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Originally published as JCO Early Release 10.1200/JCO.2004.03.005 on April 13 2004 © 2004 American Society of Clinical Oncology. Factors Associated With Breast Cancer Clinical Trials Participation and Enrollment at a Large Academic Medical CenterFrom the Division of Hematology and Oncology, Karmanos Cancer Institute at Wayne State University School of Medicine, Detroit, MI. Address reprint requests to Michael S. Simon, MD, MPH, Hudson Webber Cancer Research Building, 4th floor, 4100 John R. St, Detroit, MI 48201; e-mail: Simonm{at}karmanos.org
PURPOSE: The practice patterns of medical oncologists at a large National Cancer Institute Comprehensive Cancer Center in Detroit, MI were evaluated to better understand factors associated with accrual to breast cancer clinical trials. PATIENTS AND METHODS: From 1996 to 1997, physicians completed surveys on 319 of 344 newly evaluated female breast cancer patients. The 19-item survey included clinical data, whether patients were offered clinical trial (CT) participation and enrollment, and when applicable, reasons why they were not. Multivariate analyses using logistic regression were performed to evaluate predictors of an offer and enrollment. RESULTS: The patients were 57% white, 32% black, and 11% other/unknown race. One hundred six (33%) were offered participation and 36 (34%) were enrolled. In multivariate analysis, CTs were less likely offered to older women (mean age, 52 years for those offered v 57 years for those not offered; P = .0005) and black women (21% of blacks offered v 42% of whites; P = .0009). Women with stage 1 disease, poor performance status, and those who were previously diagnosed were also less likely to be offered trials. None of these factors were significant predictors of enrollment. Women were not offered trials because of ineligibility (57%), lack of available trials (41%), and noncompliance (2%). Reasons for failed enrollment included patient refusal (88%) and failed eligibility (12%). CONCLUSION: It is important for cooperative groups to design studies that will accommodate a broader spectrum of patients. Further work is needed to assess ways to improve communication about breast cancer CT participation to all eligible women.
Clinical trials (CTs) are a mechanism for testing new cancer therapies and provide opportunities for patients to be exposed to state-of-the art treatment.1-6 Despite rising breast cancer incidence,7 accrual to breast cancer clinical trials remains low,8-11 and significant barriers exist among women from lower socioeconomic and ethnic and racial minority groups.9,12-17 In the past, CT enrollment rates have ranged from 3% (breast cancer trials),8 to 14% for cancer trials overall.11 In an earlier review of CT accrual patterns at our institution, 11% (16 of 136 patients) of new breast cancer patients over a 7-month period were enrolled.10 It is important for physicians to encourage CT participation for all eligible women with breast cancer. This is especially urgent for women in the black community, among whom breast cancer mortality continues to exceed rates seen among women from other ethnic or racial groups.7,18 In an effort to better understand factors that contribute to referral and enrollment of women onto breast cancer CTs, we conducted a survey of practice patterns among medical oncologists associated with a large urban medical center. Our objectives were to better understand factors related to who are offered CT participation, and who are subsequently enrolled. We also looked at reasons why women were either not offered participation or were not enrolled.
Study Design From 1996 to 1997, over a 22-month period, we conducted a survey of the CT accrual practices among 11 medical oncologists who were members of the academic faculty of the Karmanos Cancer Institute (KCI). The KCI is a National Cancer Institute (NCI) designated Comprehensive Cancer Center, affiliated with Wayne State University, the Detroit Medical Center, and Harper University Hospital (Detroit, MI). The survey consisted of 19 items, including patient demographics, clinical data, and other information pertaining to the clinical trials accrual process for women with breast cancer (Table 1). We collected patient name, social security number, date of birth, race, Eastern Cooperative Oncology Group performance status (PS), oncologist name, referring physician name, stage, reason for the physician visit, diagnosis status (new or previous diagnosis), and treatment status (untreated or previously treated). We asked whether patients were offered CT participation and whether they were enrolled. When applicable, we asked why participation was not offered or why enrollment did not occur. An attending oncologist or physician extender filled out surveys for each new female breast cancer patient seen during the study period. Information on insurance and employment was obtained from the electronic administrative database of the outpatient clinic. There were 10 active breast cancer trials open during the study period including: four adjuvant trials (one node-negative, two node-positive, and two high-dose chemotherapy or bone marrow transplant); one dietary trial; four stage IV trials (two front-line, one second-line, one bone marrow transplant); and one radiation trial for local recurrence. The institutional review board of Wayne State University approved the survey and all active/ongoing protocols during the study period.
