Observations on the epidemiology and natural history of prostate cancer

OBSERVATIONS ON TIlE EPIDEMIOLOGY AND NATURAL HISTORY OF PROSTATE CANCER JAMES E. MONTIE, M.D. From the Department of Urology, Wayne State University School of Medicine, and the Detroit Medical Center, Detroit, Michigan

ABSTRACT--Objective. To place prostate cancer in an appropriate perspective by examining issues of incidence, death rates, prevalence, risk factors, and natural history. Methods. Selective literature review and extraction of data on the epidemiology and natural history of prostate cancer. Results. Prostate cancer is becoming an enormous clinical problem because of the sheer numbers of men diagnosed. A broader use of prostate-specific antigen (PSA) is likely related to a recent surge in incidence. A rather indiscriminate use of PSA is suggested by marked increase in the incidence among men > 80 years of age. Death rates from prostate cancer are relatively low when compared with other common cancers. Risk factors for prostate cancer are primarily African-American race and family history, but patients with these risks represent a relatively small amount of the total disease burden. Autopsy studies demonstrate a high prevalence of prostate cancer that may even begin at < 40 years of age. The natural history of prostate cancer is such that attempts at curative treatment can be justified in men <65-70 years of age, whereas delayed therapy is reasonable for older men. In men of 65-75 years of age, the natural history may allow several options, with patient preference generally deciding therapy. Conclusion. Recent data have enhanced our knowledge about the epidemiology and natural history of prostate Cancer, providing new insights in some areas and reinforcing traditional concepts in others.

Prostate cancer is becoming one of the more serious and controversial topics m oncology. Ten years ago, debate centered on the relative merits of radical prostatectomy versus external radiation therapy for localized disease. Although this particular issue still remains unresolved, it pales by comparison to the issues we now face. Confronted with an enormous increase in the incidence of prostate cancer, the stakes are now much higher. The potential to do good with early detection and improved therapy is offset by the concern about unnecessary detection and treatment. Many more players have recently become involved. Family practitioners, internists, biostatisticians, epidemiologists, and health policy analysts contribute expertise and opinions, much of which is difficult to integrate with the perspectives of the practitioners who actually pro, ~ d e care to prostate cancer patients. The ensuing discussion highlights aspects of the epidemiology 2

and natural history of prostate cancer that a~ relevant to a urologic practitioner in 1994. EPIDEMIOLOGY This discussion of prostate cancer focuses on incidence; mortality, risk latent cancer. The disparity between t]: incidence, and mortality of prostate established. The enormous burden society by diagnostic workups and tre as well as by the anxiety generated aT and families, is undeniable. The ii prostate cancer, relative to other ma evident from at least these dimensions. Howev~;!~ because of the relatively low mortality from prostate: cancer among younger men, the disease has traditi°~i ally received insignificant research efforts, increaS!~i~eo: understanding of factors that contribute to ~{i clinical appearance of prostate cancer may proviS¢~

UROLOGY SYMPOSIUM/ December 1994 / Volume 44, Number

Night into fundamental aspects of cancer progres-

TABLE I.

