Racial Disparities in Prostate Cancer

Anand M. Kuruvilla M.D., Walter P. Scott M.D., Shyam B. Paryani M.D., John W. Wells M.D., Douglas W. Johnson M.D., Rashmi J. Chobe M.D., Sonja L. Schoeppel M.D., Abhijit V. Deshmukh M.D., Mitchell Terk M.D., Sarah Hoffe M.D., Timothy Jamieson M.D., with the Florida Radiation Oncology Group - Jacksonville, Orange Park, St. Augustine & Palatka

 
Introduction

Prostate Cancer is the most common solid tumor in men and in Florida and is the second leading cause of cancer death.
Figure 1: Comparative Pie chart depicting Cancer deaths in Men

The epidemiology of the disease continues to be the subject of considerable scrutiny. Keen interest was triggered by the skyrocketing incidence rates noted in the early part of the last decade. This was directly attributed to the improved ability to detect disease with the Prostate specific antigen blood test. PSA has been available since the mid-eighties but only after 1991 has it's use been wide spread. PSA has complemented the ubiquitous Digital rectal exam in providing an effective screening tool. After peaking in 1992, the incidence rate has since been on the decline. This is considered to be due to the pool of latent cases being exhausted. The current consensus is that the increases are due to detection of cases that would previously have gone undetected as opposed to an absolute increase in the rate at which men get Prostate cancer. The data therefore clearly suggests that this epidemic is a result of this aggressive screening rather than a positive change in the rate of developing the cancer.

 

Table 1: Prostate Cancer Incidence Data (Florida)

Table 2: Prostate Cancer N.E Florida
Incidence & Rates (1998)

Fig 2: Age-adjusted Incidence Rates for
Prostate Cancer by Race in Florida

Fig 3: Age-adjusted Mortality Rates for
 Prostate Cancer by Race in Florida

Data accrued in Florida also not only confirms the national trend, ie., that the disease has a prediliction for older men, but obvious racial disparities are noted in that the African American men were not only more prone to get the disease but were twice as likely to present with wide spread disease and more likely to die of Prostate cancer. The Death rate in African-Americans is 2 & 1/2 times more than the rate for caucasians.

 
Fig 5: Extent of Disease by Race

Fig 6: Death Rate by Race

Table 3: Florida Distant Stage Prostate Cancer
- Percent ( Average 1981 - 1997)

Table 4: Florida Distant Stage Prostate Cancer - Rate (Average 1981 - 1997)

Table 5. Prostate Cancer Mortality
- Average (1993-1996)
White 178 22.3
Nonwhite 46 57.8
Other 0 0
Total 223 25.3
Table 6: Stage of Diagnosis for Prostate
Cancer by Race - Average (1993 -1995)
  Local Regional Distant
White 83.3 11.6 5.1
Nonwhite 78.5 10.6 10.9
       

 

Table 7: Findings of "Cancer plan 98": Duval County Health Department

  • African-American Death Rates are higher than those of white death rates
  • Cancer is found at a later stage of Diagnosis in African-American males
  • African-Americans are less likely to have a PSA performed

These issues have stimulated intense scrutiny and research. Epidemiological studies show a definite geographical and ethnic pattern pertaining to Prostate Cancer deaths. East Asian-Americans have the lowest incidence while our African-American community have the highest. Interesting geographic variations have been reported with increased death rates seen in the North West, Rocky Mountain, North Central regions, but most worrying is that in our region, the South Eastern United States, death rate clusters approaching 3 times that of the death rate for Caucasians are observed . Implicated in the etio-pathogenesis of these observations are potential susceptibility factors such as obesity, variations in dietary fats, different cooking practices, selenium intake, agricultural exposures, cadmium exposure, sexually transmitted factors, effect of multiple sexual partners, endogenous hormones & growth factors, physical activity and body size. Questions also remain whether there is an inherent genetic or biological predilection.

