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Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4452-4455 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.119
Increasing Access to Clinical Cancer Trials and Emerging Technologies for Minority Populations: The Native American Project
John T. Vucurevich Cancer Care Institute, Rapid City, SD, and Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI There are differential trends in cancer detection, treatment, clinical trials participation, and treatment outcomes among various US subpopulations.1-4 For example, prevalence of colorectal cancer in Alaskan native men and kidney cancer in Southwestern American Indian men is higher than in any other racial or ethnic group.4 There are also differences in the type and intensity of treatment offered to patients and in their overall health, as African Americans have a decreased likelihood of surviving 5 years after diagnosis compared with whites for all cancer sites and at all stages of diagnosis.5 While numerous studies document the existence of health disparities, the causes are complex, not well studied, and not fully understood. Ethnic minorities are under-represented in clinical trials, and access to experts and high-technology care is often limited. Because of these factors, minority populations are not as likely to benefit from the rapid progress being made in cancer research. The net result is more advanced disease at diagnosis, lower survival, and higher cancer death rates among certain US population groups. Because the populations served by these institutions tend to access the health care system in more advanced stages of their disease, radiation oncology represents a major treatment modality. Hospitals that provide radiation oncology services to a large number of low-income ethnic minority populations are often not linked to the nation's cancer research effort, and struggle to maintain state-of-the-art cancer care. Increased involvement of these institutions is necessary in order to develop a stronger national cancer research effort aimed at understanding and addressing the disparities of cancer incidence and mortality in special populations. The National Cancer Institute (NCI) initiated the Cancer Disparities Research Partnership (CDRP) program to develop stable, long-term radiation oncology clinical research programs, and to increase participation in clinical trials for institutions that serve a disproportionate number of ethnic minority patients. The long-term goal of the CDRP program is to better understand the causes of cancer health disparities and to develop effective interventions to eliminate these disparities. This cooperative agreement requires a partnership between a community-based grantee and one or more major national cancer centers. This commentary introduces the concepts behind the CDRP and gives an example of one of its programs. The current CDRP program has six grantee institutions—two were awarded grants in 2003 and four in 2004. Rapid City Regional Hospital (RCRH; Rapid City, SD), and Laredo Medical Center (Laredo, TX), were the initial grantees. RCRH partnered with two institutions, the University of Wisconsin Comprehensive Cancer Center (Madison, WI) and the Mayo Rochester Comprehensive Cancer Center (Rochester, MN). In that it is a cooperative agreement, all the grantees and partners share experience and expertise, an effort that is coordinated by the NCI Radiation Research Program. The Lakota, or Western Sioux, population of western South Dakota experiences significant cancer-related health disparities. In a review of tumor registery data from 1990 to 2000 at the RCRH, Native Americans present with more advanced stages of cancer, and therefore suffer from higher cancer mortality rates compared with the non-Native American population (Table 1). The age-adjusted cancer mortality for Northern Plains Native Americans is 232 v 166 per 100,000 for the general population.6
RCRH is the sole health care provider located in a town of 70,000 people. It serves all of western South Dakota and parts of adjacent states, including four large Indian reservations in western South Dakota, and other smaller Native American communities in the region. Its "service-basin" incorporates a geographic area of some 250,000 square miles, with a population base of 350,000 (Fig 1).