Cog. I~ClDENCE

In 1994 prostate cancer has become the most ~rnmonly diagnosed cancer in the United States. 1 It i~presents 32% of all male cancers. In 1991, prostate ~ncer in the State of Michigan was already more ~ramon than breast and lung cancer: prostate, 1358 cases; breast, 6031 cases; and lung, 6161 rases. 2 The American Cancer Society estimates there ~llbe 200,000 new prostate cancer cases in 1994 in ~he United States compared with 183,000 breast ~ancer casesl 1 This burden is not restricted to the ~ry elderly. Incidence rates per 100,000 in the State 0fMichigan (1987-1991) demonstrate that prostate ~ncer is comparable to breast and lung Cancers in the 50-59-year age range and substantially higher in ~ae60-64-year age group (Table I). In Michigan in 1991 there were 1208 prostate cancer cases, 1211 tung cancer Cases, and 108 lymphomas in white men aged < 65 years. In black men aged < 65 years, there were 192 prostate cancers, 226 lung cancers, and 34 lymphomas. The number of cases of prostate cancer has accelerated in recent years, increasing by 70% be~een 1988 and 1991 in the Metropolitan Detroit Surveillance Epidemi01ogy and End Results (SEER) database) In Michigan in 1991, incidence rates for ~he major malignancies in m e n (age-adjusted rates ~¢r 100,000) were: prostate, 167.2; lung, 86.2; colon, 41.9; bladder, 3t.9; and non-Hodgkinls [ymphoma, 17.5. l° The cause of this "epidemic" is ~nlikely to be a change in biologic characteristics of the disease but more certainly due to improved detection. Prostate cancer is strongly associated with increasing age; therefore some increase in the number of cases can be expected from the aging of our population. In the early 1980s, transrectal ultrasonicguided biopsy vastly simplified the diagnostic proeess and contributed to the modest increase in incidence from 1983 to 1988. Beginning in 1989, based on data from the Detroit SEER program, the incidence began a sharp r i s e 3 (Fig. 1). The most plausible explanation for this dramatic increase is the increasing use of prostate-specific antigen (PSA) in early detection practices. Demers et al. have recently examined incidence data supporting this Conclusion. The rise in utilization of PSA tests in five ~etropolitan Detroit commercial laboratories is demonstrated in Table II. Corroborative data on the role of PSA is provided by the survey of the American College of Surgeons: in 1984, 6% of men had PSA tests included in the diagnostic evaluation, whereas in 1990 the use had increased to 68%, 4

UROLOGYSYMPOSIUM /

Incidence rates (per 100,000) of several cancers in Michigan, 1987-19912

Age (yr) 55-59 60-64

Prostate (Men) 136 335

Breast (Women) 139 186

Lung 159 254

Colon 62 102

TABLE II. Frequency of prostate-specific antigen tests among five laboratories inmetropOlitan Detroit area, by calender year* Commercial Laboratory (Projection) 1 2 3 4 5 Total

1989 1990 2279 5,034 n/a 5,039 n/a 5,450 n/a 15,377 n/a 1,902 32,802

1991 12,784 12,829 14,800 44,151 3,515 88,079

1992 20,224 17,249 19,800 64,212 5,569 127,059

1993 n/a 25,788 24,900 84,500 n/a n/a

*Reproducedfrom Demers et al.3 n / a = not available.

PSA is the most effective single tool tO identify men likely to have clinically detectable prostate cancer. 5 DeteCtion by PSA has been repeatedly shown to be superior to digital rectal examination, However, it would also appear that there is a relatively indiscriminate use of PSA in the male population aged > 50 years. There remains considerable uncertainty about the benefit of active therapy for localized prostate cancer. Earlier detection of prostate cancer that might favorably impact on survival will probably be limited to men with > lO-year survival expectation. If PSA was being used as an aid for early detection in men likely to benefit, one would expect its use to be largely Rates 140 120 100 80 60 40 REMOTE

0 ~

1973

i

~

1975

t

1977

r

1979

I

I

I

I

~

t

1981 1983 1985 Yea;" of D i a g n o s i s

REGIONAL

t

I

1987

I

I

1989

I

t

1991

Rates are per 100,00O

FIGURE 1.

Incidence o f prostate cancer by stage, Metropolitan Detroit SEER Program. (Reprinted with permission from Demers et al.3)

December 1994 / Volume 44, Number 6A

3

TABLE I11.

