Is Race an Independent Prognostic Factor - NCBI

Is Race an Independent Prognostic Factor for Survival from Prostate Cancer? Mack Roach, 111, MD San Francisco, California

frican-American men have been reported to have the highest incidence and mortality rates for prostate cancer in the world. No definitive explanation currently exists to explain these two observations. Some investigators believe that one or more of these phenomena result from biologic differences corresponding to phenotypic features called "race." Unfortunately, "race" interacts with socioeconomic status, and socioeconomic status independently affects survival from cancer.1'2 Such factors as poor health status, diet, lifestyle, and the quality of health care received are difficult to quantify, thus invoking "race" is problematic, particularly when there is no clear-cut biologic definition of what race really is. Proponents of "non-race-based" explanations argue that Scandinavian countries have some of the highest incidence/mortality rates in the world, while Africa has among the lowest mortality rates, casting doubts on the independent significance of race.3'4 If "black genes" were critical, Africans should have the highest rates, while African Americans (in whom it From the Department of Radiation and Medical Oncology, University of California San Francisco, San Francisco, California. Requests for reprints should be addressed to Dr Mack Roach, 111, 20 Castleton Place, Lafayette, CA 94549. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 90, NO. 11 (SUPPL)

is believed that 30% of their gene pool is thought to be of European origin) should have an intermediate incidence of prostate cancer.5 It is also well-known that the incidence of prostate cancer increases among Asians following their migration to the United States. Since these large variations in the prostate cancer incidence/mortality rates extend across racial lines, factors other than race must dominate the impact of race on determining incidence and mortality. Until these factors are identified and accounted for, how confident can we be invoking race as a cause? Proponents of "non-race-based" explanations also argue that since neither the increased incidence nor the differences in mortality rates between blacks and whites are unique to prostate cancer, it is unlikely that there is some special "biologic relationship" between prostate cancer and race. Proponents of "non-race-based" explanations cite the fact that numerous studies demonstrate that blacks have a higher incidence of most common cancers for which established causes are well-known (eg, lung, esophageal, and head and neck cancer). They also note a lower survival for blacks for most common tumors for which early detection and treatment are thought to be valuable (eg, breast, colon, uterine, and cervical cancer). They argue that it is far more plausible that factors contributing to the excess inciS713

RACE & SURVIVAL FROM PROSTATE CANCER

dence and mortality rates for other cancer types also contribute to the risk of developing prostate cancer risk. Because the major causes for prostate cancer remain elusive, it is difficult to exclude the possibility that exposure to some yet to be characterized factor(s) are responsible for the differences in incidence.6-29 It is somewhat easier to address the issue of the excess mortality rate. By adjusting for other well-known prognostic factors, it is possible to estimate the independent contribution to outcome attributable to race. This article addresses the question, "Is race an independent prognostic factor for survival from prostate cancer?"

MATERIALS AND METHODS Definition of Race For the purposes of this article, several ground rules must be established. First, the term "race" will be used to describe different populations in the United States, characterized as "black" and "white" based on phenotypic characteristics. Although this would seem to be an unnecessary first step, it is important to realize that in this country, individuals who are of mixed origin are categorized as being "black" even if, for example, one of their parents is half black and half white, and the other parent is white, or if the individual is of mixed AfricanAmerican and Asian descent. It is important to determine whether race has independent prognostic significance or whether it is simply associated with primary factors such as socioeconomic status or access to care. For example, during the time slavery was still legal in the United States, slaves had a very high infant mortality rate.30 It was assumed by many historians of the time that the high mortality rate was characteristic of these people of African origin. We now know that the high mortality rates simply reflected the social circumstances into which the individuals were born. Poor prenatal and postnatal care, not race, was the important explanation for the excess mortality rate. There are numerous other well-documented examples of beliefs concerning differences attributed to race that are now known to be falsehoods, supported by "well-meaning" liberal

physicians.3'

Objectivity The second rule to be applied in assessing the prognostic significance of race is that the same "objectivity" should be used as is used to answer S714

questions such as: "Does a specific type of chemotherapy prolong survival?" This type of question is best answered by conducting a prospective randomized trial. Therefore, in this analysis, data based on prospective randomized trials are emphasized whenever possible. The next best data are from retrospective subset analyses from single institutions adjusting for major prognostic factors. This assumption is based on the belief that patients treated at single institutions are likely to have received a more uniform quality of treatment. Other retrospective studies that adjust for known prognostic factors are the next most valuable source. When evaluating the prognostic significance of race, we are not asking whether stage at presentation, quality of care, or access to care contribute to mortality, but rather whether race is an independent prognostic factor. To identify papers relevant to the topic of outcome following treatment for prostate cancer and race, a literature search was conducted using "prostate cancer" and "race" as key words. An effort was made to include all papers published in the past 15 years that assessed the independent significance of race on survival or disease-free survival from prostate cancer. These papers were categorized as: * those based on prospective randomized trials, * single institution studies, or * relatively "crude" population-based studies.

