1. Which Adjuvant Systemic Treatments Would Medical Oncologists Wish to Receive If They Had Colon Cancer? A Survey of 150 Physicians N Love, MD 1 ; NJ Meropol, MD 2 ; PM Ravdin, MD 3 ; C Bylund, PhD 4 ; LM Ellis, MD 3 ; A Grothey, MD 5 ; HJ Lenz, MD 6 ; JL Marshall, MD 7 ; SA Curley, MD 3 ; D Paley, BA 1 ; M Elder, BBA 1 1 Research To Practice, Miami, FL; 2 Fox Chase Cancer Center, Philadelphia, PA; 3 The University of Texas MD Anderson Cancer Center, Houston, TX; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 Mayo Clinic College of Medicine, Rochester, MN; 6 USC/Norris Comprehensive Cancer Center, Los Angeles, CA; 7 Lombardi Comprehensive Cancer Center, Washington, DC

2. Background As with many treatment decisions in current medical oncology practice, the choices regarding adjuvant chemotherapy for colon cancer are challenging for both patients and physicians because: 1. Potential benefits may be modest in the face of substantial risks. 2. The optimal management of Stage II disease is controversial (Benson 2004). 3. Relatively nontoxic (compared to chemotherapy) experimental biologic agents offer more choices in the form of adjuvant clinical trial participation and off-label treatment.

3. Background (continued) One strategy many patients use to help with clinical decision-making is asking their physicians, “What would you do, Doctor?” (Sokol 2007). The ethical implications of this approach are complex, and it has been observed that physicians don’t always select the same treatment for themselves as they would for their patients (Gardner 2005).

4. Background (continued) This study attempted to determine: How often medical oncologists are asked by their patients facing a decision about adjuvant therapy for colon cancer what treatment they would receive if they were in the same situation. Whether oncologists’ personal selections differ from standard treatment recommendations and, if so, for which specific clinical situations.

5. Methods US-based medical oncologists who treat patients with colon cancer were recruited to participate in a 10-minute online survey in September 2007. More than 5,600 medical oncologists who subscribe to Research To Practice’s educational programs were invited to take part by external market research company Medimix International. The study remained open until the goal of 150 eligible respondents was reached.

6. Methods (continued) The survey was divided into three sections: 1. Participant oncologist’s estimate of the fraction of patients considering adjuvant chemotherapy for colon cancer who ask what therapy the treating physician would select if in the same situation and how the participant generally responds 2. Survey of treatment recommendations for a hypothetical 55-year-old patient in five different adjuvant clinical decision-making scenarios (Table 1) 3. Survey of personal treatment choices the participant would make as a patient in the same five identified adjuvant clinical decision-making scenarios

7. Table 1 SCENARIOS PRESENTED ScenarioDescription 1Stage III colon cancer: 2/18 positive nodes 2Stage III colon cancer: 15/18 positive nodes 3 Stage II colon cancer: 8 negative nodes, no other high- risk features 4 Stage II colon cancer: 18 negative nodes, no high-risk features 5 Colon cancer and the following five-year risks of relapse from Adjuvant! Online data (equivalent to Scenario 4 but not identified as such):  With no further treatment: 13.0 percent  With 5-FU or capecitabine: 10.5 percent  With oxaliplatin/5-FU: 8.1 percent

8. Results Respondent demographics 75 percent of participants were male. Median age was 48 years, ranging from 31 to 71 years. Overall Participants estimated that 41 percent (mean) of their patients facing a decision about adjuvant therapy for colon cancer ask how the participant would wish to be treated as a patient in a similar situation (SD = 29.19). 70 percent of participants regularly provide an answer to this question (Figure 1).

9. Figure 1 When patients ask what therapy you would select if you were in the same situation, how do you generally respond? 4% 70% 20% 6% 0%10%20%30%40%50%60%70%80% I never or almost never provide an answer to this type of questioning I prefer not to respond, but if pressed will provide an answer I regularly tell patients what my decision would most likely be Other

10. Results (continued) Overall Participants estimated that only about half of their patients considering adjuvant therapy for colorectal cancer were interested in information about treatment options and wished to be actively involved in decision-making. Participants’ recommendations to patients were identical to their personal treatment choices for 73 percent of responses (Figures 2-3).

11. Results (continued) Standard oxaliplatin-based chemotherapy or clinical trial participation were recommended and chosen more frequently than off-study chemotherapy combined with biologic treatment. The option of participation in a clinical trial with bevacizumab was one of the two most frequently recommended and chosen treatments for Stage III disease. Participants’ treatment recommendations versus their personal treatment choices for Stage III disease (Figures 2A-2B)

12. Trials evaluating bevacizumab were favored as recommendations and choices over studies with cetuximab (p < 0.01). Participants more frequently selected off-protocol bevacizumab for themselves as patients than they recommended as routine care of patients with Stage III disease (p < 0.05), but 90 percent of participants did not recommend and 74 percent would not receive off-protocol biologic agents even for high-risk disease. Results (continued) Participants’ treatment recommendations versus their personal treatment choices for Stage III disease (Figures 2A-2B)

