. (10,11) While using this formula, previous clinical investigation has shown an improvement in the expressed prostatic secretion (EPS) and voiding symptoms. (12) The EPS is the recognized diagnostic marker for prostatitis as shown through the historic work of Stamey, Meares, and others (14,15,16,17), while voiding symptoms are common to the diagnosis of benign prostatic hyperplasia and prostatitis.

The concept of looking at prostatitis within this study group was prompted by previous research that supports a role for prostatitis in the evolution of prostate cancer. (18,19,20) It is postulated that the cellular oxidative stress associated with a chronic inflammatory process leads to proliferative inflammatory atrophy with subsequent evolution of free radicals through oxidative change leading to DNA alteration (cellular mutation), prostatic intra-epithelial neoplasia (PIN) and cancer. (18,20) While it is beyond the scope of this article to review these findings in greater depth, it is well known that the process of inflammation is commonly associated with organ specific cancers including but not limited to cancer of the esophagus, colon, stomach, liver, lung and cervix. (19,21)

Within our study group, the mean PSA at the time of diagnosis was 6.7 ng/ml (range: 2.1-14.4 ng/ml). A statistically significant reduction in mean PSA of 3.0 ng/ml was noted using the t-test and null hypothesis. (Refer to statistical analysis) The mean percentage reduction in PSA was 40% while the likelihood for organ confinement in this group was 58% referencing the Partin Prediction tables. (22,23)

While the topic of prostatitis and its role in prostate cancer evolution is likely to remain controversial for the immediate future, the topic's relevance may be best left for the health care provider and the patient to decide. Based on an average percent reduction in the white blood cells (a universal marker for inflammation) of 73% associated with the EPS, there appears to be clinical indication to support the addition of a scientifically validated nutritional formula to any prostate cancer protocol. The failure of the Ornish Diet to significantly suppress prostate cancer (based on PSA analysis) supports this position as well.

Additionally, it is not unreasonable to suggest the reduction in PSA is based on the improvement in prostatitis, as it is well known that prostatitis is a common cause of PSA elevation. Minimally, the nutritional component complements the diet and may well enhance the durability of response seen in the study patients.

In regard to voiding symptoms, there is a clear indication that the Nutritional formula evaluated had an impact on voiding symptoms, as there was a mean percentage reduction in the International Prostate Symptom Score Index (IPSS-Index) of 65%, consistent with findings from a previously performed randomized, double blind, placebo controlled study (12). This response compares favorably to any prostate nutritional formula in the world in this category. While it is difficult to isolate any ingredient as singularly responsible for the identified result, the role of saw palmetto continues to be controversial and has never shown any benefit to prostatitis albeit some limited benefit is noted with voiding symptoms. Clearly, one cannot expect any singular nutritional element to have the same clinical impact of a validated blend of nutrients. (24)

Two patients (with a Gleason 6) who originally entered the study were not candidates for statistical evaluation. Specifically, one gentleman aged 54 decided on Radical Prostatectomy despite performing quite well at 7 months. Importantly, the delay in surgery had no adverse effect on the outcome, as his PSA was 0 ng/ml, 1 year post-prostatectomy. While further research could evaluate the potential benefit of this protocol to an ultimate outcome, the delay in definitive treatment minimally allowed for improved awareness and decision making on the part of the patient and his family. A second patient aged 55 had only been on the nutritional portion of the program while he improved his understanding and conviction for the dietary changes necessary to excel. Nonetheless, in a period of 3 months, his PSA had dropped from the diagnostic PSA value of 4.1 ng/ml to 2.4 ng/ml (a 42% decrease). Further research may demonstrate the use of the Peenuts ®, formula or similarly validated formulas to be the best first step in avoiding additional unnecessary biopsies in patients where prostatitis is present primarily and/or where cancer may be present but doesn't need to be discovered.

While the use of the modified Mediterranean diet and a prostate nutritional formula represents Chronic Disease Management in its most conservative application and has been shown to be effective when used alone; additional ingredients and/or products may be added to enhance an as yet unknown, clearly defined collective benefit in the prostate cancer disease suppression process. Notwithstanding the previous statement, the mechanisms of action are well known for most of the adjunctive medications mentioned. Beyond the modified Mediterranean diet, 20 patients used the Peenuts ®, formula, 14 patients used an active form of vitamin D, 11 patients used an anti-cholesterolemic agent, 11 patients used omega 3 fatty acids, 10 patients used a 5-alpha Reductase inhibitor (5-ARIs), 7 patients used a COX II inhibitor and 3 men used an alpha-blocker. When the men using 5-ARIs were studied versus the men who didn't use them, there was a 42% reduction in PSA in the 5-ARIs group (n=10) over 26 months versus a 39% reduction in the cohort not on 5-ARIs (n=10) over 33 months. This speaks to an insignificant benefit for PSA reduction to the men on the 5-ARIs at this point in the study. Interestingly, when the nutritional formula was evaluated alone (n=4), a percent reduction in mean PSA was 49% over 35 months of surveillance. Despite the potential significance to this finding, it is premature to postulate on the possible meaning without an evaluation of additional candidates.