Furthermore, the full effect of screening & treatment practices have currently not yet been established. The obvious explanation is that African-Americans are less likely to be screened, hence tend to present with more advanced disease. The reasons for this are myriad , primarily though, poor access to care, secondary to being uninsured & being uninformed are considered to be major causative factors. Aggravating and compounding the problem is the African-American communities negative pre civil rights experience, which has left an overall inherent distrust of medical institutions, providers and interventions.

Recent data detailing the International incidence of Prostate Cancer clearly demonstrates North American rates to be dramatically higher. The results of the following study raises troublesome questions. Shimizu et al, 1 compared the rates of Prostate Cancer development in Japanese, Spanish & Non Spanish white males who had immigrated to the Los Angeles basin with the incidence rates of their cohorts in their own native countries. The startling finding was that the US immigrants had higher rates, particularly in the case of the Japanese Americans who were 3 to 4 times more likely to develop Prostate Cancer. Note the data detailed above also do not show the rates to be particularly high in the African sub-continent. However since being exposed to the North American environment, the intriguing question is has the African-American become more susceptible or can this be attributable to the more aggressive screening programs in place in the United States. Nationally, racial minorities are expected to grow from 28 % of the U.S population in 1998 to nearly 40% in 2030 and these issues and the answers to these questions are urgently being sought and need to be addressed to avoid an unacceptable toll on the Nations future economic & social fabric. In fiscal year 2000, the NIH is spending over $ 1.3 billion on research, public information & community out reach efforts to reduce these racial health disparities. Basic laboratory research underway to understand the molecular basis of Prostate cancer it is hoped will unravel the Genetic influences that play a role in accounting for the evident racial disparities. Since the early forties, it has been known that male hormones stimulate & fuel Prostate cancer. Prostate cancers androgen dependency have led researchers to evaluate if different levels are encountered in different populations. Ross R et al 2 originally demonstrated a higher mean testosterone level among college-age African-Americans compared to their white cohorts. Makridakis NM et al 3 estimate that 8% of the African-American & Hispanic men in Los Angeles are at risk for an amino acid substitution resulting in a variant of the 5 alpha-reductase enzyme which catalyzes an increased conversion of testosterone to dihydortestosterone. What apparently specifically occurs is a mis-sense substitution which results in an alanine residue being replaced with threonine, and this essentially accelerates the rate at which testosterone is converted to dihydrotestosterone.

Changes in chromosome 8,10,16 & 17 are associated with Prostate cancer, but the exact genes involved are not known. Study of Prostate tumors have commonly noted distinct alterations, namely losses of chromosomes 6q, 8p,10q, 16q and gaines of 7, 8q & Xq. Visakorpi T, 4 has suggested that the androgen receptor gene (AR), e-cadherin & the candidate tumor suppressor gene PTEN (MMAC1) are involved with the development and progression of the disease, but to date, the actual target genes for the above alterations and causation of the disease have not yet been cloned. Kantoff P et al, 5 reported that the mean number of CAG repeats was smaller in African-Americans than in whites and noted that the fewer number of CAG repeats was associated with a poorer prognosis. Men with 19 CAG repeats were 250% more likely to develop advanced disease than those with 25 CAG repeats.CYP3A4, a member of the cytochrome P450 gene family is involved with testosterone metabolism. A mutation of this gene has been identified in some older men of European American extraction which explains why they have higher basal rates of testosterone and present with higher stage disease than men without this variant. Bcl-2 oncogene immunopositive African-American men are shown by flow cytometry to have tumors with higher S phase fractions.The expression of this protein is associated with dysregulation of Apoptosis (programmed cell death) and results in unchecked cellular proliferation & oncogenesis.