13. Figure 2A Recommendations for a 55-year-old patient and the treatments oncologists would choose as patients Stage III colon cancer, 2/18 positive nodes Would recommend to a patient 0%10%20%30%40%50%60% 3% 1% 11% 3% 7% 31% 44% 2% 4% 5% 6% 30% 51% Other 5-FU/LV + bevacizumab FOLFOX + bevacizumab* Trial: FOLFOX vs FOLFOX + cetuximab Capecitabine + oxaliplatin Trial: FOLFOX vs FOLFOX + bevacizumab FOLFOX Would choose if he/she were a patient * p < 0.05

14. Figure 2B Recommendations for a 55-year-old patient and the treatments oncologists would choose as patients Stage III colon cancer, 15/18 positive nodes Would recommend to a patient Would choose if he/she were a patient * p < 0.05 0%10%20%30%40%50%60% Other 5-FU/LV + bevacizumab FOLFOX + bevacizumab* Trial: FOLFOX vs FOLFOX + cetuximab Capecitabine + oxaliplatin Trial: FOLFOX vs FOLFOX + bevacizumab FOLFOX 2% 1% 26% 3% 42% 23% 0% 1% 10% 5% 3% 50% 31%

15. With only eight nodes examined, most participants would recommend and choose adjuvant systemic treatment (Figure 3A). Participants would elect to receive adjuvant chemotherapy for lower-risk Stage II disease somewhat more frequently than they would recommend it for their patients (Figure 3B). Results (continued) Participants’ treatment recommendations versus their personal treatment choices for Stage II disease

16. Figure 3A Off-protocol recommendations for a 55-year-old patient and the treatments oncologists would choose as patients Stage II colon cancer, 0/8 negative nodes, no other high-risk features Would recommend to a patient Would choose if he/she were a patient 0% 8% 14% 16% 14% 48% 1% 4% 13% 16% 19% 47% 0%10%20%30%40%50%60%70%80% Other Capecitabine + oxaliplatin Capecitabine alone No chemotherapy 5-FU/LV alone FOLFOX

17. Figure 3B Off-protocol recommendations for a 55-year-old patient and the treatments oncologists would choose as patients Stage II colon cancer, 0/18 negative nodes, no high-risk features Would recommend to a patient Would choose if he/she were a patient * p < 0.05 0%10%20%30%40%50%60%70%80% Other Capecitabine + oxaliplatin Capecitabine alone* No chemotherapy* 5-FU/LV alone FOLFOX 0% 3% 17% 53% 13% 14% 1% 8% 70% 11% 9%

18. Although adjuvant therapy is not usually recommended for patients with Stage II colon cancer without high-risk features, when presented only with a set of quantitative recurrence risks derived from Adjuvant! Online for that clinical scenario, almost all participants would recommend and choose adjuvant treatment (Figures 3B & 4). Results (continued) Participants’ treatment recommendations versus their personal treatment choices for Stage II disease

19. Figure 4 Case based on Adjuvant! Online data: Five-year risk of relapse with no further treatment: 13.0 percent Five-year risk of relapse with 5-FU or capecitabine: 10.5 percent Five-year risk of relapse with oxaliplatin/5-FU: 8.1 percent Would recommend to a patient Would choose if he/she were a patient 8% 7% 3% 4% 78% 7% 3% 4% 3% 83% 0%20%40%60%80%100% Capecitabine + oxaliplatin Capecitabine alone No chemotherapy 5-FU/LV alone FOLFOX 10%30%50%70%90%

20. A significant proportion of patients with colon cancer regularly ask their medical oncologists what their personal treatment choices would be in the same situation, and most clinicians provide an answer. Participants generally recommend the same treatments to their patients that they would choose for themselves. However, for certain clinical scenarios, a higher fraction of clinicians favored more proactive personal treatments. Most medical oncologists would not elect to receive biologic agents off protocol even for high-risk Stage III disease, and participation in clinical trials evaluating these agents was a more common choice. However, for Stage III disease with two positive lymph nodes, only one third of the participating oncologists would recommend and elect clinical trial participation. Conclusions

21. Conclusions (continued) Approximately half of medical oncologists would receive treatment in a situation perceived qualitatively as “lower-risk Stage II,” yet almost all would receive treatment based on the quantitative risk reductions for a similar case as described in Adjuvant! Online. This likely reflects ongoing uncertainty about the benefit of adjuvant chemotherapy for Stage II disease but also suggests that medical oncologists would quickly adopt this treatment approach even for a relatively small reduction in recurrence risk if convinced that this modest benefit exists. This survey was hypothesis generating, and further study is warranted to determine whether the perceptions of this small cohort are representative of the broad oncologist community.

22. References André T et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350(23):2343-51. Benson AB III et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16):3408-19. De Gramont A et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. Proc ASCO 2007;Abstract 4007. Gardner M, Ogden J. Do GPs practice what they preach? A questionnaire study of GPs’ treatments for themselves and their patients. Patient Educ Couns 2005;56(1):112-5. Kuebler JP et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: Results from NSABP C-07. J Clin Oncol 2007;25(16):2198-204. Love N et al. How well do we communicate with our patients? A survey of patients who received adjuvant chemotherapy for colorectal cancer. Proc ASCO GI Cancers Symposium 2007;Abstract 239. Sokol DK. What would you do, doctor? Br Med J 2007;334:853.

23. Acknowledgment This work was supported by an educational grant from Sanofi-Aventis.