Deaths in 1990 from several cancers in individuals < 75 years o f age 1

Cancer

Deaths

Lung Breast Colon/recturn Non-Hodgkins lymphoma

100,253 29,931 29,805 2,290

Prostate

12,423

the use of PSA for early detection nor the threat of medical malpractice for failure to obtain a PSA oi~ everyone is the solution to this complex pr0ble~ The increased diagnosis of asymptomatic localize~ prostate cancer in men > 80 years of age, whether 8~{i not they receive therapy, is unlikely to be benefiei~[ to either the patient or the healthcare system. MORTALITY

confined to men < 75 years of age. The increased incidence, largely driven by PSA, would be confined to this same age range. However, in the Detroit SEER database, the increased incidence since 1989 was even more Striking in men > 80 years of age than those 50-79 years (Figs. 2, 3). Are men > 80 years of age receiving PSA to detect a malignancy that otherwise would have gone undetected in an earlier era? These data support such an interpretation. If this conclusion is valid, clinical judgment must be questioned, and efforts are needed to educate urologists, family practitioners, internists, and the public on an appropriate role for PSA in the detection of prostate cancer. Neither prohibition of

900

Rate per

100,000

700 500 300 " 100 -80

81

82

8'3

8'4 8'5 86 8'7 Year of Diagnosis - - Whites

~-

8'8

8'9

9'0

91

Blacks

Age-specific rates (per 100,000) of prostate cancers, all stages, Metropolitan Detroit SEERProgram. (Age: 50-79 years.) FIGURE 2.

2300

/

2000-]" 1700 •- 1 . . ~

/ / ~w/

./~'~

1400 • 1100 80

81

82

83

84 85 86 87 Year of Diagnosis Whites

~

88

89

90

91

Bla(:ks

FIGURE 3. Age-specific rates (per 100,000) of prostate cancers, all stages, Metropolitan Detroit SEERProgram. (Age:

>_8o.)

4

Prostate cancer is the second most common cau~j of death from cancer in men. 1 Practitioners who ~ ! for patients appreciate not only the number of ~-~I dying from prostate cancer but also the offal protracted course of the disease, with painful b~h~i metastases that are difficult to palliate. These C~II cians find it difficult to understand how the terr/Bi~l consequences or prostate cancer can De vaewecV~'! anything but a critical healthcare problem. This concern is not universal, howew simply believe that prostate cancer is a dise; men, more of whom die with the disease tha Prostate cancer deaths do pale in comparis tremendous mortality burden from lun~ Prostate cancer causes substantially few¢ than lung, breast, or colorectal cancers in als < 75 years of age 1 (Table III). Kra colleagues6 have stressed that prostate c~ the lowest average life-years lost of all major can¢~i in men or women. These data are used to supp~!~ the position that even a perfect screening test w6~]@ not have a large impact in saving life-years f r ~ prostate cancer deaths 6,7 (Table IV). However', placed in the context of the large numbers of~ iek~ who die from prostate cancer, the total n u m b e i ~ potential life-years lost from this cancer was tlq~ among 17 malignancies examined in men. Thus; aggregate impact of prostate cancer is substantia also causes more deaths in individuals < 65 yea age than diseases receiving much more publici~ research support: cervical cancer, nephritis, lymphoma.1 Among African-American men, the { rate is at least twofold higher than in Caucasian g The disparity is more accentuated in younger mi In the 50-54 year age group, the death rate African-Americans is 3.1 times higher t h a n whites. 9 Interestingly; the prostate cancer death r,l (per 100,000) for African-American men in Mi~ : gan during 1970-1991 increased from 39 0 to 4{ a 26.7% change. For the same period, lung gan{:{ death rates increased at essentially the same r~{! 81.4 to 102.9, or 26.4% (Table IV). By compariS{!¢ breast cancer death rates increased from 34.7 to4ii;:* per 100,000 (29.5%) in African-American wo.mefi

UROLOGY SYMPOSIUM / December 1994 / Volume 44, Nurnber~:~

tABLE IV.

