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The Challenges of
Safety Data Collection

Linda Messett RN BSN MA CCRP
Research Associate, Data Management
American Colleg...
How NOT to Ensure Accuracy in AE Reporting
Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
ACRIN
NSABP

EORTC GOG

ECOG

NCIC

NCIC

COG

RTOG

SWOG
NCCTG

CALGB

NCI
Radiation Therapy Oncology Group

ACOSOG

Nati...
New Therapies, New Dilemmas
• Combined Therapeutic
Modalities Are
Proving Beneficial in
Many Studies
• Concerns Are
Growin...
The Delicate Balance

Toxicity
Efficacy

Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
Treatment Toxicity Timelines
Start of
Treatment

End of
Treatment

Acute Toxicity

Radiation Therapy Oncology Group

180 d...
Comparison of Survival and Toxicity
• 9003 Standard of Care (Radiotherapy 2 Gray/FX QD 5
Days/week 70 Gray)
– Acute Grade ...
Our Challenge
• Solve the Dilemma of Poor AE Reporting
• Devise Methods to Improve Accuracy and
More Complete Capture of A...
Oncology Uses The Common
Terminology Criteria for
Evaluating
The Negative Effects of
Cancer Treatment
Radiation Therapy On...
Evolution of Adverse Events
Grading Systems
System

# Terms # Organs

WHO (1979)
28
CTC (1984)
48
RTOG-A (1984)
14
RTOG-L ...
Use Common Language

I can’t help you unless you are more specific.
Do you feel “icky” or just “yucky?”
Radiation Therapy ...
CTC Grading
General guidelines
Low Grade

High grade

1

2

Mild

Moderate

A Symptomatic
No Interventions
Indicated

Symp...
Adverse Event
Terminology & Grading
Important Because It Provides:
• Recognition of the Injury
• Common Language for Commu...
Interpret Subjective Symptoms in
an Objective Manner

Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
At Issue With the Grading System
Currently No Reporting Guidelines For:
• Data Collection
• Patient Screening

Radiation T...
The Negative Result
53 Papers From 41 Trials Show Wide Variations
in Grading Systems and Reporting Methods:
• Only 47% Rep...
Identified Improvements for
RTOG Head & Neck Studies
•

Form Redesign for The Following Studies:
–
–

•

0421 (Revision pe...
RTOG 0129
Form

RT Summary
(Acute)
Follow-up (Late)
Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
New AE
Case Report
Form
Protocol-Specific
AE Form

Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
RTOG 0022 Phase I/II Study: Conformal & Intensity
Mod. Radiation for Oropharyngeal Cancer
Eligibility: Squamous Cell Ca of...
0022 Protocol Objectives
• Assess the Feasibility of Adequate Target
Coverage and Major Salivary Gland Sparing in
Patients...
Dry Mouth Syndrome
(Xerostomia)
• Determines Nature and
Prevalence of Acute
and Late Side Effects
(Using RTOG Scales)
• De...
RTOG Head & Neck Form 0022
• Form Design Weakness Identified: Dry
Mouth/Xerostomia AE Not Captured on the
Majority of CRFs...
Revised FS Form for Study 0022

Form Now
Includes Hard
Coded
Element: “Dry
Mouth”
Accurate Analysis of Adverse
Effects Needed
Which Treatment(s) Might Provide the Best
Outcome to Preserving Salivary Gland...
RTOG 0421 Phase III Trial for Locally Recurrent,
Previously Irradiated Head and Neck Cancer:
Concurrent Re-irradiation and...
0421 Study Shows Why Baseline
Data Is Important
Patients in 0421 Study Have Had at Least 45
and up to a Maximum of 75 Gray...
Differentiating Between a
Baseline Symptom and A New
One Can Be Challenging.

Radiation Therapy Oncology Group

SOCRA 9/20...
Collect Baseline Dysphagia

Example:
Study Form
0421 I1 CRF
Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
RTOG Head & Neck Study 0234
Mild

Moderate

• Chemotherapy
• Radiotherapy
• C-225 (Cetuximab)
• Recognition and
Grading of...
Criteria Problems RTOG
Head & Neck Study 0234
•

Proper Grading Needed to Capture Skin
Rash

•

Some Reports Suggest the M...
CTC Terms Relevant for Grading EGFRi Rash
Mild
Mod
Severe
Disabling
Pruritus/itching*

1
Mild of Localized

2
Intense or W...
Early And Late Effects Are Pivotal
in Deciding New Standards of
Care
• Randomized Trials Needed to Estimate the
Benefits o...
RTOG Plan of Action
 Provide Clear Definitions for Grading AEs Not
Clearly Defined in CTCAE 3.0
 Provide a Check List to...
What You Can Do ...
• Review the Protocol Become Familiar With
the Expected AEs for All Modalities Used
• Create a Checkli...
Thank You!

