PRO-CTCAE Face-To-Face Meeting #2Advancing the Science of Adverse Symptom Monitoring

in Cancer Treatment Trials

Tito Mendoza, PhDThomas Atkinson, PhD

Development of PRO-CTCAE Items

May 24, 2010National Cancer InstituteRockville, MD

Task 2: Item development

Input and expertise from multidisciplinary participants in various institutions

Clinical trial design, health research, psychometrics, survey design, biostatistics, health literacy MSKCCMD AndersonMayoDFCIFDANCI Patient advocate

Overview of Task 2 Item Development

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Identification of CTCAE items amenable to patient reporting

1. Laboratory (non-subjective; assessment requires equipment)

2. Measurable (non-subjective; assessment requires technical training)

3A. Primarily subjective phenomena, without observable component

3B. Primarily subjective phenomena, with observable component

3C. Primarily observable phenomena, with subjective component

Selection of PRO-CTCAE items: initial steps

• Identified existing PRO instruments that could supply items to be used as PRO-CTCAE items

• Conducted literature review for each symptom term from the CTCAE

• Searched and reviewed identified publications’ references • Searched for non–symptom-specific and health-related

quality of life instruments• Considered single-item and multi-item questionnaires from

cancer-specific and non–cancer-specific populations

Selection of PRO-CTCAE items:requirements and procedures

• Appropriate and simple language patient terms were used as much as possible

• Systematic review results were presented and discussed by the Task 2 committee members to select optimal initial draft patient terms

• Discussions were facilitated using secondary analyses of patient-reported datasets – M. D. Anderson Symptom Inventory (MDASI) data from MD Anderson– Symptom Tracking and Reporting (STAR) system data from MSKCC– Patient Reported Outcomes Measurement Information System

(PROMIS) initiative data from the NCI

Information systematically abstracted from publications and instruments for each symptom

• Available intensity/severity items for each symptom of interest• Available interference items for each symptom• Available frequency items for each symptom• Source instrument of each candidate item• Exact verbiage of question and response options for each candidate item• Patient cognitive interviewing results from development of these

questions, with particular attention to the rationale for selection (or rejection) of specific terms, based on patient responses

• Measurement properties available for each item: validity, reliability, sensitivity, clinical relevance of score changes, recall period

• Correlations available for each item with other measures of the symptom or measures of overall health state or disease status

PRO-CTCAE review template

• Table 1. CTCAE v3 Item (updated to V4 later)• Table 2. Dimensions included in CTCAE v3 Items (updated to

V4 later)• Table 3. Items From Multisymptom Instruments for (name

symptom here) and Related Concepts• Table 4. Items From Single-Symptom Instruments for (name

symptom here) and Related Concepts• Table 5. Terms Selected for Severity Item (Pre-Cognitive

Interviewing) • Table 6. Terms Selected for Secondary Item(s) (if applicable)• Supplementary information

Design of question structures and response option formats for items

Which attributes to include?

MDASI, STAR and PROMIS datasets were used to evaluate the degree to which asking about different attributes of the same symptom is statistically redundant vs. provides added information (e.g., does asking patients about frequency of nausea add information beyond asking about severity alone).

Concepts in CTCAE Response OptionsCTCAE TERM GRADE 1 GRADE 2 GRADE 3 GRADE 4 CONCEPTS

IN RESPONSES

Fatigue Mild fatigue over baseline

Moderate or causing difficulty performing some ADL

Severe fatigue interfering with ADL

Disabling Severity

Interference

Nausea Loss of appetite without alteration in eating habits

Oral intake decreased without significant weight loss, dehydration or malnutrition; IV fluids indicated <24 hours

Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN indicated ≥24 hours

Life-threatening consequences

Severity

Interference

Duration

Design of question structures and response option formats for items

Which response option format to use? • Previously noted systematic review of existing

questionnaires was used to identify the spectrum of formats used in existing PRO instruments

• A separate literature review was conducted to characterize the scientific evidence, strengths, and limitations of the various available response-option formats