The primary long-term goal of the CDRP Program at RCRH is to lower cancer mortality rates for Native Americans in the region. The following specific objectives support that goal: (1) to document the major factors responsible for cancer health disparities in the Native American population served by RCRH; (2) to determine whether shorter, but equally effective, courses of treatment will enhance the acceptability and completion rate of radiotherapy; and (3) to ascertain whether there may be a genetic basis for anecdotal reports that Native Americans experience increased radiation toxicities. Native Americans attending the cancer center live a median of 110 miles from Rapid City (Fig 1). It is postulated that the extensive travel needed to complete a traditional 6- to 8-week course of radiation may create a major barrier to seeking treatment. Therefore, clinical trials have been developed to shorten the treatment duration to 1 to 4 weeks. An unwelcome consequence of schedule-shortening or hypofractionation may be an increase in the incidence of radiation toxicities.7 To minimize the likelihood of these toxicities, all schedule-shortened protocols within this research project minimize the volume of normal tissue irradiated by using highly conformal radiotherapy technologies such as intensity-modulated radiotherapy, tomotherapy, and brachytherapy. Although the reports are for the most part anecdotal, the Native American patient population appears to be hypersensitive to fractionated radiotherapy. This hypersensitivity presents as severe skin and mucosal reactions, more severe than reactions in non-Indian populations. A possible explanation for the observed increase in toxicity is an underlying genetic susceptibility.8 This phenomenon has been observed in other conditions, perhaps most dramatically in patients with homozygous mutations of the ataxia telangiectasia (AT) gene.9 Approximately 1% to 5% of the general population is heterozygous for the AT gene. A recent report positively correlated ATM heterozygosity with increased late subcutaneous toxicities for breast cancer patients undergoing adjuvant radiotherapy.10 The incidence of the AT heterozygote within the Native American population remains unknown. We plan to investigate the baseline mutation rate of the AT gene in the Native American cancer population, to correlate this with acute and late radiation toxicities, and to compare it with a matched non-Native American cancer population from the same region. A Patient Navigator Program has been developed in Rapid City in collaboration with the NCI Center to Reduce Cancer Health Disparities (Dr Harold Freeman, Director; NCI Center to Reduce Cancer Health Disparities, Rockville, MD). This pioneering program will endeavor to provide culturally appropriate community education on cancer, screening, and treatment; to facilitate participation in the project's clinical trials and community survey; and to assist Native American patients with cancer to utilize the health care system. This "grass roots" effort is critical infrastructure for the overall project. One premise of this study is that Native Americans often do not access cancer treatments and clinical trials because of barriers, both real and perceived. Potential barriers include distance, treatment duration, acute toxicities, lack of information, personal fears, and cultural beliefs. A culturally sensitive survey has been developed to document these potential barriers and suggest possible solutions. A second survey is being developed as an educational module that will be administered to Native American patients with breast and prostate cancer—two commonly observed cancers in this population that have complex treatment choices. The purpose of the survey is to document barriers to timely screening, diagnosis, and treatment, including individual and cultural beliefs and perceptions that influence choices. Patients in western South Dakota have some of the highest mastectomy rates in the nation. A Medicare survey from 1992 to 1993 reported that only 1.4% of Medicare patients underwent breast conservation in Rapid City, SD.11 Although many reasons are cited, the distance from the cancer center is presumed to be a major impediment to breast conservation. To address the issue of treatment prolongation with external-beam radiation, a number of investigators have examined accelerated, partial-breast radiotherapy, using either external-beam radiation or brachytherapy. Eligible Native Americans patients will be able to undergo a multiplane interstitial implant in which high-dose-rate (HDR) brachytherapy will be delivered twice a day for either 4 or 5 days, using well-established criteria.12 While the majority of prostate cancer patients in the United States are diagnosed with organ-confined disease, this has not been observed in the Native American population of western South Dakota (Table 1). Dose escalation has been shown to improve biochemical control rates, especially for higher-risk prostate cancer, as recently reported in a phase III trial by Pollack et al.13 HDR brachytherapy is being increasingly used as a method to escalate dose. Some of these advantages include a potential radiobiologic rationale, markedly lower acute toxicities and improved dosimetry compared with a permanent seed boost, and elimination of radiation exposure to personnel.14-17
