David Cella, Ph.D. Evanston Northwestern Healthcare and Northwestern University

1. Quantifying Treatment Benefit from the Patient’s Perspective: From quality of life to symptom relief David Cella, Ph.D. Evanston Northwestern Healthcare and Northwestern University

2. FDA Position: Oncology • Two primary endpoints • Survival • Quality of Life • Secondary endpoints • Response rate • Disease free survival • Time to progression

3. Key Strategies in Trial Design • Concealed randomization • Controlled by placebo • Clinically-relevant assessment • reliable • valid • responsive to familiar anchors • Concomitant medications • Complete data • Controls in design • QoL assessment pre-disclosure • Control for pre-study impact • Control for improvements in emotional well-being

4. Evolution of QOL Studies in Oncology • Old idea (cytotoxic):“Chemotherapy makes patients worse in the short run; justified in the long run.” • Discovery: Symptomatic patients who respond to cytotoxic chemotherapy usually improve even during chemotherapy • New idea (cytostatic): “Chemotherapy can make patients better in the short and long run.”

5. Physical wellbeing • – disease symptoms • – treatment side effects Emotional wellbeing – coping – distress – enjoyment • Functional wellbeing • – ADLs • – role performance • Social wellbeing • – social activity/support • – relationship quality • – family wellbeing Quality-of-life dimensions Quality of life

6. FACIT measurement system Functional Assessment of Chronic Illness Therapy An array of multidimensional self-report quality-of-life questionnaires • Over 400 items • Over 40 languages (selected scales)

7. FACT includes: • FACT-G: • Physical wellbeing (7 items) • Social/family wellbeing (7 items) • Emotional wellbeing (6 items) • Functional wellbeing (7 items) • Plus... • Additional questions specific to the disease, treatment or condition

8. FACT-G (Version 4)Below is a list of statements that other people with your illness have said are important. By circling one (1) number per line, please indicate how true each statement has been for you during the past 7 days Physical well-being Not at all A little bit Somewhat Quite a bit Very much GP1 I have a lack of energy 0 1 2 3 4 GP2 I have nausea 0 1 2 3 4 GP3 Because of my physical condition, I have trouble meeting the needs of my family 0 1 2 3 4 GP4 I have pain 0 1 2 3 4 GP5 I am bothered by side effects of treatment 0 1 2 3 4 GP6 I feel ill 0 1 2 3 4 GP7 I am forced to spend time in bed 0 1 2 3 4

9. FACIT disease-specific subscales Cervical Breast Hepatobiliary Colon Bladder Lung Esophageal Brain Ovarian Head and neck CNS Prostate

10. Fatigue subscale • Feel fatigued • Feel weak all over • Feel listless • Feel tired • Have trouble starting things • Have trouble finishing things • Have no energy • Able to do usual activities • Require sleep during day • Too tired to eat • Need help doing usual activities • Frustrated/too tired for usual activities • Must limit social activity because too tired

11. Anorexia/Cachexia subscale - 12 • Appetite • Ability to eat a sufficient quantity • Worry over weight • Unpleasantness of food • Body image concern • Loss of interest in food • Difficulty with “heavy” foods • Pressure to eat from family • Vomiting • Early satiety • Stomach pain • General health rating

12. Lung Cancer Subscale Questions • I have been short of breath • I have been coughing • I feel tightness in my chest • Breathing is easy for me • I am losing weight • My thinking is clear • I have a good appetite Overall score range is 0-28 (severe to asymptomatic).

13. Phase III Trial of 5-FU vs Gemcitabine in Advanced Pancreatic cancer • Randomized clinical trial of 126 patients • End-points • Clinical benefit • Pain • Performance status • Weight • Survival Burris, H.A., et al, (1997). J Clinical Oncology. 15 (6), 2403-2413.