Generic question structures and response options for PRO-CTCAE items

Attribute Question Structure Response Options

Frequency (26 items)In the last [recall period], how OFTEN did you have [symptom]

Never / Rarely / Occasionally / Frequently / Almost Constantly

Severity (53 items)In the last [recall period], what was the SEVERITY of your [symptom] at its worst

None / Mild / Moderate / Severe / Very severe

Interference (25 items)

In the last [recall period], how much did [symptom] INTERFERE with your usual activities

Not at all / A little bit / Somewhat / Quite a bit / Very much

Amount (2 items) In the last [recall period], did you have any [symptom]

Not at all / A little bit / Somewhat / Quite a bit / Very much

Present/Not Present (21 items)

In the last [recall period], did you have any [symptom]

Yes / No

PRO-CTCAE Items

• Number of dimensions per symptom varies from 1 to 3– Pain has 3 dimensions (frequency, severity, and

interference)– Shortness of breath has 2 dimensions (severity

and interference)– Hoarseness has 1 dimensions (severity)

• 78 CTCAE v4.0 items• 125 PRO-CTCAE questions were drafted

Numerical rating versus verbal descriptor Scale Advantages Disadvantages

0-10 NumericalRating Scale

Easier to translate than verbal descriptorsOnly requires anchors at extremesSelf-explanatory to patientsQuick to completeHighly correlated with visual analog scale responsesCan generate ratio-level dataUsed in common patient-reported efficacy measures (e.g., Brief Pain Inventory, MDASI) with demonstrated acceptance by patients and clinicians

Not appropriate for grading frequencyNot consistent with number of response options in current CTCAEScale cutpoints delineating different levels of severity may vary between symptoms (e.g., patients may view “mild nausea” as score 1-4, but mild fatigue as score 1-3)Difficult to display summary statistics in drug labelsLevel of granularity may be unnecessary for AEs

Numerical rating versus verbal descriptor Scale Advantages Disadvantages

5-Point VerbalResponse Scale

Easy to summarize the proportion of patients experiencing each magnitude level in data tables or drug labelsEasy to dichotomizeNumber of response options is consistent with current CTCAEEach level is anchored to clearly understandable verbiage (e.g., “severe” nausea)Used in common patient-reported efficacy measures (e.g., FACT, PROMIS, MSAS) with demonstrated acceptance by patients and clinicians

Terms may lose meaning in language translationUnderstanding of terms may differ by cultureMay lose granularity compared with 0-10 scale

Determination of “Core” PRO-CTCAE symptom items – data sources

Five data sources were reviewed to identify prevalent adverse symptoms that are important to patients and clinicians across cancer populations:

1) PRO data from 23,553 patients in cancer clinical trials via the European Organisation for Research and Treatment (EORTC)’s QLQ-C30 instrument

2) PRO data from the development of the Memorial Symptom Assessment Scale (MSAS)

3) PRO data from the development of the M. D. Anderson Symptom Inventory (MDASI)

4) Adverse event data via the NCI’s Adverse Event Expedited Reporting System (AdEERS) and Clinical Data Update System (CDUS) for all phase II and III clinical trials sponsored by the NCI between 2005-2009 (unpublished, internal NCI data)

5) Adverse event data in the 29 most recent clinical trials in the North Central Cancer Treatment Group (unpublished, internal NCCTG data)

Determination of “Core” PRO-CTCAE symptom items

• Symptoms were reviewed and compared to determine the most common adverse symptoms of any severity and the most common symptoms of high severity

• Symptom considered as common were those reported by >10% of patients via the QLQ-C30, MSAS, or MDASI; or those reported by staff on behalf of >1% of patients via the CTCAE

• Inclusion of these Core items across trials is intended to facilitate systematic screening for prevalent and important symptoms

• By administering identical Core items across trials, cross-study comparisons of the patient experience with treatment could be facilitated (i.e., comparative effectiveness/safety analyses)