Analysis The primary end points were: whether patients were offered CTs participation (yes or no), and whether they were enrolled (yes or no). Independent variables included age, race, insurance, employment, stage, PS, diagnosis status, and treatment status. Race was coded as white, black, or other (Asian/Pacific Islander, Hispanic, and Arab/Chaldean). Insurance types were coded as Medicaid and Medicare versus commercial. Employment status was coded as employed (full-time, part-time, and self-employed) versus unemployed (also including retired, student, or other). Stage was defined by the American Joint Committee for Cancer Staging.19 All of the analyses were performed using SAS version 8.1 (SAS Institute, Cary, NC). Associations between primary end points and continuous variables were analyzed by Student's t tests. Associations between primary end points and categoric variables were assessed by two-sided Fisher's exact tests. Multivariate analyses using logistic regression were performed to assess associations between the primary end points and the independent variables. For descriptive purposes, population cancer statistics for 1996 and 1997 from the tri-county Detroit Metropolitan area were obtained through the NCI's Surveillance, Epidemiology and End Results (SEER) program.7 SEER staging guidelines were used to define stage for population cases.20 SEER staging is defined as local (invasive carcinoma confined to the breast), regional (invasive carcinoma spread beyond the breast, either by direct extension or to regional lymph nodes), and remote (direct extension to organs other than regional, discontinuous metastases, or to distant lymph nodes).
Questionnaires were completed for 319 (93%) of the 344 new breast cancer patient visits. Visits were classified as consult for ongoing care (45%), second opinion (32%), evaluation for CT participation (2.5%), or no reason provided (20%). Table 2 shows demographic and clinical characteristics of the study patients compared to population statistics. Women at the study site were on average younger than the women in the surrounding population (age, 55 years; standard deviation, 13.2 v age, 62 years; standard deviation, 14.4). Study site women were also more likely to be black then women in the surrounding population (32% v 19%) and to have advanced stage disease (27% stage IV v 5% remote disease). Approximately one third of study site patients used Medicare or Medicaid as their primary coverage.
Proportion of Patients Offered Clinical Trials Participation Of 319 women with completed questionnaires, there were 106 women (33%) who were offered participation (Table 3). Women were more likely to be offered participation in a CT if they were referred specifically for a CT (87%) than if they were referred for a second opinion (37%) or as a consult for ongoing care (32%). Women offered participation were more likely to be younger (mean age, 52 years v 57 years; P = .0005), white (42% of white women v 21% of black women and 22% of women from other racial groups; P = .0009), to have commercial insurance (41% with commercial insurance v 20% with Medicaid or Medicare; P = .0002), to be diagnosed with stage II cancer (50% with stage II, 19% with stage I, 27% with stage III, and 33% with stage IV; P = .0003), to have a PS of 2 or less (36% with a PS of 2 or less v 0 with a PS of 3 or 4; P = .0017), to be previously untreated (41% untreated v 25% previously treated offered; P = .053), or newly diagnosed (48% newly diagnosed v 26% previously diagnosed offered; P = .013). Employment status had no significant impact on whether a CT was offered.
Table 4 shows the results of a multivariate logistic regression analysis of factors associated with whether a CT was offered. Age at diagnosis  65 years, black race, stage 1, PS of 3 or 4, and previous diagnosis were all significant negative predictors of whether a CT trial was offered.
Proportion of Patients Enrolled in Clinical Trials Of the 106 women who were offered a CT, 36 (34%) subsequently enrolled (Table 5). Women enrolled were more likely to be previously treated (52% previously treated v 27% previously untreated; P = .041) and previously diagnosed (50% previously diagnosed v 28% newly diagnosed; P = .056). Women with stage IV disease were also more likely to be enrolled, but this was not statistically significant. Age, race, insurance, and employment status were not significant predictors of enrollment.
Reasons Why Patients Were Not Offered Participation The most common reason for not offering participation was "likely to be ineligible" (57%), followed by "lack of available protocols for stage" (41%), and concern about compliance (2.4%; Table 6). Black patients were more likely to be considered ineligible compared to white or other race patients (61% v 53%). Of the reasons for ineligibility, black patients were more likely to be considered ineligible because of poor performance status and inadequate organ function (32%) and white and other race patients were more likely to be considered ineligible because of prior or current treatment or second opinion only (53%). All five patients listed as likely to be noncompliant were black. None of the providers indicated that they disagreed with the science of the protocol, or that they did not have enough time or support to enroll patients. There was a roughly equal distribution of reasons why patients were not offered participation by age and insurance status.
