Patient-Centered Solutions for Improving Patient Symptoms & Quality of Life

1. Patient-Centered Solutions for Improving Patient Symptoms & Quality of Life Dawn L. Hershman MD MS Professor of Medicine and Epidemiology Leader, Breast Cancer Program Columbia University Medical Center

2. Value of Cancer Therapies • Cancer clinical trials are the cornerstone of drug development. • Frameworks for assessing the relative value of cancer therapies that have been compared in clinical trials have been developed by ASCO, ESMO, NCCN and others. • The frameworks define value as a combination of clinical benefit, side effects, and improvement in patient symptoms or quality of life in the context of cost. • For decision making – understanding the burden of symptoms and toxicities of treatments is essential

3. Toxicity / Symptom Reporting • In cancer treatment trials, the standard source of adverse symptom data is clinician reporting (CTCAE). • Consequently, during the drug approval process the FDA has access only to clinician impressions of adverse symptoms but not to patient accounts of these events. • This approach has been criticized because of its exclusion of the patient's perspective, with suggestions that patients are in the best position to describe their own symptoms.

4. Toxicity: Conceptual Framework PATIENT FACTORS Symptom Management CANCER FACTORS Recognition • OUTCOME • Survival • QOL TREATMENT SYMPTOM ADHERENCE PROVIDER FACTORS ORGANIZATION AND HEALTH SYSTEM FACTORS

5. Important Outcomes SAFETY: the medical risk to the subject, usually assessed in a clinical trial by laboratory test, vital signs, clinical adverse events and other specific diagnostic tests or evaluations Tolerability: The degree to which overt adverse effects can be tolerated by the subject

6. Definitions • Common Terminology Criteria for Adverse Events (CTCAE) • Physician reporting: Mild, Moderate, Severe, Life threatening, Death • Patient Reported Outcomes (PRO) • Any report of the status of a patient's health condition that comes directly from the patient without interpretation by a clinical or anyone else (many different scales…) • NCI PROMIS – for symptoms (not ae’s) • PRO-CTCAE • PRO measure developed to evaluate symptomatic toxicity in patients on cancer clinical trials as a companion to CTCAE • Health Related QOL • Multi-dimensional measure that includes domains related to physical, mental, emotional, and social functioning

7. CTCAE and PRO’s • The Common Terminology Criteria for Adverse Events (CTCAE) is the predominant system for describing the severity of AEs commonly encountered in oncology clinical trials. • The method of data collection is clinician based. • Limitations of the CTC system include potential for incomplete reporting and limited guidance on data analysis and presentation methods. • CTC-based data presentations are the primary method of AE data reporting used in scientific journals and oncology meetings. Troti, JCO 2009

8. Effect of Ruxolitinib on mylelofibrosis related symptoms and other patient-reported outcomes Mesa, R et al, J. Clin. Oncol. 2013

9. Patient Reported Outcome Measures Information System (PROMIS) • Set of person-centered measures that evaluates and monitors physical, mental and social health • Can be used with general populations and individuals living with chronic conditions

10. Physician vs. Patient Reporting Basch, E, JNCI 2009

11. Cumulative Incidence of Adverse Symptom Events as Reported by Patients versus Clinicians Patient-reported symptoms were collected directly from 467 persons with breast, lung, genitourinary, or gynecologic malignancy Clinician-reported symptoms were recorded by physicians and nurses at the same visits. Both patients and clinicians reported symptoms according to the CTCAE The graphs reflect the incidence of moderate-severity symptoms according to the CTCAE Patients report symptoms earlier and more frequently than do clinicians. Basch, E, JNCI 2009

12. Relative Strengths of Concordance of Patient-Reported versus Clinician-Reported Adverse Symptom Events with Overall Health Status. Patients' reports are more highly concordant with overall health status than clinicians' reports. Overall health status was measured with the use of the EuroQoL EQ-5D instrument Basch, E, JNCI 2009

13. Digital Phenotyping: Measuring Functional Status J. Ligibel, SABCS. 2018

14. Prevalence of joint symptoms in women on AI’s for early stage BC (N=200) Prevalence of AI-Related Joint Symptoms ATAC SAE = 8% 40 Pain (47%) Stiffness (44%) 35 30 25 Patients on AI TherapyWith Joint Symptoms (%) 20 15 10 5 0 Crew/Hershman; ClinOncol; 2007 New Onset Joint Symptoms Worsening Joint Symptoms

15. Discontinuation and Non-adherence to BC hormonal therapy for women in Kaiser Permanente Only 50% full duration >80 % Hershman, DL et al J. Clin.Oncol; 2010

16. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer Hershman, DL et al BCRT2010

17. PREDICTORS OF DISCONTINUATION: TOXICITY Time to discontinuation 32.4% discontinued because of adverse effects 24.3% discontinued because of musculoskeletal symptoms Henry N L JCO 2012

18. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment Basch, E et al

19. Standard Approach to Symptom Monitoring Limited Time Forget to Discuss REACTIVE APPROACH Problems Connecting Reluctance to Contact Presented by: Ethan Basch, MD, 2017

20. Alternative: Systematic Symptom Monitoring e-Reminder e-Alert Reports Symptoms PROACTIVE APPROACH Presented by: Ethan Basch, MD

21. Study Hypothesis Proactive symptom monitoring during chemotherapy will improve symptom management, leading to better clinical outcomes Presented by: Ethan Basch, MD