Nutritional Factors

Possible nutritional factors that increase the prediliction for the disease:

  • Dietary fats with particular reference to Linoleic acid found in Red meats has been studied in its role in Prostate Cancer tumorigenesis but no epidemiological study so far has confirmed that this is a "bad fat". Associated with increased fat intake & Obesity is the presence of Insulin like Growth factor I (IGF-I) which has been linked to a greater than 4 fold increase in Prostate cancer risk amongst men in the highest percentile of IGF-I expression.This is one of the basis for the current low-fat diet recommendations being touted for Prostate cancer prevention.
  • Soy Isoflavones: Attempts at correlating the low incidence seen in Orientals with their high Soy intake compared to Americans (100 vs. 3 mgm/day) have led researchers to determine that the Soy isoflavones Genistein & Daidzein lower Prostate cancer incidence in mice by inhibiting angiogenesis & inducing Apoptosis (Programmed cell death) via IGF-I downregulation. Several anticarcinogens in addition to the isoflavones have been identified in Soybeans, such as protease inhibitors, phytate, phytosterols, saponins & lignans. Intestinal bacterial action convert isoflavones into compounds with estrogenic & antiestrogenic properties. Phytoestrogens increase hepatic synthesis of serum sex hormone binding globulin, (SHBG) which results in decreased bioavailability of Testosterone. Lignans decrease cytochrome P450 enzyme aromatase, inhibiting conversion of androgens to estrogens, which would otherwise prevent Prostate cancer from developing. Therefore, in addition to the above antiproliferative properties, these Soy products & Isoflavonoids with their molecular structure similar to steroids are thought to modulate the metabolism of testosterone and its effect on target tissues.
  • Vitamins: Various double blind, placebo controlled studies using the following Vitamin A, E & C by themselves or in combination have shown little influence in affecting the onset of the disease but subset analysis of some of these studies have shown a trend that these vitamins may confer some protection against the disease. Vitamin E is an antioxidant, preventing free radical damage in biotical membranes & critical cellular proteins and DNA. Specifically, studies have shown it plays an important role in preventing the conversion of latent cancers to clinically aggressive disease. Vitamin D deficiency secondary to reduced Ultraviolet radiation has been implicated as a potential causative factor in African-Americans. Calcitriol, in the lab, has been shown to inhibit Prostate cancer cell lines. Seleniums' active metabolite, selenomethionine induces aberrant mitoses and apoptosis in cancer cell lines and dietary deficeincies in this anticarcinogen may be a contributory factor. Zinc is normally found in high concentrations in prostate tissue but markedly less so in prostate cancer cells, leading to investigational work that has confirmed that zinc causes apoptosis and cell cycle arrest in cancer cell lines. The postulate is therefore that zinc deficiencies may result in Prostate cancer.
  • The presence of Tomato Lycopenes in the diet has been shown in studies to actually confer protection from developing Prostate cancer. This is the predominant carotenoid in western diets and is the most abundant carotinoid in human serum. In addition to being a free radical scavenger and a powerful antioxidant, lycopenes induce cell-cell communication and exert an influence on growth control. Numerous studies have shown categorically the inverse link between a diet high in tomato lycophenes and Prostate cancer.

Effect of Race on Survival

The data available legitimize & establish the facts that not only do African-American men have a higher incidence of the disease, but that they present with more advanced disease at diagnosis. Whether this is due to deficient & inadequate screening or whether in fact African-Americans have more biologically aggressive disease is being intensely debated and conflicting data are being reported. A study by Powell et al, 6 which examined autopsy data of young men in 3 age groups, (20-29, 30-39,& 40-49 years) showed that the age of onset of the disease was similar between African-American & White men.

