1. Clinical Trials that Address Health Care Disparities Daniel G. Petereit, MD Department of Radiation Oncology University of Wisconsin Medical School University of South Dakota Medical School Rapid City, South Dakota e-mail: dpetereit@rcrh.org John T. Vucurevich Cancer Care Institute R APID C ITY R EGIONAL H OSPITAL R APID C ITY R EGIONAL H OSPITAL

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3. Clinical Trials that Address Health Care Disparities Historical background –Minority mistrust research CDRP Trials –Cooperative Group –CDRP trials –Other: behavioral, molecular Successful Recruitment Clinical Trials Future trials

4. Tuskeegee Syphilis Study Purpose: To observe the natural history of syphilis Subjects: African American men in rural Alabama (N=405, 1932-72) Men diagnosed with syphilis were enrolled and examined periodically, but not given treatment for their disease Treatment was withheld to preserve the study even after it became generally available No informed consent for participants

5. Removal Policy: Eastern Tribes “Trail of Tears”

6. Trail of Tears Federal relocation program of American Indians to Oklahoma 1830-1860 Majority relocated under President Andrew Jackson 60 Tribes, including 5 “civilized tribes” Tens of Thousands died in route Historical trauma Massacre at Wounded Knee, SD –Recent memory?

7. 1960-1970s Sterilization of AI Women American Indian women were sterilized at selected IHS clinics during the 1960s and 1970s 3,406 sterilizations in 3 IHS Areas between 1973 and 1976 No informed consent, no 72H waiting period, no right to withdraw US Department of Health, Education, and Welfare, Office of the Secretary “Sterilization Guidelines,” Federal Register 38 August 3, 1973; pp. 20 930-31 and September 21, 1973, pp. 26 459-61. Also Federal Register 39 April 18, 1974. pp.13 873 Government Accounting Office (GAO), Comptroller of the United States, Investigations of Allegations Concerning Indian Health Services; Washington, DC. US Government Printing Office, November 4, 1976.

8. Native American Cancer Research http://www.NatAmCancer.orghttp://www.NatAmCancer.org Linda Burhansstipanov, MSPH, DrPH

9. CDRP: Supporting the Nation’s Goal of Eliminating Cancer Health Disparities Increase minority access to and participation in radiation oncology clinical trials Increase the number of clinical and translational scientists studying cancer disparities Develop new institutions’ ability to engage in long-term research efforts Investigate new areas of health disparities research

10. Clinical Trials that Address Health Care Disparities Historical background –Minority mistrust research CDRP Trials –Cooperative Group RTOG, ECOG, NSABP, NCCTG, GOG –CDRP trials: PI initiated –Other: behavioral, molecular Successful Recruitment Clinical Trials Future trials

11. Successful Cooperative Group Trials: Recruitment CDRP Sites NSABP 35: anastrozole vs tamoxifen in postmenopausal DCIS patients undergoing lumpectomy & radiation therapy RTOG 245: PET pre and post treatment assessment for locally advanced NSCLC RTOG 0315: Phase III Study to Determine the Efficacy of Octreotide in Reducing Severity of CT/XRT-Induced Diarrhea Anal or Rectal Cancer RTOG 0321: Phase II Trial of HDR and EBRT Prostate CA NSABP, CALBG Breast cancer studies that include a radiation component

12. Moderately Successful Cooperative Group Trials: Recruitment CDRP Sites RTOG 9804: Phase III Trial Observation +/- Tamoxifen vs. RT +/- Tamoxifen for Good Risk DCIS NSABP B-39: Phase III Trial WBRT vs APBI RTOG 0232: A Phase III Study EBRT & PSI vs PSI Alone for Intermediate Risk Prostate CA Carcinoma NCIC MA20: A Phase III Study of Regional Radiation Therapy in Early Breast Cancer RTOG 0247: Phase II Trial of Neoadjuvant Combined Modality Therapy for Locally Advanced Rectal Cancer