22. Study Design R A N D O M I Z E • INTERVENTION ARM • Self-report 12 common symptoms • Prior to / between visits, by web • Weekly email reminders to patients • Alerts to nurses (by email) • Reports to oncologists (at visits) • Outcomes • QOL • ER visits • Survival Patients receiving chemotherapy for metastatic breast, lung, GU, GYN cancer CONTROL ARM “Standard” symptom monitoring Treatment discontinuation, withdrawal, hospice, death Stratified by level of prior computer use Randomized 2:1 for those w/o prior use Presented by: Ethan Basch, MD

23. Patient Self-Reporting Interface • Example: Pain

24. Patient Self-Reporting Interface • Example: Shortness of Breath (Dyspnea)

25. Email Alert to Clinical Nurse

26. Printed Report to Oncologist at Clinic Visit

27. Results • 766 patients enrolled between June 2007 and January 2011 • Overall survival analysis June 2016 • Median follow-up 7 years • 517/766 (67%) participants had died Presented by: Ethan Basch, MD

28. Patient Participation • Patients self-reported symptoms 73% of the time when prompted to do so • Nurses took action in response to alerts 77% of the time • Counselling, supportive medications, referrals to ER, chemotherapy dose modifications, imaging Presented by: Ethan Basch, MD

29. Quality of Life 16% • Assessed at 6 months, compared to baseline • Compared to standard care, 31% more patients in the self-reporting arm experienced QOL benefits (P<0.001) 15% Self- Reporting Standard Care Basch: J Clin Oncol 2016;34:557-565

30. Proportion of Patients Visiting Emergency Room • Compared to standard care, 7% fewer patients in the self-reporting arm visited the ER, with durable effects throughout the study (P=0.02)

31. Overall Survival • Compared to standard care, median survival was 5 months longer among patients in the self-reporting arm 31.2 vs. 26.0 months) (P=0.03) • Remained significant in multivariable analysis: • Adjusted hazard ratio 0.832 • (95% CI; 0.696, 0.995)

32. Potential Mechanisms of Action • #1: Proactive monitoring prompts clinicians to intervene early, before symptoms worsen and cause serious downstream complications • Evidence in this trial: • Nurses took action in response to most alerts • Patients were kept out of the emergency room Presented by: Ethan Basch, MD

33. Potential Mechanisms of Action • #2: Symptom control enables patients to stay more functional, which is known to be associated with better survival • Evidence in this trial: • Compared to standard care, self-reporting associated with better physical functioning and self-care (P=0.01) Presented by: Ethan Basch, MD

34. Potential Mechanisms of Action • #3: Symptom monitoring enables control of chemotherapy side effects, enabling more intensive and longer duration of cancer treatment • Evidence in this trial: • Compared to standard care, patients who self-reported were able to receive chemotherapy 2 months longer on average (6.3 months vs. 8.2 months) (P=0.002) Presented by: Ethan Basch, MD

35. Randomized trial simultaneous standard cancer care with palliative care co-management from diagnosis versus control group receiving standard cancer care only: Improved quality of life Reduced major depression Reduced intense utilization (less chemo < 14d before death, more likely to get hospice, less likely to be hospitalized in last month) Improved survival 11.6 mos. vs 8.9 mos., p<0.02 Palliative Care Improves Quality in Cancer NEJM 2010;363:733-42.

36. Automated home monitoring and management of patient‐reported symptoms during chemotherapy: results of the symptom care at home RCT Mooney, Cancer Medicine, 2017

37. PRO’s as outcome measuresSymptom Management Trials

38. Randomized, placebo-controlled trial of duloxetine for AI-associated musculoskeletal symptoms in early stage breast cancer (SWOG S1202) Toxicity: Fatigue Nausea Headache N=299 Henry/Hershman JCO 2018

39. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors (N=121). * * * Change in Pain Score *p < .05 Irwin, M et al. J. Clin. Oncol; 2014

40. Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain: SWOG S0927 (N=249). WEEK 6 WEEK 12 WEEK 24 Hershman, DL et al J. Clin. Oncol; 2015

41. Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor-Induced Musculoskeletal Pain: SWOG S0927. WEEK 6 WEEK 12 WEEK 24 Hershman, DL et al J. Clin. Oncol; 2015

42. Percent change Brief Pain Inventory for true and sham acupuncture groups • 43 were randomized and 38 were evaluable at 6 weeks • 80% in the TA group reported >2-point improvement in the BPI-SF worst pain compared to 22% with sham (p<0.001) • 74% wanted to continue • 59% were willing to pay for acupuncture A: BPI worse pain score B: BPI pain severity C: BPI pain related interference Crew...Hershman. J Clin. Oncol; 2010

43. 6-WEEK RESULTS - WORST PAIN (BPI) Percent with 2-point change * Corrected for baseline score and study site Hershman, D et al, JAMA 2018

44. Linear Mixed Model - Worst Pain (BPI) Hershman, D et al, JAMA 2018

45. Limitations of Symptom Management Trials • Interventions patients will tolerate • Control groups for behavioral interventions • Placebo effects • Primary outcome; Design and Durability • Implementation & dissemination of behavioral interventions • Cost and Access

46. CONCLUSIONS • Increasing role for patient reported outcomes in drug development. • Still work to be done on defining measures as primary endpoints for symptom management trials • Need to define clinically meaningful change • Need to still figure out objective measures to correspond with PRO’s