Reasons Patients Were Not Enrolled For both black and white/other race patients, the most common reason for failure to enroll was patient refusal (Table 7). For white and other race patients, the most common reason for refusal was "follow-up at an outside clinic" and for black patients the most common reason was "refused protocol chemotherapy". There was a roughly equal distribution of reasons why patients refused enrollment by age or insurance type. Fourteen percent of white and other race patients failed eligibility criteria as a result of inadequate insurance, poor performance status, or other reasons. None of the black patients were listed as failed eligibility criteria.
The results of this survey are demonstrative of the problems facing accrual to cancer CTs.8,9,11,13 This issue is not unique to our institution, and similar to the disproportionate share of cancer mortality faced by minorities,21 low accrual to clinical trials is more prevalent among women from racial minority groups.12,15-17 While this report is based on practice patterns at one institution with a large proportion of minority and later stage patients, to our knowledge only one other survey of clinical trials practice patterns has been done.11 One factor that may negatively impact accrual is the low rate of referrals for consideration of clinical trials. Only a small proportion of patients seen were referred specifically for consideration of a CT, but of these women, 87% were offered participation. The low rate of referrals may be because of the increasing availability of CTs in the community2 and/or low awareness of the number and types of trials open at our center. Another barrier is the lack of available studies. Lack of an available protocol and ineligibility were the most common reasons listed for not offering CTs. Even among women that were offered a CT, an additional 12% later failed eligibility criteria. These findings are similar to those seen at the University of California Davis (UCD) Cancer Center (Sacramento, CA) where an appropriate protocol for stage and site (all cancer sites combined) was not available for 67% of patients, and an additional 5% were later found to be ineligible.11 An additional factor was the availability of a single lymph node-negative protocol that closed to accrual during the study period and the failure to open up other alternatives for node-negative patients. The trend towards higher enrollment for women with stage IV disease may reflect the lack of other good treatment options for these women in contrast to numerous adjuvant treatments available for women with earlier stages. Of significant concern is the low rate of minority participation in cancer and other clinical trials.15 Since results from CTs are used to set national standards for treatment, low participation of minority groups questions the generalizability of findings.14 The results reported suggest that age and race influence which patients are offered CTs, but once women are offered participation, age and race have no impact on enrollment, suggesting that more women would enroll if they were provided the opportunity. In a previous report, older age had a negative impact on accrual, but race had no impact.10 Blum et al9 showed that almost one third of patients at two New York City hospitals were not eligible because of issues related to medically undeserved populations, while in contrast at the UCD cancer center, neither age nor race had an impact on protocol accrual and women with private insurance were less likely to be enrolled.11 It is interesting to note that for black patients, "likely to be ineligible" was checked as a reason more often than for white patients. Also for blacks, poor performance status and inadequate organ function were the predominant reasons listed for ineligibility, while for white patients, "prior or current treatment" and "second opinion" were more commonly listed. These results suggest that other factors that influence the rates of comorbid conditions among blacks and whites with breast cancer may negatively affect the opportunity for black patients to participate in clinical trials. While provider encouragement is important, other patient-related factors may also be relevant. Surveys have shown that up to 85% of cancer patients are unaware of clinical trials as an option, and among patients who are aware of clinical trials, many had common misperceptions about trials.22 These perceptions are present despite legislation passed by many states that require health insurance plans to cover clinical trials costs.23 For minority women, lack of information has been cited as a significant barrier to participation.24 Fouad et al,16 using focus groups, found that the majority of patients are unclear about the nature of clinical trials, and Brown et al14 found that women across different racial groups had little or no knowledge about clinical research, with the lack of knowledge more prevalent among minority women. Whereas physician referral and encouragement is essential, improving patient knowledge and demand for clinical trials may have a significant impact on whether they are offered participation. The results of this survey show that almost 90% of all patients, and 100% of black patients who were offered participation, and who did not enroll, refused which is in contrast to a refusal rate of 49% of eligible patients at the UCD.11 Recently, the NCI has developed a series of high-quality patient education materials, which includes a 19-minute educational videotape titled "Cancer Clinical Trials: An Introduction for Patients and Their Families Which is Currently Undergoing Testing at our Institution". At the Karmanos Cancer Institute, a new initiative entitled, "The IRIS Project: Information, Resources and Individual Support for Breast Cancer Patients in Clinical Trials", is one attempt to overcome patient barriers. Other national efforts have been made towards recognizing and addressing provider concerns regarding CTs. In a meeting of physicians from the Eastern Cooperative Oncology Group and the National Medical Association, new strategies were developed to improve minority accrual.25 It is important for medical providers to improve communications with patients about treatment options and for cooperative groups to design studies that will accommodate a broader spectrum of the population.
