Background

1. Validation Study of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Amylou C. Dueck (Mayo Clinic) Ethan M. Basch (Memorial Sloan-Kettering) Jeff A. Sloan (Mayo Clinic) Additional Collaborators: NCI: Andrea M. Denicoff, Shanda Finnigan, Ann M. O'Mara, Bryce Reeve, Sonja Stringer FDA: Eugenio Andraca-Carrera, Mandi Yu MD Anderson: Charles S. Cleeland, Tito R. Mendoza Memorial Sloan-Kettering: Thomas Atkinson, Jennifer L. Hay, Yuelin Li Patient Advocates: Cindy Geoghegan, Diane Paul

2. Background • More than one-third of adverse events in drug labels are symptoms (nausea, fatigue, sensory neuropathy) • In clinical trials, adverse symptom information is reported by research staff, not directly by patients • Health professionals underestimate incidence and severity of symptoms vs. patients’ own accounts • Staff-based adverse symptom assessments occur at clinic visits, missing remote between-visit events

3. CTCAE • In oncology, standard instrument for AE reporting is CTCAE • Item bank of ~1000 AE items • Magnitude graded on ordinal scale • Created by consensus, never validated • About 10% of items are symptoms • Purpose is adverse event screening, not endpoint evaluation

4. PRO-CTCAE Development • 10/08: NCI issued contract to create PRO-CTCAE • Item development: complete • Identified 77 CTCAE items amenable to PRO • Subset of “Core” symptoms • Drafted patient terms (sensory neuropathy = numbness and tingling) • Determined “attributes” of symptoms to be assessed • Presence, frequency, severity, interference, amount • Determined response option scales (verbal descriptors) • Selected default recall period (7-day) • Cognitive interviews: in progress • Web administration platform: v1 complete • Current study to assess measurement properties of items

5. Objective of this Study • To assess measurement properties of newly developed PRO-CTCAE items • Validity • Reliability • Sensitivity • Recall period • Purpose of items is adverse event screening, not granular assessment of symptoms as clinical trial endpoints • N=400 to be accrued at 5 sites • Mayo, Memorial Sloan-Kettering, MD Anderson, Duke, Dana-Farber

6. Types of PRO-CTCAE Items • PRESENT/NOT PRESENT (18 symptoms): • In the last 7 days, did you have any ______ (e.g., unusual darkening of the skin): • ○ Yes ○ No • FREQUENCY (24 symptoms): • In the last 7 days, how OFTEN did you have ______ (e.g., vomiting): • ○ Never ○ Rarely ○ Occasionally ○ Frequently ○ Almost Constantly • SEVERITY (53 symptoms): • In the last 7 days, what was the SEVERITY of your ______ (e.g., pain) at its worst: • ○ None ○ Mild ○ Moderate ○ Severe ○ Very severe • INTERFERENCE (20 symptoms): • In the last 7 days, how much did ______ (e.g., fatigue, tiredness, or lack of energy) INTERFERE with your (daily activities): • ○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much • AMOUNT (2 symptoms): • In the last 7 days, did you have any ______ (e.g., hair loss): • ○ Not at all ○ A little bit ○ Somewhat ○ Quite a bit ○ Very much

7. Types of PRO-CTCAE Items (con’d) • Number of items per symptom varies from 1 to 3 • Pain has 3 items (frequency, severity, and interference) • Shortness of breath has 2 items (severity and interference) • Insomnia has 1 item (severity) • Total: 77 symptoms; 117 items • Items currently available in English • Future plan to translate/validate in other languages

8. PRO-CTCAE Web Interface Study staff view: Custom forms can be created per study by selecting from available symptoms.

9. PRO-CTCAE Web Interface Study staff view: Timing of assessments is also customizable.

10. PRO-CTCAE Web Interface Patient view: When a patient logs in, forms which need completing are displayed.

11. PRO-CTCAE Web Interface Patient view: For a symptom with multiple items, if “Never” or “None” is selected for the first item, the remaining items are not displayed.

12. PRO-CTCAE Web Interface Patient view: Additional items are displayed because “Occasionally” is selected for the first item.

13. Eligibility (Inclusions) • ≥18 years of age • Disease and treatment matching 1 of the 6 following cohorts: • Adjuvant breast: initiating adjuvant chemotherapy within the next 7 days or already receiving adjuvant chemotherapy within the first cycle of treatment • Lymphoma/Myeloma: initiating chemotherapy within the next 7 days or currently receiving chemotherapy • Metastatic prostate/bladder: initiating chemotherapy within the next 7 days or currently receiving chemotherapy • Metastatic lung: initiating chemotherapy within the next 7 days or currently receiving chemotherapy; OR receiving daily radiation therapy for at least 28 more days (concurrent chemotherapy allowed) • Metastatic colorectal: initiating chemotherapy within the next 7 days or currently receiving chemotherapy • Head/Neck/Gastroesophageal: receiving daily radiation therapy for at least 28 more days (concurrent chemotherapy allowed) • Patient is expected to return to clinic in 1-6 weeks • Patient can be reached at a single telephone number (daily phone call portion only) • Able to complete web and paper questionnaires in English by themselves or with assistance • Provide informed written consent • NOTE: CAN BE ANY ECOG PS • We are particularly interested in accruing patients with ECOG PS 2-4!

