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 StringerFDA: Eugenio Andraca-Carrera, Mandi YuMD Anderson: Charles S. Cleeland, Tito R. MendozaMemorial Sloan-Kettering: Thomas Atkinson, Jennifer L. Hay, Yuelin LiPatient Advocates: Cindy Geoghegan, Diane Paul

• 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

Background

• 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

CTCAE

• 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

PRO-CTCAE Development

• 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

Objective of this Study

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

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

PRO-CTCAE Web Interface

Study staff view: Custom forms can be created per study by selecting from available symptoms.

PRO-CTCAE Web Interface

Study staff view: Timing of assessments is also customizable.

PRO-CTCAE Web Interface

Patient view: When a patient logs in, forms which need completing are displayed.

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.

PRO-CTCAE Web Interface

Patient view: Additional items are displayed because “Occasionally” is selected for the first item.

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!

Eligibility (Exclusion)

• Clinically significant cognitive or memory impairment in the opinion of clinical or research staff

Schema

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)

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)

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)

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

Comments / Questions?

Contact info:Contact info:Amylou Dueck

dueck@mayo.edu