PRO-CTCAE items, beta version 1.0

• Initially identified 77 CTCAE items amenable to PRO from CTCAE v3.0• 78 items were identified amenable to PRO from CTCAE V4.0• For the CTCAE v4.0 items depression and irregular menstruation, two PRO-CTCAE

symptoms were mapped to each in order to capture a broader spectrum of patient experiences. Thus, a total of 80 PRO-CTCAE symptoms are mapped to the 78 CTCAE v4.0 items

• 125 PRO-CTCAE questions were drafted (e.g. sensory neuropathy = numbness and tingling)

• 18 “Core” symptom items were identified• Attributes of symptoms to be assessed have been determined• Verbal descriptor scale was selected• A 7-day recall period was selected

PRO-CTCAE items, updated May 2010

• 81 PRO-CTCAE symptom items

• 126 PRO-CTCAE questions

• 20 “Core” symptom items

PRO-CTCAE items, beta version 1.0 sample items

• Please answer the following questions about your symptoms.

• In the last 7 days, did you miss an expected menstrual period:– Yes / No

• In the last 7 days, how OFTEN did you have aching joints:– Never, Rarely, Occasionally, Frequently, Almost Constantly

• In the last 7 days, what was the SEVERITY of your aching joints at their WORST:– None / Mild / Moderate / Severe / Very severe

• In the last 7 days, how much did aching joints INTERFERE with your daily activities:– Not at all / A little bit / Somewhat / Quite a bit / Very much

•  In the last 7 days, how much hair loss have you experienced:– None at all / A little bit / Somewhat / Quite a bit / Very Much

CTCAE v4 / MedDRA Term PRO-CTCAE Term

Dimensions Included in PRO-CTCAEFre-

quency Severity Inter-ference

Present/Absent Amount

1. Abdominal distension

Bloating of the abdomen (belly) X X

2. Abdominal pain Pain in the abdomen (belly area) X X X

3. Alopecia Hair loss X4. Anorexia Decreased appetite X X5. Anorgasmia Orgasm or climax X6. Anxiety Anxiety or worry X X X7. Arthralgia Aching joints (such as elbows,

knees, shoulders) X X X

8. Blurred vision Blurred vision X X9. Body odor Body odor X10. Bruising Bruise easily (black and blue

marks) X

PRO-CTCAE items, beta version 1.0 (1)

CTCAE v4 / MedDRATerm PRO-CTCAE Term

Dimensions Included in PRO-CTCAEFre-

quency Severity Inter-ference

Present/Absent Amount

11. Chills Shivering or shaking chills X X12. Concentration

impairmentProblems with concentration X X

13. Constipation Constipation X14. Cough Cough X X15. Delayed orgasm Took too long to have an

orgasm or climax X

16. Depression Feelings that nothing could cheer you up X X X

Sad or unhappy feelings X X X17. Dermatitis

radiationSkin burns from radiation X

18. Diarrhea Loose or watery stools (diarrhea) X

19. Dizziness Dizziness X X

PRO-CTCAE items, beta version 1.0 (2)

CTCAE v4 / MedDRA Term PRO-CTCAE Term

Dimensions Included in PRO-CTCAEFre-

quency Severity Inter-ference

Present/Absent Amount

20. Dry mouth Dry mouth X

21. Dry skin Dry skin X

22. Dysgeusia Problems with tasting food or drink X

23. Dyspareunia Pain during vaginal sex X24. Dyspepsia Heartburn X X25. Dysphagia Difficulty swallowing X26. Dyspnea Shortness of breath X X

27. Edema limbs Arm or leg swelling X X X28. Ejaculation

disorderEjaculation problems X

29. Epistaxis Nosebleeds X X

PRO-CTCAE items, beta version 1.0 (3)

CTCAE v4 / MedDRA Term PRO-CTCAE Term

Dimensions Included in PRO-CTCAEFre-

quency Severity Inter-ference

Present/Absent Amount

30. Erectile dysfunction

Difficulty getting or keeping an erection X

31. Fatigue Fatigue, tiredness, or lack of energy X X

32. Fecal incontinence

Loss of control of bowel movements X X

33. Flashing lights Flashing lights in front of your eyes X

34. Flatulence Increased passing of gas (flatulence) X

35. Floaters Spots of lines (floaters) that drift in front of your eyes X

36. Gynecomastia Breast area enlargement or tenderness X

37. Hiccups Hiccups X X38. Hoarseness Hoarse voice X39. Hot flashes Hot flashes X X

PRO-CTCAE items, beta version 1.0 (4)