In the current trial, patients with intermediate- to high-risk prostate cancer will be given 6 months of a luteinizing hormone-releasing hormone agonist, either before and/or concurrent with three-dimensional conformal radiotherapy followed by an HDR boost. External-beam radiation will be given in 16 fractions at 2.2 Gy per fraction for a period of 15 treatment days. The HDR implant will deliver a minimum peripheral dose of 6.5 Gy x 3 for a period of 2 days. Assuming an Helical tomotherapy is a new form of radiation treatment delivery. While standard radiotherapy is currently given by a few static fields, helical tomotherapy delivers radiation by a rotating, intensity-modulated fan beam.18 Its superior conformal avoidance and intrinsic verification capabilities provide an extra margin of safety for adjacent normal tissues during the delivery of fewer, larger fractions. The clinical feasibility of using helical tomotherapy to deliver increasingly hypofractionated treatment courses, thereby reducing the overall treatment time for prostate cancer and other cancer sites, will be investigated. Progressively larger fraction sizes will be delivered in a phase I/II design based on both acute and long-term tolerances to the treatment. The lessons learned by the individual Cancer Disparities Research Partnership grantees, and by the collaborative effort among all grantees and partners, will be used to increase the number of clinical scientists engaged in radiation oncology research in health disparities locations, to increase the access of health disparities populations to clinical trials and emerging technologies, and most importantly (for our program), to lower the cancer mortality rates for the Native American population. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract No. N01-CO-12400 and NIH grant RFA 1U56CA99010-01. REFERENCES 1. Bobinski MA: Health disparities and the law: Wrongs in search of a right. Am J Law Med 29:363-380, 2003[Medline] 2. Geiger HJ: Racial and ethnic disparities in diagnosis and treatment: A review of the evidence and a consideration of causes, in Smedley BD, Stith AY, Nelson AR (eds): Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC, National Academies Press, 2003, pp 415-454
3. Sateren WB, Trimble EL, Abrams J, et al: How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 20:2109-2117, 2002 4. Haynes MA, Smedley BD: The Unequal Burden of Cancer: An assessment of NIH research and programs for ethnic minorities and the medically underserved. Washington, DC, National Academy Press, 1999, p 338 5. Anonymous: Cancer facts & figures for African Americans 2003-2004. Atlanta, GA, American Cancer Society, 2003-2004 6. Espey DK, Paisano RE, Cobb N: Cancer mortality among American Indians and Alaska Natives: Regional difference, 1994-1998. Indian Health Service Pub. No. 97-615-28, 2003
7. Goffman TE, Glatstein E: Hypofractionation Redux? J Clin Oncol 22:589-591, 2004 8. Weichselbaum RR, Epstein J, Little JB: In vitro radiosensitivity of human diploid fibroblasts derived from patients with unusual clinical responses to radiation. Radiology 121:479-482, 1976[Abstract] 9. Swift M, Morell D, Massey RB, et al: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831-1836, 1991[Abstract] 10. Iannuzzi CM, Atencio DP, Green S, et al: ATM mutations in female breast cancer patients predict for an increase in radiation-induced late effects. Int J Radiat Oncol Biol Phys 52:606-613, 2002[CrossRef][Medline] 11. Wennberg JE: Breast sparing surgery, in Sciences TDMSCfEC (ed): The Dartmouth Atlas of Health Care. Chicago, Ill, American Hospital Publishing, 1996, pp 128-129 12. Arthur DW, Vicini FA, Kuske RR, et al: Accelerated partial breast irradiation: An updated report from the American Brachytherapy Society. Brachytherapy 1:184-190, 2002[CrossRef][Medline] 13. Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002[CrossRef][Medline] 14. Hsu IC, Pickett B, Shinohara K, et al: Normal tissue dosimetric comparison between HDR prostate implant boost and conformal external beam radiotherapy boost: Potential for dose escalation. Int J Radiat Oncol Biol Phys 46:851-858, 2000[CrossRef][Medline] 15. Duchesne GM, Peters LJ: What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high-hose-rate brachytherapy. Int J Radiat Oncol Biol Phys 44:747-748, 1999[CrossRef][Medline] 16. Martinez A, Kestin L, Stromberg J, et al: Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: The William Beaumont phase II dose escalating trial. Int J Radiat Oncol Biol Phys 47:343-352, 2000[CrossRef][Medline] 17. Blasko JC, Mate T, Sylvester JE, et al: Brachytherapy for carcinoma of the prostate: Techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 12:81-94, 2002 18. Mackie TR, Balog J, Ruchala K, et al: Tomotherapy. Semin Radiat Oncol 9:108-117, 1999[CrossRef][Medline] This article has been cited by other articles:
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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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/ß ratio of 1.5, this fractionation schedule will deliver an equivalent external-beam dose of 82 Gy at 2 Gy per fraction. Therefore, the total treatment duration will be as short as 3.5 weeks. 
