Review of the FACT: Analytic Strategies to Improve Sensitivity

1. Review of the FACT: Analytic Strategies to Improve Sensitivity David Cella, Ph.D. Evanston Northwestern Healthcare and Northwestern University www.facit.org

2. Buchanan et al, JCO, 2005 • QOL assessment in Sx trials is rising without good justification • Single symptom improvement often fails to improve overall QOL • Acceptable rationales • Gauge importance patients assign to symptom relief • Gain dx information about offsetting tx effects • Advance a compelling conceptual model of the relationship between symptoms and QOL

3. Conceptual Framework: Relationship Among Patient Outcome Measures Characteristics of the Individual Values / Preferences General Health Perceptions Biological and Physiological Variables Symptoms Functional Status Overall QOL Characteristics of the Environment From: Wilson & Cleary (1995)

4. Symptom-targeted interventions can have overall QOL benefits Velikova et al., JCO, 2004.

5. Some, not all, benefit in emotional well-being Velikova et al., JCO, 2004.

6. Some studies actually suggest overall QOL benefit without target symptom benefit • Osterborg, JCO, 2002 • Placebo vs epo beta for CIA • No difference in FACIT-Fatigue • Significant difference in overall QOL

7. QOL Model HRQoL Global (synthesized) Total/Overall (aggregated) PWB MWB SWB Symptoms Function Symptoms Function Concerns Function Adapted from WHO

8. Overall versus Global HRQLBoth have problems in symptom trials • Overall (Total score) • Tension between content validity and focused relevance • Unresponsiveness caused by mistargeted questions • Global rating • Intuitively appealing but coarse • Vulnerable to several cognitive biases that affect reporting of general well-being and satisfaction

9. Are we doomed to be happy? • Life satisfaction research consistently places people near the 75% of satisfaction/happiness scales • Short term improvements in environmental conditions, wealth, etc, have a modest effect • Most human happiness is independent of life’s ups and downs • Implications for measuring GLOBAL QOL in cancer trials • May see small short term benefits, unlikely to see lasting effect • Background noise caused by positive cognitive bias • Background noise caused by “doing something” Thoughts drawn from Cummins & Nistico, 2002

10. FACT Profile of Cancer Patients (n=2,236) Referenced to General Population (n=1,075)

11. Symptom Prevalence Among Patients with Cancer or HIV Percentage Reporting Symptom, any severity Cella D, 1998

12. FACT/NCCN Survey Results 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

13. Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592) Clinically Significant Symptoms (%)

14. Clinically Significant Symptoms in NSCLC Patients With Provider-Rated PS0-1 at Baseline (E5592) Clinically Significant Symptoms (%)

15. 100 pain 90 insomnia weakness nausea 80 FACT-G Total Diarrhea 70 60 50 Very much Quite a bit A little Not at all Symptoms and QOL (N=1,163)

16. 100 90 80 Breast (n=529) Colon (n=254) FACT-G (26-items) 70 Head/Neck (n=233) 60 50 Very much Quite a bit Somewhat A little Not at all Side Effect Bother and QOL

17. FACIT measurement system Functional Assessment of Chronic Illness Therapy An array of multidimensional self-report quality-of-life questionnaires • Over 400 items • Over 50 languages (selected scales) • Over 30 targeted subscales www.facit.org

18. Disease Symptoms Social Emotional Functional Physical Framework for FACT Trial Outcome Index = Physical + Functional + Symptoms (e.g., 36-item FACT-L includes 17 symptoms)

19. 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 wellbeing 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

20. Breast cancer Bladder cancer Brain tumor Colorectal cancer CNS cancer Cervical cancer Esophageal cancer Endometrial cancer Head and neck cancer Hepatobiliary cancer Lung cancer Leukemia Lymphoma Ovarian cancer Prostate cancer Vulvar cancer FACT Cancer-Specific Scales www.facit.org

21. FACT-Lung Subscale • I have been short of breath • I am losing weight • My thinking is clear • I have been coughing • I have a good appetite • I feel tightness in my chest • Breathing is easy for me

22. FACT-Breast Subscale • Short of breath • Self-conscious about dress • One or both arms swollen or tender • Sexually attractive • Bothered by hair loss • Other family members might get same illness • Effect of stress on illness • Bothered by change in weight • Feel like a woman

23. FACIT symptom-specific subscales Anorexia/cachexia Anemia Diarrhea Endocrine symptoms Fatigue Fecal incontinence Urinary incontinence