CTCAE v4 / MedDRA

TermPRO-CTCAE Term

Dimensions Included in PRO-CTCAE

Fre-quency Severity Inter-

ferencePresent/Absent Amount

40. Hyperhidrosis Unexpected or excessive sweating during the day or nighttime (not related to hot flashes)

X X

41. Hypohidrosis Decreased sweating X42. Injection site

reactionPain, swelling, or redness at a site of drug injection or IV X

43. Insomnia Insomnia (including difficultly falling asleep, staying asleep, or waking up early)

X X

44. Irregular menstruation†

Irregular menstrual periods XMiss an expected menstrual period X

45. Libido decreased

Decreased sexual interest X

PRO-CTCAE items, beta version 1.0 (5)

CTCAE v4 / MedDRA

TermPRO-CTCAE Term

Dimensions Included in PRO-CTCAE

Fre-quency Severity Inter-

ferencePresent/Absent Amount

46. Memory impairment

Problems with memory X X

47. Mucositis oral Mouth or throat sores X X48. Myalgia Aching muscles X X X49. Nail

discolorationChange in the color of your fingernails or toenails X

50. Nail loss Lose any fingernails or toenails X

51. Nail ridging Ridges or bumps on your fingernails or toenails X

52. Nausea Nausea X X53. Pain Pain X X X54. Palmar-plantar

erythrodysesthesia syndrome

Hand-foot syndrome (a rash of the hands and feet that can cause cracking, peeling, redness, or pain)

X

PRO-CTCAE items, beta version 1.0 (6)

CTCAE v4 / MedDRATerm PRO-CTCAE Term

Dimensions Included in PRO-CTCAEFre-

quency Severity Inter-ference

Present/Absent Amount

55. Palpitations Pounding or racing heartbeat (palpitations) X X

56. Peripheral sensory neuropathy

Numbness or tingling in your hands or feet X X

57. Photosensitivity Increased skin sensitivity to sunlight X

58. Pruritus Itchy skin X59. Rash acneiform Acne X60. Rash maculo-

papularRash X

61. Skin and subcutaneous tissue disorders - Other, specify (Cheilitis)

Skin cracking at the corners of your mouth

X

PRO-CTCAE items, beta version 1.0 (7)

CTCAE v4 / MedDRATerm PRO-CTCAE Term

Dimensions Included in PRO-CTCAE

Fre-quency Severity Inter-

ferencePresent/Absent Amount

62. Skin and subcutaneous tissue disorders - Other, specify (Striae)

Stretch marks

X

63. Skin hyperpigmentation

Unusual darkening of the skin X

64. Skin ulceration Bed sores or pressure sores X

65. Tinnitus Ringing in your ears X66. Tremor Tremors X X67. Urinary frequency Frequent urination X X68. Urinary

incontinenceLoss of control of urine (leakage) X X

PRO-CTCAE items, beta version 1.0 (8)

CTCAE v4 / MedDRA

TermPRO-CTCAE Term

Dimensions Included in PRO-CTCAE

Fre-quency Severity Inter-

ferencePresent/Absent Amount

69. Urinary tract pain

Pain or burning with urination X

70. Urinary urgency

Sudden urges to urinateX X

71. Urine discoloration

Urine color change X

72. Urticaria Hives X73. Vaginal

dischargeUnusual vaginal discharge X

74. Vaginal dryness Vaginal dryness X75. Voice

alterationVoice changes

X

76. Vomiting Vomiting X X77. Watering eyes Watery eyes (tearing) X X78. Wheezing Wheezing (whistling noise in

the chest with breathing) X

PRO-CTCAE items, beta version 1.0 (9)

Comments/Questions?