Potential and average life-years lost for premature death from several cancers in the United States, 19847

;potential years of life lost ~verageyears of life lost

Prostate (Men) 228,547 9.0

Breast (Women) 763,511 19.2

RISK FACTORS The 50-70% prevalence of prostate cancer in iaatopsy studies of older men essentially indicates !that being a male growing old is a strong risk factor (for prostate cancer. 1° For clinically evident disease, ace and family history have both been identified as eliable predictors of increased risk. The situation is i~omplex, however, because during risk assessment !~any individuals classified as free may actually have Clinically undetected disease.

i}i

PACE Racial variability in the incidence of prostate Cancer is striking. The highest rates in the world are ~mong African-American men; the lowest rates are ~mong the mainland Chinese. As much as a 120-fold :difference in the incidence in these two populations has been observed, n In the United States, racial differences do not appear to be related to socioeconomic status. 12 The explanation for this racial variability is unknown, but hypotheses have been based on altered endocrine metabolism, diet, or growth factor stimulation. FAMILYHISTORY There is approximately a twofold increased risk for a man to develop prostate cancer if his father or brother has the disease. 13 True hereditary prostate cancer represents a relatively small proportion of the total number of cases of prostate cancer seen. However, as with hereditary breast cancer, it appears at earlier ages ( < 55 years of age) in succeeding generations. 13 If an individual has more than two first-degree relatives with prostate cancer, his cumulative risk is approximately ninefold. 14 Fewer data are available on familial prostate cancer than other hereditary, malignancies such as colon, renal, and breast cancer. GEOGRAPHY The variability in prostate cancer incidence around the world may be partially due to racial factors. Confounding this is the observation that migration from countries with an historic low incidence to countries with higher incidence usually results in

Lung (Both Sexes) 2,870,113 13.5 (men) 14.8 (women)

Non-Hodgkins Lymphoma (Both Sexes) 348,008 15.9 (men) 16.0 (women)

incidence patterns of the host country. For example, risk of prostate cancer increases among oriental populations with migration from China or Japan to Hawaii or the United States mainland. There is a longitudinal variation as well, because the farther one lives from the equator, the higher the prostate cancer risk. 15 The highest death rate in the world (22 per 100,000) is in Scandinavian countries; Japan provides one of the lowest death rates (7 per

I00,000). DIETARY FAT Several studies suggest that dietary fat contributes to the incidence of prostate cancer. A recent study by Giovannucci et al. suggested that the increased risk was primarily due to animal fat and the strongest positive association was with red meat intake. 16 Another commentary outlines much of the supportive data that dietary fat has a role in prostate cancer and reviews several possible mechanisms. 17 VASECTOMY TWO recent studies by Giovannucci et al. 18,19 reaffirmed a weak but identifiable link between vasectomy and prostate cancer risk. A prospective cohort study showed a relative risk for vasectomy of 1.85 and a retrospective cohort study showed a relative risk for vasectomy of 1.56. These data are provocative but alternative explanations of the data are available; recommendations do not currently advocate fundamental changes in the use of vasectomy for sterilization. 2° VITAMINS Vitamin A consumption has been implicated in increasing risk for cancer and specifically prostate cancer. Theoretically, decreased vitamin A levels could increase risk for cancer by influencing cellular differentiation or lack of inhibition of angiogenesis. 21 Vitamin D3 deficiency has also been implicated as a growth factor for prostate cancer. Since vitamin D can function as a differentiating agent, lower vitamin D levels may encourage growth of prostate cancer, n The observation of geographic differences based on ultraviolet radiation exposure

UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A

5

has been postulated to be a consequence of vitamin D metabolism: less exposure to sunlight is associated with higher incidence rates of prostate cancer. ANDROGENIC HORMONES Ross et al. in 198622