14. 5-FU vs Gemcitabine Results Improvement in clinical benefit index 5-FU 4.8% Gemcitabine 23.8% (p=.0022) Survival 5-FU 4.4 mos. Gemcitabine 5.6 mos. (p=.0025) Burris, H.A., et al, (1997). J Clinical Oncology 6), 2403-2413

15. Baseline to 12-week change in Lung Cancer Subscale score (best overall response) CR/PR > PD

16. Initial TOI and improvement at 6 weeks* (n=352) 1.0 0.8 0.6 0.4 0.2 >58, no <58, no >58, yes <58, yes 0.0 0 11 12 1 3 4 5 6 8 9 2 7 10 Proportion surviving Initial, improved? *Patients with missing QoL excluded

17. What is a (clinically) meaningful change? • Meaningful change: A difference or change in score on a health-related quality of life (HRQoL) questionnaire that is important to the involved person or people • “Clinically” meaningful corresponds to a clinically important difference or change in patient status.

18. (Range: 0-28) E5592 - Lung Cancer SubscaleBest overall response to treatment

19. (Range: 0-28) E5592 - Lung Cancer SubscaleProgression status

20. E5592 - Shortness of Breath Very much Not at all

21. E5592 - Weight loss Very much Not at all

22. E5592 - Cough Very much Not at all

23. Tumor Sites • Advanced • Bladder • Brain • Breast • Colorectal • Head & Neck • Hepatobiliary • Lung • Ovarian • Prostate

24. SummaryRevised Number of times symptom is in “top 5%?” lack of energy (fatigue) 9/9 pain 8/9 nausea 7/9 losing weight 5/9 worry condition worse 5/9 content w/ QOL 4/9 certain areas experience pain 3/9 swelling/cramps in stomach 3/9 able to enjoy life 2/9 short of breath 2/9 trouble meeting needs of family 2/9

25. Colorectal (chance probability=20.8%)

26. Hepatobiliary (chance probability=14.3%)

27. FACT Hepatobiliary Symptom Index(FHSI)

28. FACT Hepatobiliary Symptom Index - 8 item (FHSI-8) • pain • weight loss • fatigue (I feel fatigued) • nausea • jaundice • back pain • stomach pain/discomfort • fatigue (I lack energy)

29. Performance Comparison FHSI-8 versus FACT-Hep Yount et al, 2002

30. Performance Comparison FHSI-8 versus FACT-Hep

31. Colorectal and Hepatobiliary Cancer QOL studies: What to evaluate? • Definitely • General pain and abdominal cramping • Fatigue • Appetite and weight loss • Diarrhea • Nausea • Probably • Other bowel concerns (e.g., constipation) • Other side effects (e.g., mucositis, fever, alopecia) • Activity limitation; Life enjoyment • Worry, Distress, Hope • Overall (global) quality of life • Maybe • Multidimensional health status

32. Internal Consistency Reliability and 2 Week Reproducibility of the GCSI Total and Subscale Scores Reproducibilityb Subscale Number Of Items Cronbach’s Alphaa ICC Mean Score Difference (SD) GCSI Total 9 0.84 0.76b -0.02 (0.72) Bloating 2 0.84 0.69 -0.14 (1.29) Post-prandial fullness/Early satiety 4 0.83 0.68 -0.05 (0.94) Nausea/Vomiting 3 0.85 0.81 0.10 (0.82) aN=159-166, with variation due to missing data bN=23 stable patients over 2 week period Source: Revicki et al. (2002)

33. References • Cella, D.F., Bonomi, A.E., Lloyd S.R., Tulsky, D.S., Kaplan, E., Bonomi, P. (1995). Reliability and validity of the Functional Assessment of Cancer Therapy - Lung (FACT-L) quality of life instrument. Lung Cancer, 12, 199-220. • Yellen, S.B., Cella, D.F., Webster, K.A., Blendowski, C., & Kaplan, E. (1997). Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) Measurement System. Journal of Pain and Symptom Management, 13 (2), 63-74. • Ribaudo, J.M., Cella, D., Hahn, EA, Lloyd, S.R., Tchekmedyian, N.S., Von Roenn, J., & Leslie, W. (2001). Re-Validation and Shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Quality of Life Research, 9, 1137-1146. • Cella, D., Lai, J-S., Chang, C-H., Peterman, A., & Slavin, M. (2002). Fatigue in Cancer Patients Compared with Fatigue in the General United States Population. Cancer, 94(2), 528-538. • Cella, D., Hahn, E., & Dineen, K. (2002). Meaningful change in cancer-specific quality of life scores: Differences between improvement and worsening. Quality of Life Research, 11 (3), 207-21.