RESULTS

Randomized Trials on Race and Prostate Cancer Table 1 summarizes major prospective randomized trials published that reported outcome by race. Crawford et a132 reported their results in patients with metastatic prostate cancer and found that although blacks tended to present with more advanced metastatic disease, when adjusted for the number of metastases and severity of disease, race was not an independent prognostic factor. In a retrospective analysis of 1200 men treated by three prospective randomized trials in the Radiation Therapy Oncology Group Protocols, Roach et a133 reported race did not appear to be a significant independent prognostic factor. Once again, blacks tended to present with more advanced disease as manifested by higher serum prostatic acid phosphatase. In a prospective randomized trial reported by Vogelzang et al,34 race was observed to have no influence on outcome or efficacy endpoints. Smith

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 90, NO. 1 1 (SUPPL)


Table 1. Randomized Trials Reporting Outcomes Following Treatment for Prostate Cancer by Race NED/Survival Comparable Year Study Treatment Stages Difference Care?* Comments Crawford 1990 Leuprolide +1- NA/no D2t Yes Race not significant when et al32 flutamide corrected for severity of extent of disease Kennealey 1996 D2 LHRH drugs + NA/no (based Yes Race not significant when et al36+ on updated poster bicalutamide corrected for severity of or flutamide presentation) extent of disease Roach et al33 1992 Ti NOMO XRT No/yes & no Yes Survival difference seen for thru one of three studies, probably due to differences in the T4N2MO extent of disease as suggested by higher acid phosphatase in blacks Smith et a135 1996 Refractory Systemic Yes No/no Blacks tended to do better metastatic than whites 1995 Vogeizang Goserlin vs D2t Yes NA/no Race not significant when et al34 orchidectomy corrected for severity of extent of disease *Comparable care is assumed because care was delivered on standardized protocols. tA-D staging according to the American Urologic System. tAbstracts only. NED=disease-free survival, NA=not available, and XRT=radiotherapy. et a135 reported outcome in patients with hormone refractory prostate cancer, treated on three phase II randomized trials. They found no difference in outcome by survival, although blacks tended to do better than whites. Of particular note is an abstract reported by Kennealey et al.36 These investigators initially suggested that there were differences in outcome between blacks and whites; however, by the time of their poster presentation, they concluded that race was not a significant factor. In summary, although there are scattered reports suggesting that race is an independent factor, in every major prospective randomized trial to date, race has been shown to have no independent prognostic significance.

Nonrondomized, Retrospecfive, Singlelnstitution Studies The major retrospective single-institution series reporting outcome by race are summarized in Table 2. In none of these 15 studies was race clearly demonstrated to independently impact survival. Of note, Moul et al37 concluded that race was an independent prognostic factor despite the fact that after adjustment for margin status, it was no longer statis-


tically significant. Perez et al38 found race significant in men with locally advanced disease but not with early disease. In a report by Powell et al,39 it was concluded that young black men had a lower survival but older black men had a higher survival than whites. Kim et al40 reported that blacks had much higher prostate-specific antigen levels, with the mean and median being 31.7 and 15.8 versus 71.6 and 68.4, respectively, for whites and blacks. Furthermore, 40% of blacks had high-grade tumors compared with 26% for whites (P70 years or in men with meta& district static disease *Comparable care is assumed because care was delivered at the same institution, and the same lype of treatment (surgery or XRT). tPersonal communication, Bagshaw MA, 1990. tA-D staging according to the American Urologic System. Perez et al38

1989

T3NXMO T1

-T4NXMO T1 NXMO- XRT T4NXMO

XRT

§Abstract only. NED=disease-free survival, NA=not available, XRT=radiotherapy, and PSA=prostate specific antigen.

Other Nonrandomized, Retrospective Studies Other major retrospective series reporting outcome by race are summarized in Table 3. Most of these studies suggest that there is a difference in outcome by race. However, in these studies, is it likely that the initial workup, treatment, and evaluation were not uniform. In addition, due to a lack of uniformity of treatment, these studies also are characS716

terized by "lumping" men with a wide range of stages into crude categories such as "local, regional, and distant." Because of these shortcomings, the conclusions based on the studies summarized in Table 3 cannot be assumed to be as accurate as those of Tables 1 and 2. Despite these limitations, even the studies in Table 3 raise serious doubts about the independent prognostic significance of race.



Table 3. Other Prostate Cancer Studies with Outcomes Reported by Race NED/ Survival Comparable Comments Care?* Treatment Difference Year Stages Study Based on tumor registry data in Conneticut No XRT NA/ 1993 T2-3 Austin & blacks did worse but older blacks younger yes & no Convery52 had a similar survival to that of olderwhites No Survival differences not adjusted for differNA/yes Surgery, Mettlin et al53 1994 Stage ences in stage at diagnosis radiation, I-IV

Murphy5A4

Natarajan et a155 Optenberg et al56

1981 1989

A-D Ti -4

1995

A-D2

hormonal therapy NA NA

NA/yes Yes & not

NA/no Surgery, radiation, hormonal therapy Nonstandard NA/no

No No

American College of Surgeons data American College of Surgeons data

No

Department of Defense tumor registry

Yes & no National VA data Local, regional & distant SEER data, Detroit area; no differNo NA/ NA Pienta et al58 1995 Local, ence by race in men >70 years or in men yes & no regional with metastatic disease & distant *Care is not assumed to be comparable because it was not delivered at the same institution, the same type of treatment, or on a standardized protocol. tA-D staging according to the American Urologic System. $No differences in T1;