13. Moderately Successful Cooperative Group Trials: Recruitment CDRP Sites RTOG 0433: Phase III Trial of Single Versus Multiple Fractions for Re-Irradiation of Painful Bone Metastases RTOG 0215: Treatment of Erectile Dysfunction in Patients Treated with Neoadjuvant Androgen Suppression and Radiotherapy for Prostate Cancer: Impact on Patient and Partner Quality of Life RTOG 9813: Phase III Study of EBRT & TMZ vs EBRT and Nitrosourea for Anaplastic Astrocytoma and Mixed Anaplastic Oligoastrocytoma RTOG 0229: Phase II Trial of Neoadjuvant Therapy with Concurrent Chemotherapy and High Dose Radiotherapy Followed by Surgical Resection and Consolidative Therapy for Locally Advanced Non-Small Cell Lung Carcinoma

14. Successful CDRP Trials: Recruitment IMRT H&N Trial –PI: Patrick Maguire, MD –New Hanover Regional Medical Center Phase II Trial APBI for DCIS using MammoSite brachytherapy –PI: Oscar Streeter, MD –USC, Centinela Freeman: David Khan, MD Rapid City Trials: PI: Daniel Petereit, MD Surveys: general, cancer, navigation IMRT / Tomotherapy Prostate Trial HDR Prostate Trial HDR Breast Trial ATM Trial

15. Phase II Trial of Hyperfractionated IMRT with Concurrent Weekly Cisplatin for Stage III & IVa Head & Neck Cancer PI: Patrick D. Maguire, M.D. New Hanover Radiation Oncology Designed & opened in community with IMRT planning advice from university

16. Breast Brachytherapy

17. Partial Breast Irradiation for DCIS Using MammoSite Brachytherapy: A Phase II Trial Oscar Streeter, Pamela Benitez, Frank Vicini et al. N =133 patients enrolled, Eligibility criteria: age > 45, unicentric DCIS, m size < 3 cm, negative margin 1mm 34 Gy in 10 fractions BID, 1 cm peripheral to the balloon surface 133 patients enrolled, MammoSite was placed in 117 patients, and 17 explanted – 25% not eligible for intracavitary method – < 5 mm skin bridge (5%), poor cavity conformance (5%), positive margin (3%), final histology (1%), MD decision (1%)

18. Phase II Trial HDR Brachytherapy Stage I and II Breast Cancer: Rapid City PI Petereit Similar criteria as previous APBI RTOG trial 34 Gy/10 Fxs Endpoints: Evaluate the rate acute, late toxicities Efficacy, local control, cosmesis 16 pts enrolled out of 100 (3 AIs) Majority interstitial technique 2 G3 toxicity: recurrent infection requiring drainage Mammosite technique Mainly interstitial technique

19. Phase II Study HDR Brachytherapy Intermediate Risk Prostate Cancer – Rapid City PI Petereit Patient eligibility: intermediate, high-risk prostate cancer Androgen ablation: 6 to 12 months EBRT: 2.2 Gy X 16 over 15 treatment days, HDR 6.5 Gy X 3 Endpoints: Evaluate the rate acute, late toxicities Efficacy HDR boost 4 patients enrolled (0 AIs) out of 100 No G3 toxicities Lower accrual because of tomotherapy trial HDR FX schedule recently changed from 6.5 x 3, to 9 Gy x 2 to increase accrual by eliminating need for hospitalization

20. TOMOTHERAPY PROSTATE TRIAL Rapid City PI Petereit 4.3 Š 50 PTS Š 50 PTS Š 50 PTS Phase I/II Hypofractionation Trial Multi-institutional Phase I/II trial (PI: Mark Ritter, MD, PhD) -Level I/II completed (2006 ASTRO abstract #19) -160 patients: No G3 toxicities Rapid City: 30 patients enrolled (2 AIs) minimal toxicities, no G3 -Most rapidly accruing trial ever opened Level I nearly completed in Rapid City, adding 20 patients

21. ATM MUTATIONS in Native Americans: Possible Association with Cancer and Radiotherapy Toxicities PI: Petereit, DG To determine the association between ATM heterozygosity and sensitivity to radiation Gene sequencing underway Amy Moser, PhD 20 American Indians, 39 non-Natives

22. American Indians Entered on Research Trials Rapid City CDRP Era Official start of Program: June 2004 –General Survey: 713 –Patient navigation: 181 –Cancer Survey: 24 –ATM: 20 –CDRP treatment trials: 6 –Cooperative Group Trials: 6 –TOTAL: 769 - 950 if navigated pts included Number of AIs on clinical trials nationally: 7 –AACR 2006, Washington, DC