and 199223 suggested increased testosterone production or 5o~-reductase activity could explain some of the racial differences noted in prostate cancer. However, three studies of prediagnostic hormone values of testosterone and dihydrotestosterone provide conflicting data with no definite association evident. 24-26 LATENT (AUTOPSY) PROSTATE CANCER The prevalence of prostate cancer in men dying of other causes clouds much of the information about the natural history of the disease. Recent data suggest that the malignancy commonly starts at an earlier age than previously thought3 ° Sakr et al. 1° have studied the prostate in 152 men < 50 years of age dying from trauma. Whole-mount step sections of the prostate were used to map early cancers and prostatic intraepithelial neoplasia (PIN). The prevalence of prostate cancer was 2 7% in men aged 30-39 years and 34% in those aged 40-49 years. The incidence in African-American and white men was similar. Also of interest in this study were the findings that more instances of multiple loci of prostate cancer were found in African-Americans compared with whites and that areas of PIN and well-differentiated cancer were geographically next to each other in only 1 of 32 cases. Studies comparing morphologic characteristics of cancers found at autopsy and those identified clinically by PSA in the same age range are not precisely available. Stamey and McNea127 suggest that only a small fraction (5-10%) of "latent" cancers are of sufficient size to be detected clinically. In a series studied by Epstein et al. 28 among patients with stage Tic (highly selected for surgery because of an emphasis on preservation of potency), only 16% of cancers had a volume of < 0.2 cm 3, were believed to have a low risk for progression, and thus were thought to be comparable to the typical latent "autopsy" cancer. Gleason grade is also important. Only a few autopsy cancers in the Wayne State series had any Gleason 3 grade carcinoma and, thus, almost all had a Gleason score of _%<4. In contrast, only 4% in Hopkins Tic series were well differentiated, 28 as were 18% in a similar series from the Mayo C l i n i c . 29 NATURAL HISTORY Prostate cancer is a heterogeneous disease. 3° In general, grade is a potent predictor of the future behavior of the cancer. The conventional wisdom in 6

urology for 40 years has been that aggressive lod{~ surgical therapy for localized disease (i.e., radi~ai, prostatectomy) is best reserved for men with at le~i a. 10-year life expectancy. This philosophy remaifi~ widely accepted and practiced. In 1990, 6 5 % ~ stage A (Tla and Tlb) and 17% of stage B (t2 prostate cancer were treated with expectant manage ment (observation and delayed therapy) accordi~; to an American College of Surgeons survey. 4 Mo recently, data from several studies have emphasizi again the relatively low death rate at 10 years fr8 initially localized, well-differentiated prostate canci that has been expectantly managed. 31,32 This is n{ new news. Life expectancy in the United States ~ increased so that an average 70-year-old man approximately a 10-year life expectancy. Data fr6 prostate cancer observation studies indicate that disease progression is inexorable but slow. In*i recent compilation of data from six nonrandomizet studies, Chodak et al. 32 found that metastases curred in 19%, 42%, and 74% of men with Gleag~ grades I, II, and III cancers, respectively, on~ metastases develop, the 5-year survival rate based ~i American College of Surgeons data has been eS{i mated to be 32%. 4 Thus, for example, a 60-year'6ii man with a grade II prostate cancer (moderatd differentiated carcinoma, presumably Gleason 5~{ has a 42% chance of developing metastases byii years. At least two thirds of those with metastas{! will die from prostate cancer in 5 years. At best; ~ 60-year-old man with moderately differentiated pr~{!~ tate cancer has a 30% chance of dying from prosta{~ cancer in 15 years. Using data on survival frog group pension annuities in the United States,i.! 60- Year-old man has a 72% chance of living~ to t~ ~,~ age of 75 years.33 The question is, therefore, wheth~ a 60-year-old man's chance of dying from prosta!~ cancer is similar to or greater than dying from an$ other cause. It seems that the apparently conflicting viewS, between the advocates of observation and of trea{~ ment are really not that divergent Patients with Ti~ cancers, which represent the majority of patients i~ the largest single observation series in the world, are also not generally offered treatment in the Unite{ States.31 Exceptions may be noted by some surgeon~i advocating treatment in certain individuals < 6 { years-of-age. This is not a major area of contention:~~: For patients with clinically evident disease, fe~ would deny that the benefits of local treatment fo~ men 70-75 years of age and older relative tO' preventing death from prostate cancer are smalli Treatment must be viewed in that perspective bui still may be sought by the patient. This same debar{

UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6/i

Ncurs regarding breast cancer therapy in elderly

~ 0 m e n . 34

Whitmore's classic conundrum of prostate can~er~"Is treatment necessary in those for whom it is gffective, and is it effective in those for whom it is ~ecessary? --remains one of the most insightful ~erspectives in urologic oncology. However, there {0es exist a portion of younger prostate cancer )atients in whom treatment is necessary and likely ~urative and who can be identified using currently ilable data on disease progression and on therai :

Development of distant metastases with follow-up of 4 to 9 years after iodine-125 brachytherapy35

TABLE V.