24. 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

25. Littlewood et al (JCO 2000) Epoetin alfa Trial Treatment Schema 150 IU/kg (if Hb ­³1 g/dL or reticulocytes ­³40,000/mL) at Week 4 150 IU/kg epoetin alfa 300 IU/kg (if Hb ­ <1 g/dL andreticulocytes ­ <40,000/mL) at Week 4 or Placebo (if Hb ­³1 g/dL or reticulocytes ­³40,000/mL) at Week 4 Placebo Double placebo (if Hb ­ <1 g/dL andreticulocytes ­ <40,000/mL) at Week 4 4 8 16 24 28 20 12 0 Weeks Chemo-therapy* *Chemotherapy duration 3-6 cycles; includes 3-4 weeks after the last dose of chemotherapy

26. Epoetin alfa Placebo FACT-G, FACT-An: Fatigue, andFACT-An: Anemia ScoresChange From Baseline to Last Assessment n=200 n=200 n=192 4.02 2.97 2.42 Change in Score -2.18 -2.64 -3.31 n=90 n=90 n=87 FACT-G:TotalP<.05 FACT-An:Fatigue P<.01 FACT-An:AnemiaP<.01*

27. Decrease in FACT-G Total Vs No History of Specified Illnesses Decrease in FACTG (Effect size) (-0.34) (0) (0.34) (0.69) (1.03) (1.37) 1.71)

28. FACIT-Fatigue Subscale All Respondents No History of Illness History of Anemia History of Cancer Placebo EPO Baseline History of Anemia No History if Illness History of Cancer All Respondents Placebo EPO Final Assessment 26 31 36 41 46 EPO = Erythhropoeitin

29. FACT-G Total All Respondents History of Anemia No History of Illness History of Cancer Placebo EPO Baseline History of Anemia No History of Illness History of Cancer All Respondents Placebo EPO Final Assessment 68 73 78 83 88 EPO = Erythhropoeitin

30. FACT-Endocrine Symptoms Subscale • Hot flashes • Cold sweats • Night sweats • Vaginal discharge • Vaginal itching/irritation • Vaginal bleeding or spotting • Vaginal dryness • Pain or discomfort with intercourse • Lost interest in sex • Gained weight • Lightheaded/dizzy • Vomiting • Bloated • Breast sensitivity/tenderness • Mood swings • Irritable

31. ATAC Trial: Trial Outcome Index Fallowfield et al. 2002, 2003 Fallowfield et al, JCO, 2004

32. ATAC Trial: FACT-ES Scores Fallowfield et al. 2002, 2003 Fallowfield et al, JCO, 2004

33. ATAC Trial: Specific Symptoms Fallowfield et al. 2002, 2003 Fallowfield et al, JCO, 2004

34. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 E 5592: Overall Survival Probability CP/CP+G CE Log rank p=0.034 Wilcoxon p=0.012 Time (months)

35. Baseline to 12-week change in LCS score by best overall response LCS change CR/PR > PD CR/PR, complete response/partial response; SD, stable disease; PD, progressive disease Cella et al, JCE, 2002 Time to completion was 12 weeks

36. Baseline to 12-week change in LCS score by time to progression LCSchange Late > Early Late (>116 days)(n=196) Early (<116 days)(n=69) Time to progression Cella et al, JCE, 2002. Time to completion was 12 weeks

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

38. FACT Symptom Indexes:Undoing the Original Structure • Most FACT site-specific scales assess about 50% symptoms and 50% function/perception • FACT-G includes most common symptoms (e.g., pain; fatigue; nausea) • FACT disease subscales focus on sympoms unique to that condition • Common and unique need to be brought together to index the symptom burden of each specific cancer

39. Colorectal (chance probability=21%)

40. Head and Neck

41. Ovarian (Chance probability=19%)

42. Lung

43. Why is more precision needed? • Cancer is many diseases and has many effects upon HRQL • Most instruments can’t cover all important content • Disease trajectory includes • Diagnosis (acute anxiety) • Active treatment (various and chronic symptoms) • Disease-free survivorship (emerging social issues and stress responses, negative and positive) • End of life (emerging physical, social and existential issues) • Most instruments have floor and/or ceiling effects

44. Looking ahead 5-10 years:Standardizing Metrics and Improving Precision Item Banking Computerized Adaptive Testing (CAT)

45. National Item Banks Are Coming NIH Roadmap Cooperative Group: Patient Reported Outcome Measurement Information System (PROMIS)

46. A Better Mousetrap? • PROMIS and the future of (some) outcome measures • Fatigue • Pain • Physical Function • Social Role participation • Emotional Distress • ??? www.NIHPROMIS.org