14. Eligibility (Exclusion) • Clinically significant cognitive or memory impairment in the opinion of clinical or research staff

15. Schema

16. For most patients… • Clinic Visit 1: • Patient completes PRO-CTCAE items • Wireless touchscreen tablet or laptop in waiting room or private room • Patient completes EORTC QLQ-C30 • Coordinator completes 3 CRFs (clinical anchors) • ECOG PS + treatment info (RT yes/no; surgery yes/no; chemotherapy yes/no + regimen) • Concurrent meds (yes/no for each): hormonal therapy, opioid (narcotic) pain medications, laxatives, nausea meds, sleep aids, anti-diarrhea meds, antacids, anxiety meds, inhalers, depression meds • CTCAE grades for 17 symptoms • Clinic Visit 2: • 1-6 weeks later • Same as Clinic Visit 1 • Except Patient Booklet has 3 additional items (Global Impression of Change items)

17. For willing patients with 5 weekly clinic visits… • Clinic Visit 1: • Patient completes PRO-CTCAE items • Wireless touchscreen tablet or laptop in waiting room or private room • Patient completes EORTC QLQ-C30 • Coordinator completes 3 CRFs (clinical anchors) • ECOG PS + treatment info (RT yes/no; surgery yes/no; chemotherapy yes/no + regimen) • Concurrent meds (yes/no for each): hormonal therapy, opioid (narcotic) pain medications, laxatives, nausea meds, sleep aids, anti-diarrhea meds, antacids, anxiety meds, inhalers, depression meds • CTCAE grades for 17 symptoms • Patient is entered into IVR telephone system and will receive an automated telephone call daily to score symptoms • Clinic Visit 2: • 1 week later • Same as Clinic Visit 1 • Except Patient Booklet has 3 additional items (Global Impression of Change items) • Clinic Visit 3: • Another week later • Patient completes PRO-CTCAE items electronically (2-week recall) • Clinic Visit 4: • Another week later • Patient completes PRO-CTCAE items electronically (3-week recall) • Clinic Visit 5: • Another week later • Patient completes PRO-CTCAE items electronically (4-week recall)

18. For patients receiving daily RT for next 28 days… (Head/Neck/Gastroesophageal + some of Lung) • Clinic Visit 1: • Patient completes PRO-CTCAE items • Wireless touchscreen tablet or laptop in waiting room or private room • Patient completes EORTC QLQ-C30 • Coordinator completes 3 CRFs (clinical anchors) • ECOG PS + treatment info (RT yes/no; surgery yes/no; chemotherapy yes/no + regimen) • Concurrent meds (yes/no for each): hormonal therapy, opioid (narcotic) pain medications, laxatives, nausea meds, sleep aids, anti-diarrhea meds, antacids, anxiety meds, inhalers, depression meds • CTCAE grades for 17 symptoms • Patient is entered into IVR telephone system and will receive an automated telephone call daily to score symptoms • Clinic Visit 1b: • 1 day later • Patient completes PRO-CTCAE items electronically • For test-retest reliability • Clinic Visit 2: • 1 week after Clinic Visit 1 • Same as Clinic Visit 1 • Except Patient Booklet has 3 additional items (Global Impression of Change items) • Clinic Visit 3: • Another week later • Patient completes PRO-CTCAE items electronically (2-week recall) • Clinic Visit 4: • Another week later • Patient completes PRO-CTCAE items electronically (3-week recall) • Clinic Visit 5: • Another week later • Patient completes PRO-CTCAE items electronically (4-week recall)

19. Statistics / Power • Primary: Assess validity of each PRO-CTCAE item • Compare each item between patients with ECOG PS 0-1 vs 2-4 at the Visit 1 time point using t-tests • Adjust for multiplicity using Hochberg’s step-up method • Power • Core items: 99% for large effect size, 63-91% for moderate effect size • Non-core items: 49-99% for large effect size, 9-65% for moderate effect size • Other planned analyses: • Assess the test-retest reliability of selected PRO-CTCAE items • Assess the responsiveness (sensitivity to change) and clinical significance of each PRO-CTCAE item • Investigate cut-points for notification of severe PRO-CTCAE symptoms • Compare clinician- and patient-reported CTCAE items • Compare daily, 7-day, 2-week, 3-week, and 4-week recall periods • Explore construction of an overall grade for symptoms with multiple items

20. Comments / Questions? Contact info: Amylou Dueck dueck@mayo.edu