Subsequent examination of the Surveillance, Epidemiology and End Results (SEER) database for age-specific incidence rates of metastatic Prostate cancer demonstrated across the board that for all age groups examined that African-American men categorically had a higher incidence of metastatic disease. The conclusion was that despite the fact that the two races had similar ages of onset but different rates of metastatic disease when controlling for age, the disease must therefore be more biologically aggressive in African American men younger than age 70. A randomized clinical trial, that accrued 1387 patients with metastatic disease, was conducted by the South West Oncology Group (SWOG), to study the effect of the antiandogen Flutamide after orchiectomy. A retrospective analysis of this data by Thompson et al, 7 was done to ascertain in this group of men with metastatic disease, whether race was indeed independently associated with poorer survival. Univariate analysis of the data revealed that African-Americans had more advanced disease, more symptoms in terms of pain and lower performance status. Multi-variate analysis noted that even after controlling for disease extent, performance status, bone pain & age , Race was not only a highly significant independent predictor of poorer survival but also a harbinger that seemed to result in an inferior quality of life experience. Roach et al, 8 did a similar retrospective analysis of data which involved 2012 men from four Radiation Therapy Oncolgy Group (RTOG) prospective randomized clinical trials.(1976-1985) Though univariate analysis appeared to demonstrate that African-American men had lower overall & disease free survival, multvariate analysis of the data demonstrated that when factors such as Stage at presentation and Gleason Grade of cancer were corrected for, Race was then no longer a predictor of worse outcomes. Though the RTOG findings appear to conflict with that of the two, it has been noted that the RTOG patients studied were those diagnosed in the pre PSA era, so it was entirely possible that the patient cohorts encountered today would perhaps behave differently.

Correcting for this possible bias, more recent post PSA era data by Vijaykumar S et al 9 reported results of RTOG 94-12 a multi-center prospective randomized study where they analyzed 709 newly diagnosed nonmetastatic Prostate Cancer patients (17.5% African-American) and documented that African-Americans have a higher serum PSA levels than whites (14.68 vs.9.82 ng/ml, p=0.0001) at diagnosis, implying a higher tumor cell burden. Since this was a multi-center study, (65 institutions & covering 26 states) the data could be analyzed by zip code and place of residence, and therefore a wide geographic region. Though lower socioeconomic status measured by educational level & income was associated with higher PSA for both ethnic groups, the Race factor clearly portended more serious disease for African-Americans. Most notably, PSA levels of well educated, high income African-Americans were higher than their white counterparts. Narain et al, 10 found no difference in biochemical recurrence rates ( 22% vs. 25%) following Radical Prostatectomy in 671 patients (1991 - 1996) when controlling for Race & Family history. Though the follow up was relatively short (34 months), the patients were appropriately stratified for disease extent and Gleason Grade.

This most important reassuring finding appears to indicate that once the cancer is treated, Stage for Stage, patients do equally well, regardless of their race. A Louisiana State University Medical center study 11 have recently confirmed the above with their analysis of 205 mixed race patients with early disease. Though the African-Americans had a higher PSA indicating more advanced disease at Presentation, no Biopsy or pathological variables was found to be different. Specifically, they looked at the ultrasound volume, Gleason grade, millimetres of cancer in the biopsy specimen and percentage of actual cancer within the biopsy specimen, but none of these were statistically significantly different. This again indicates that Stage for Stage there are no differences in apparent Biological aggressiveness, thereby detecting and treating the disease early in African Americans is probably the winning formula that will even out the mortality rates.

Therefore it is fair to state that though the data has serious implications, the answers are far from resolved and in fact to address this issue the National Cancer Institute, (NCI) and the other groups are studying whether barriers to early detection and treatment or true biological differences exist to explain the current data.

Preventive Measures

Prostate cancer has a latent period in excess of 10 years. Genetic alterations and loss of cellular control functions occur over many years. Like in other epithelial cancers the natural progression of cell & tissue phenotype changes is from normal to dysplasia, ie, from prostatic intra epithelial neoplasia (PIN) to severe dyplasia high grade (HGPIN), to superficial cancers onto invasive disease. Clinical trials attempting chemo prevention will soon be underway to study the effects Soy & Tomato products into the diets of adolescents belonging to susceptible ethnic groups, in a bold attempt to thwart the disease. Similarly Vitamin D, E & Selenium have been identified as potential chemopreventative agents. An excellent review reported by Thompson, D & Hopkins R , 12 Prostate Cancer Incidence & Mortality Rates for Florida by Race & Age 1990 - 1997 published on the world wide web by The Florida Dept of Health, Bureau of Epidemiology is available for review on the following web :http://www.doh.state.fl.us/disease%5Fctrl/epi/cancer/prostate.pdf .