Stage and Grade

Metastases (%)

B~/NoG1 B1/No-G2 B2/No-G1 B2/No-G2 Bg-C/No-G1 B3-C/No-G2 B3-C/No-G3

14/71 (20) 12/66 (18) 19/72 (26) 56/120 (47) 9/33 (27) 35/62 (56) 5/10 (50)

~etltlC s u c c e s s .

::The natural history of prostate cancer has been determined from a series of selected patients followed with deferred therapy. 35 Does ineffective local ~erapy provide information on the natural history of ~rostate cancer? In 1970, iodine-125 (125I) brachyiherapy was initiated at Memorial Sloan-Kettering ::~ancer Center for localized disease. 36 Lymph node ~mtus was known on all patients and the analysis of @ta on lymph node-negative patients should progde a better group for comparison with surgical ~eries than observation studies that are based only on clinical staging. Despite the fact that patients had negative nodes, the metastatic rates for clinical stage B, grade MI cancers are substantial (Table V). The metastatic rate for individuals with unilateral grade I Or II disease at risk of death within 4-9 years was 18-47%. For bilateral disease, grade 1 or 2, metastaSes developed in 27-57%. If 25-50% of men develop metastases with follow-up at 4-9 years, the :10-year survival rate may well be reasonable, but many of the disease-related deaths will occur between 10 and 15 years. This metastatic rate is not dissimilar to data of Chodak et al. 32 on patients ~eated with observation only. Yet, 125I implants in the format initially delivered is viewed as ineffective treatment and has been totally abandoned in the United States even though the morbidity was very :low If it was just as good as other treatments or no .treatment, why has it been abandoned? An alternative explanation of the adverse outcome noted in the t251 data is that sublethal radiation actually makes the cancer dedifferentiate more quickly and progress more rapidly# 7 However, no confirmatory data for this hypothesis exist. It would seem plausible that data provided by ineffective local therapy can contribute information on the natural history of the disease. The following observations on the natural history of prostate cancer are offered for elucidation on the benefits of its early detection. 1. Data support treatment for men with clinically evident prostate cancer who are < 65 years of age and in good general health. 38 2. Cancers detected by PSA-based detection (Tic) UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number 6A

programs are of similar pathologic characters to small stage T2 cancers; only a fraction are potentially comparable to latent autopsy canc e r s . 28,29 In men < 65 years of age, there is no reason to believe that the natural history of these cancers will be different from those clinically detected by traditional methods. . In men aged > 70-75 years, the natural history of the disease and competing illnesses will make prostate cancer less of a threat for shortening life. Early detection of asymptomatic, localized prostate cancer in this age group makes little sense, Unfortunately, PSA is apparently being indiscriminately used in this and even older age groups. Once the diagnosis is established, unnecessary treatment may be initiated. . In the age group 65-70 (or 65-75) years of age, there is a margin of doubt. The health of the patient, characteristics of the cancer, morbidity of the treatments, and patient perceptions about the cancer all strongly influence decisions. Mthough a randomized trial of treatment versus observation with deferred therapy would be the most efficient and scientifically sound means to provide needed data, this is unlikely to be reliably accomplished in the United States. Patients perceive that the decision about therapy for a cancer is a "life and death" decision, one of the most important decisions they make in their lives• Submission of such a critical decision to a randomly assigned outcome in which one arm is no therapy is understandably unacceptable for most patients. In addition, if only a small fraction of eligible subjects--5% or less--agree to participate in such a randomized trial, can the results from this highly selected group be generalized to the rest of the population? Until data can be ascertained from epidemiologic sources on declining prostate cancer mortality, the therapy 7

decisions will be b a s e d o n p a t i e n t preference a n d the best available j u d g m e n t of clinicians. James E. Monte, M.D.

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8

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UROLOGY SYMPOSIUM / December 1994 / Volume 44, Number ~ii