23. CDRP Enrollment Clinical Trials Centinela Freeman (PI: Steinberg, M) –26 patients on clinical trials; 208* patients navigated UPMC McKeesport (PI: Heron, D) –20 patients on clinical trials; 34 on behavioral trial; 261* patients navigated Rapid City (PI: Petereit, D) –769 patients on clinical trials (includes behavioral); 181* patients navigated Singing River (PI: Dennis, S) –6 patients on clinical trials; 353* patients navigated –Complete recovery from setbacks from hurricane Katrina

24. Clinical Trials that Address Health Care Disparities Historical background –Minority mistrust research CDRP Trials –Cooperative Group RTOG, ECOG, NSABP, NCCTG, GOG –CDRP trials: PI driven –Other: behavioral, molecular Successful Recruitment Clinical Trials Future trials

25. Successful Recruitment Clinical Trials Patient considerations –Patient preference: randomized trial often difficult (RTOG 9804), no treatment or treatment not desired –Convenience, effectiveness HDR prostate, IMRT prostate, partial breast radiation –Stage at presentation, co-morbidities, performance status MD consideration –Most effective and current regimens –B-39: surgeons preference Mammosite device –RTOG 9804- Med Oncs prefer aromotase inhibitors –NCIC MA.20: regional nodal RT: RO preference –Complexity of trial –RTOG 0229: difficulty in obtaining tissue from N2 nodes via mediastinoscopy RTOG 0412 allows for trans-esophageal biopsy

26. Successful Recruitment Clinical Trials Quality of life studies, accrual easier Non-invasive Investigator ownership RTOG 0245 study PI UPMC McKeesport Special considerations –Disparate populations Phase II: limited institutional basis Often difficult commit randomized trial, eg RTOG 0232 –Unforeseen: Katrina! Singing River

27. Successful Recruitment Clinical Trials Good studies for common cancers –How does it “fit” into community standards Community-Based Participatory Research Key to successfully enrolling AIs Western, SD Community trust is the critical issue! ATM study »Evidence of trust established AI community

28. Timeline IRB Approval 2003 - 2004 AAIRB Prot 6: Tomo Prostate Prot 3: Community Survey Prot 4: Navigator Prot 2/1: Breast Brachy - NAI Prot 5: Tomo Bone Prot 1/1: Prostate Brachy - NAI Prot 3: Community Survey Nat.IRB Prot 2/1: Breast Brachy - NAI Prot 4: Navigator Prot 5: Tomo Bone Prot 1/1: Prostate Brachy - NAI Prot 6: Tomo Prostate UW IRB Prot 2/1: Breast Brachy - NAI Prot 5: Tomo Bone Prot 2/2: Breast Brachy Prot 1/1: Prostate Brachy - NAI Prot 1/2: Prostate Brachy Prot 6: Tomo Prostate Prot 2/1: Breast Brachy - NAI RCRH IRB Prot 1/1: Prostate Brachy - NAI Prot 5: Tomo Bone Prot 3: Community Survey Prot 4: Navigator Prot 2/2: Breast Brachy Prot 1/2: Prostate Brachy Prot 6: Tomo Prostate Submitted Approved with final letter Ready to enroll after NCI appr. September 03 October 03 February 04 March 04 April 04 November 03 December 03 January 04 May 04June 04 August 03 July 03June 03 Sep/Oct 04 August 04 July 04

29. Clinical Trials that Address Health Care Disparities Historical background –Minority mistrust research CDRP Trials –Cooperative Group RTOG, ECOG, NSABP, NCCTG, GOG –CDRP trials: PI driven –Other: behavioral, molecular Successful Recruitment Clinical Trials Future trials

30. Considerations Future Clinical Trials “With precise, treatment delivery systems, cooperative groups need to think about hypofractionation rather than delivering a higher total dose over a longer period of time” –Michael Steinberg, MD, Centinela Freeman Patients are asking for more convenient, cost effective and equally effective treatments

31. Considerations Future Clinical Trials Presenting randomized study is difficult because patients want to choose their treatment Phase II trials might be a better option for these special populations -American Indians Western, SD, choice is often mastectomy or brachytherapy, situation in Anchorage, Al, magnified by factor of 10 –Strong rationale for offering phase II trials limited institutional basis through cooperative group mechanism NCCTG proposal

32. Geographic Distance from The Cancer Center in Western, SD Live 70 to 180 miles away (Median 140 miles)

33. Travel Distances Alaskan Natives

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