CONCLUSIONS:

Prostate cancer is recognized as the number one male health risk with a new case of prostate cancer diagnosed every 3 minutes. With baby boomers aging and health care costs rising (25), an opportunity to examine novel concepts for the care of patients diagnosed with prostate cancer could not be more relevant. When consideration is given to the potential benefit of adding 3 years, 1.5 years, and 0.4 years to the life of a man in his 50s, 60s or 70s, respectively, (26) (when Radical Prostatectomy is successfully performed for cure), is weighed against the possibility of failure to cure, a dietary and nutritional protocol may present a reasonable alternative.

Furthermore, when the financial impact is calculated in an aging population and quality of life is threatened (example: bowel injury, incontinence and/or impotency), regardless of success or failure versus cancer, a conservative approach may be welcomed as a viable first choice in Gleason 5 and 6 prostate cancer patients by Governmental agencies such as Medicare, the Health Care Insurance Industry, and patients alike. While it is premature to state unequivocally that prostate cancer is over treated, there appear to be indicators that speak to this fact. Critical to research regarding the concept of living with the disease (CDM) is to locate and allocate funding to study this protocol in greater depth adding more patients over a longer period of time. Minimally, this study has provided the first step in improved understanding of this concept. Beyond the issue of prostate cancer treatment is the potential role of prevention. Ultimately through this research effort and that of others, the landscape of prostate cancer treatment will become better defined.

REFERENCES

1.	Greenlee RT, Harmon MB, Murray T etal. : Cancer Statistics, 2001. Journal Clinical Cancer 51:15-36, 2001.
2.	American Cancer Society: Cancer Facts and Figures 2004. Atlanta, Georgia: American Cancer Society, Page 16-7, 2004.
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4.	Fowler FJ, McNaughton-Collins M, Albertsen MS, etal. Comparison of Recommendations by Urologists and Radiation Oncologists for Treatment of Clinically Localized Prostate Cancer. JAMA Vol. 283, 2000.
5.	Tefilli MV, Gheiler EL, Tiguert R, etal. Should Gleason Score 7 Prostate Cancer be considered a Unique Grade Category? Urology 53: 372-377, 1999.
6.	Nelson CP, Rubin MA, Strawerman M, etal. Preoperative Parameters for Predicting Early Prostate Cancer Recurrence after Radical Prostatectomy. Urology 59: 740-46, 2002.
7.	Ornish, D, Weidner G, Fair WR, Marlin R. Intensive Lifestyle Changes May Affect the Progression of Prostate Cancer. Journal of Urology: Vol. 174, 1065-1070, 2005.
8.	Knoops K, deGrout L, Kromhout D, etal. Mediterranean Diet, Lifestyle Factors, and 10-year Mortality in Elderly European Men and Women (The Hale Project). JAMA: Vol. 292, No. 12, 1433-39, 2004.
9.	Margolis S, Carter HB. The Johns Hopkins White Papers (Prostate Disorders). P: 28, 2002.
10.	Memorial Sloan-Kettering Editorial Board. About Herbs, Botanicals, & Other Products. Internet Site 2004
11.	PDR for Herbal Medicines. The Information Standard for Complementary Medicine. Medical Economics 2nd Edition, 2000.
12.	Wheeler RE, Selah RG. Evaluation of the Benefit of a Nutritional Formula on Voiding Symptoms (a Randomized, Double Blind, Placebo Controlled Study), Unpublished, 1997.
13.	Anderson RU, Fair WR: Physical and Chemical Determinations of Prostatic Secretion in Benign Prostatic Hyperplasia, Prostatitis, and Adenocarcinoma. Invest Urology. 14:137,1976.
14.	Anderson RU, Weller C: Prostatic Secretion Leukocyte Studies in Non-Bacterial Prostatitis. J Urol: 121:292, 1979.
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16.	Drach GW, Fair WR, Meares EM, Stamey TA: Classification of Benign Diseases associated with Prostatic Pain: Prostatitis or Prostatodynia? J Urol: 120:266, 1978.
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18.	Nelson WG, DeMarzo AM, DeWeese TL, etal. The Role of Inflammation in the Pathogenesis of Prostate Cancer. JUrol: Vol.172, S6-S12, 2004.
19.	Bostwick DG, Bostwick Laboratories
20.	American Association of Cancer Research (AACR): National Meeting, Naples, Fl., December 2001.
21.	Robbins Pathology: Inflammation Associated with Organ Cancers.
22.	Partin AW, Walsh PC, Kattan MW, etal. Combination of Prostate-Specific Antigen, Clinical Stage, and Gleason Score to predict Pathological Stage of Localized Prostate Cancer: a multi-institutional update. JAMA.1997.
23.	Partin AW, Walsh PC, Epstein JL, etal. Contemporary Update of Prostate Cancer Staging Nomograms (Partin Tables) for the New Millennium. Urology. 2001.
24.	Kaplan SA, Volpe MA, TE AE. A Prospective, 1-year trial using saw palmetto versus Finasteride in the treatment of category III prostatitis chronic pelvic pain syndrome. JUrol. Vol. 171, 284-288, 2004.
25.	Gelman EP. The Relative Impact and Future Burden of Prostate Cancer (Discussion), 4th International Conference. J Urol (Supplement): 172: No. 5, Page 17, 2004.
26.	Coley CM, Barry MJ, Mulley AG. Clinical Guideline: Part III, Screening for Prostate Cancer. AnnIntMed. 126: 480-4, 1997.

ARTICLES - STUDIES - REFERENCES


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