Bureau of Epidemiology

"Expected deaths" in the graph were computed by applying white cancer death rates to the black population. The "Excess deaths" are represented by parts of the graphs above the expected deaths & are constituted by combining "Deaths attributed to a high Incident rate" with the "Deaths attributed to a high Mortality rate". The component of excess deaths, labeled " Deaths attributed to High Incident Rate", depict the deaths, that could be avoided if the black incidence rate, was reduced to the level of the white incidence rate. Similarly, the component labeled "Deaths attributed to High Mortality Rate" are considered those due secondary to the higher inherent death rate seen in African-Americans. It is considered that this could be eliminated by better screening and treatment, while the excess deaths due to higher incident rates could be eliminated by reducing risk factor exposure. The above statements in an essence distills the strategies that are currently being employed to combat this disease, ie., prevention & early detection. The latter enables the disease to be diagnosed at an earlier Stage when treatments are likely to be more efficacious.

The use of Complementary & Alternative medicine agents in persons at high risk of getting Prostate cancer, namely African-Americans and those with a family history has been estimated to range from 25 to 80 percent. 13 Patient frustration with conventional remedies, sense of self empowerment and the current fad that all things "Natural" must be good is fueling this increased use. PC-SPES is one such commercially available capsule comprised of 8 different herbs with documented anti-estrogenic activity. The exact proportions of the herbs is unknown but apparently no estrogen is included. More than one study on patients with Prostate Cancer have shown a decrease in testosterone & PSA, reduction in the tumor volume, improvement in bone metastasis and decreased narcotic requirement. Mechanism of action is purported to be due to promoting Apoptosis & decreasing the expression of the androgen receptor. The consequence of the latter would be prevent Testosterone from binding and activating Prostate cell growth. Side effects that have so far been encountered include, significant Gynecomastia, breast tenderness, loss of libido, venous thrombosis and pulmonary Embolism. The above toxicities justify the calls for it to be used under medical supervision. Since it costs about $162-486 per month, 14 and as it is not as yet reimbursed by Medicare or Private insurance, it is fortunately unavailable for the majority. The public needs to be informed that long term effects and the efficacy of PC-SPES in preventing cancer are far from known. Its potential benficial effects need to be compared to currently available Estrogens and other agents. Therefore until long term studies are available, its use in the prophylaxsis arena should not be encouraged. Along these lines the following NCI studies have been designed to evaluate and answer some of these questions.

The SELECT (Selenium & Vitamin E) study, launching in 2000 is a multi-center, placebo controlled Phase III, 12 year study to determine whether these two agents have a protective effect and can successfully prevent Prostate cancer. 15 The NCI in June of 2000 has sponsored a Prostate cancer chemoprevention Phase I study of Lycopene, the carotenoid antioxidant found in Tomatoes. Similarly, a Phase I study of the Soybean phytochemical Genistein has been ongoing since 1999 on patients with advanced disease to establish its efficacy and toxicity profile before chemoprevention studies can be instituited. 16 Efforts are being made to inform the public that until the results of the above and other studies are available, it is currently unknown whether any benefit is confered by supplementing a nutritionally adequate diet with Vitamin E, Selenium, Lycopene or Genestein.

An encouraging and definitely noticeble declining trend has been apparent in Prostate Cancer deaths over the past decade.

Fig 7: Decreasing Prostate Cancer Deaths

 

Table 8: Prostate Cancer Mortality Data
INCIDENCE / MORTALITY (Rate/100,000)

1990 2439/24.9
1991 2433/23.7
1992 2520/23.9
1993 2508/23
1994 2566/22.4
1995 2535/21.5
1996 2511/20.8
1997 2520/19.9
1998 2372/19.3