The authors indicated no potential conflicts of interest.
Supported in part by the National Action Plan on Breast Cancer Small Grant, Contract Number CA 95-016, the Barbara Ann Karmanos Cancer Institute Core Grant CA-22453, and the United Foundation of Detroit. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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7. Howe HL, Wingo PA, Thun MJ, et al: Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93:824-842, 2001 8. Johansen MA, Mayer DK, Hoover HC Jr: Obstacles to implementing cancer clinical trials. Semin Oncol Nurs 7:260-267, 1991[CrossRef][Medline] 9. Blum RH, Alter RS, Wasserheit C, et al: Assessment of barriers to minority participation in therapeutic cancer protocols. Proc Am Soc Clin Oncol 14:162, 1995 (abstr 340) 10. Simon MS, Brown DR, Du W, et al: Accrual to breast cancer clinical trials at a university-affiliated hospital in metropolitan Detroit. Am J Clin Oncol 22:42-46, 1999[CrossRef][Medline]
11. Lara PN Jr, Higdon R, Lim N, et al: Prospective evaluation of cancer clinical trial accrual patterns: Identifying potential barriers to enrollment. J Clin Oncol 19:1728-1733, 2001 12. Roberson NL: Clinical trial participation. Viewpoints from racial/ethnic groups. Cancer 74:2687-2691, 1994 (suppl 9)[CrossRef][Medline]
13. Swanson GM, Ward AJ: Recruiting minorities into clinical trials: Toward a participant-friendly system. J Natl Cancer Inst 87:1747-1759, 1995 14. Brown DR, Fouad MN, Basen-Engquist K, et al: Recruitment and retention of minority women in cancer screening, prevention, and treatment trials. Ann Epidemiol 10:S13-S21, 2000 (suppl 8)[CrossRef][Medline] 15. Fouad MN, Partridge E, Green BL, et al: Minority recruitment in clinical trials: A conference at Tuskegee, researchers and the community. Ann Epidemiol 10:S35-S40, 2000 (suppl 8)[CrossRef][Medline] 16. Fouad MN, Partridge E, Wynn T, et al: Statewide Tuskegee Alliance for clinical trials. A community coalition to enhance minority participation in medical research. Cancer 91:237-241, 2001 (suppl 1)[CrossRef][Medline]
17. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998 18. Simon MS, Severson RK: Racial differences in survival of female breast cancer in the Detroit Metropolitan Area. Cancer 77:308-314, 1996[CrossRef][Medline] 19. American Joint Committee on Cancer. Manual of staging for cancer, in Beahrs O, Hensen D, and Hutter R (eds): Manual for staging of cancer. Philadelphia, PA, JB Lippincott, 1992 20. Henson DE, Ries L, Shambaugh EM: Survival results depend on the staging system. Semin Surg Oncol 8:57-61, 1992[Medline] 21. Edwards BK, Howe HL, Ries LA, et al: Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94:2766-2792, 2002[CrossRef][Medline] 22. Harris Interactive. Misconceptions and lack of awareness greatly reduce recruitment for cancer clinical trials. Healthcare News at http://www.harrisinteractive.com/about/vert_healthcare.as0. January, 2001 23. MCC Update. A newsletter of Michigan Cancer Consortium Initiative on the latest health care information. http://www.michigancancer.org.2002 24. Pinto HA, McCaskill-Stevens W, Wolfe P, et al: Physician perspectives on increasing minorities in cancer clinical trials: An Eastern Cooperative Oncology Group (ECOG) Initiative. Ann Epidemiol 10:S78-S84, 2000 (suppl 8)[CrossRef][Medline]
25. McCaskill-Stevens W, Pinto H, Marcus AC, et al: Recruiting minority cancer patients into cancer clinical trials: A pilot project involving the Eastern Cooperative Oncology Group and the National Medical Association. J Clin Oncol 17:1029-1039, 1999 Submitted March 3, 2003; accepted December 8, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