Oncologists & Urologists believe that the main reason for the improvements are the efficacious curative treatments that are currently available for early cancer. Long term results (10 year follow-up) of studies 17 are today available that unequivocally prove that excellent & equivalent cure rates can be obtained with either Surgery or Radiation therapy alone or in various combinations with or without adjuvant hormone therapy. Combination regimens of 3-Dimensional CT Treatment planned External Pelvic irradiation with Radioactive seed implants are often recommended when aggressive local disease is suspected. These techniques allow for higher tumoricidal doses (in excess of 13,000 cGy) to be delivered to the Prostate & immedeate extra-prostatic tissues and yet safely deliver 4500 cGy to the lymph node basins at risk where occult disease is often present. Sophisticated CT based treatment planning allows for the tailoring of the treatment fields to spare normal tissue and serious adverse effects are usually less than 3% with potency being preserved in the majority. Chemotherapy regimens today are usually reserved for Hormone refractory advanced disease with excellent palliation being reported.

The available data should put to rest the initial controversy which questioned whether Early Detection was really beneficial or whether it resulted in exposing many men to needless treatment. Currently the view that predominates is that if a person has a life expectancy of greater than 3 to 5 years and is otherwise relatively functional he should be offered some form of treatment. Obviously, not all patients should therefore be offered treatment. Hormonal manipulation alone serves only to temporarily delay the inevitable failure which then exposes the patient to the rigours of untreated disease, namely bleeding obstructive urinary & rectal symptoms, lymphedema, pelvic & pereneal pain & eventually painful metastatic bone disease.An additional beneficial trend unveiled by the recent epidemiological data is that the early detection programs have resulted in far less patients presenting today with advanced disease.

The American Cancer Society currently recommends that Men should be counselled regarding the potential risks and benefits of Early detection and treatment. Current screening protocols recommend that men over 50 have an Annual Digital Rectal Exam and the Prostate Specific Antigen blood test. For those men with a family history and for African-Americans, the above screening procedures are advocated from age 45 onwards.In conclusion, with reference to Prostate Cancer, it is important to acknowledge that Racial disparites do exist today. This is an intolerable state of affairs. With better understanding of the processes involved, willingness to do the required hard work in a coordinated fashion in the multiple arenas outlined, it is hoped that in time, these inequities will be overcome, and eventually disappear.

References

  1. Shimizu T, Ross RK, Bernstein L, et al, Cancer of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer. 1991;63:963-966.
  2. Ross R et al, J.Natl. Cancer Inst. 76:45-48;1986
  3. Makridakis NM et al, Lancet 1999 Sep 18;354(9183):975-8
  4. Visakorpi T, Ann Chir Gynaecol 1999;88(1):11-6
  5. Kantoff P et al, Focus Newslett. Harvard Med. Dent. Public Health Schools June 6:1-2; 1996
  6. Powell et al, Abstract from American Urological Associations 95th Annual meeting; April 29-May 4, 2000; Atlanta, Georgia. Abstract 243,6.
  7. Thompson et al, Abstract from American Urological Associations 95th Annual meeting; April 29-May 4, 2000; Atlanta, Georgia. Abstract 242
  8. Roach et al, Int. J.Radiat. Oncol. Biol. Phys. 24:441-449:1992
  9. Vijaykumar S et al, Int. J.Radiat.Oncol. Biol. Phys. 40:17-25:1998
  10. Narain et al, Abstract from American Urological Associations 95th Annual meeting; April 29-May 4, 2000; Atlanta, Georgia. Abstract 240
  11. Bozeman, C et al, South Med J 93(4): 400-402: 2000
  12. Thompson, D & Hopkins R , Prostate Cancer Incidence & Mortality Rates for Florida by Race & Age 1990-1997 published by The Florida Dept of Health, Bureau of Epidemiology http//www.doh.state.fl.us/disease_ctrl/epi/cancer/cancerindex.htm
  13. Nam, RK et al, J Urol. 1999;161:1521-24
  14. Moyad MA et al, Urol. 1999;54:319-23
  15. Brawley, OW et al, Eur J Cancer 2000;36: 1312-1315
  16. Woo, EW et al, Onc issues, 2000;15 (6): 23-27
  17. Holm, HH Semin Surg Oncol 1997 Nov-Dec;13(6):431-7   

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