Radiation Therapy Oncology Group

SOCRA 9/2005

L. Messett
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Adverse Event Reporting for Clinical Trials 9.23.05

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Adverse Event Reporting for Clinical Trials 9.23.05

  1. 1. The Challenges of Safety Data Collection Linda Messett RN BSN MA CCRP Research Associate, Data Management American College of Radiology Radiation Therapy Oncology Group
  2. 2. How NOT to Ensure Accuracy in AE Reporting Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  3. 3. ACRIN NSABP EORTC GOG ECOG NCIC NCIC COG RTOG SWOG NCCTG CALGB NCI Radiation Therapy Oncology Group ACOSOG National Cancer Institute Cooperative Groups SOCRA 9/2005 L. Messett
  4. 4. New Therapies, New Dilemmas • Combined Therapeutic Modalities Are Proving Beneficial in Many Studies • Concerns Are Growing Regarding the High Rate Adverse Events Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  5. 5. The Delicate Balance Toxicity Efficacy Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  6. 6. Treatment Toxicity Timelines Start of Treatment End of Treatment Acute Toxicity Radiation Therapy Oncology Group 180 days Late Toxicity SOCRA 9/2005 L. Messett
  7. 7. Comparison of Survival and Toxicity • 9003 Standard of Care (Radiotherapy 2 Gray/FX QD 5 Days/week 70 Gray) – Acute Grade 3+ 39% – Late Grade 3+ 27% – 4-Year Survival 33% • 9914 72 Gray/42 FXs/6 Weeks AFX-CB Plus Cisplatin 100mg/M2 days 1 &22 – Acute Grade 3+ 92% – Late Grade 3+ 42% – 4-year Survival 54% – Feeding Tube Prior to Registration 24% – Follow-up 83% One Year From Start of TX 41%, 4 Years From Start of TX 17% Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  8. 8. Our Challenge • Solve the Dilemma of Poor AE Reporting • Devise Methods to Improve Accuracy and More Complete Capture of AEs • Continuously Improve Data Collection to Meet New Therapies Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  9. 9. Oncology Uses The Common Terminology Criteria for Evaluating The Negative Effects of Cancer Treatment Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  10. 10. Evolution of Adverse Events Grading Systems System # Terms # Organs WHO (1979) 28 CTC (1984) 48 RTOG-A (1984) 14 RTOG-L (1984) 16 SOMA (1995) 152 CTC v 2.0 (1998) 260 9 13 13 13 22 24 CTCAE v 3.0 (2003) 1058* Al Modality Chemo Chemo Acute RT Late RT Late RT Chemo/Acute RT All Acute & Late The First Comprehensive Grading System for All Modalities
  11. 11. Use Common Language I can’t help you unless you are more specific. Do you feel “icky” or just “yucky?” Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  12. 12. CTC Grading General guidelines Low Grade High grade 1 2 Mild Moderate A Symptomatic No Interventions Indicated Symptomatic: Interventions Such As Local Treatment or Meds May Be Indicated; Some Interference With Function, but No Impact on ADLs Radiation Therapy Oncology Group 3 Severe Very Undesirable; Multiple, Disruptive Symptoms; More Serious Interventions, Including Surgery or Hospitalization May Be Indicated. SOCRA 9/2005 4 Life Threatening Life Threatening Catastrophic, Disabling or Result in Loss of Organ, Organ Function, or Limb. L. Messett
  13. 13. Adverse Event Terminology & Grading Important Because It Provides: • Recognition of the Injury • Common Language for Communication • Common Schema for Severity Grading • Data for Toxicity/Safety Profiles • Drives Interventions Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  14. 14. Interpret Subjective Symptoms in an Objective Manner Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  15. 15. At Issue With the Grading System Currently No Reporting Guidelines For: • Data Collection • Patient Screening Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  16. 16. The Negative Result 53 Papers From 41 Trials Show Wide Variations in Grading Systems and Reporting Methods: • Only 47% Reported on Late Events • Late Organ Function: – Only 3% Addressed Feeding Tube Dependence; – Only 7% Discussed Tracheostomy Dependence • Only 51% Reports Addressed Treatment Related Mortality Systematic Review of Variations in Safety Reporting In Phase III H&N Trials (1990-2003) Trotti A., Gwede C. (Submitted: ASTRO 3/2005) Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  17. 17. Identified Improvements for RTOG Head & Neck Studies • Form Redesign for The Following Studies: – – • 0421 (Revision pending January) 0234 (The forms will not be updated) Improve Directed Patient Assessments for Capturing AEs (RTOG 0522) Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  18. 18. RTOG 0129 Form RT Summary (Acute) Follow-up (Late) Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  19. 19. New AE Case Report Form Protocol-Specific AE Form Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  20. 20. RTOG 0022 Phase I/II Study: Conformal & Intensity Mod. Radiation for Oropharyngeal Cancer Eligibility: Squamous Cell Ca of the Oralpharyngeal (Tonsil, Base of Tongue or Palate) • T1-T2, No-n1, Mo • No Prior Surgery to the Tumor or Nodal Disease • No Radiotherapy to the Head and Neck; • No Previous Chemotherapy, Etc. Treatment Plan: • Conformal and or IMRT Techniques Utilized to Deliver a Maximum of 66 GY/30 Fractions. • The Major Salivary Gland Will Be Spared According to Specific Criteria. • Salivary Output Will Be Measured Before and Following Therapy. Oncology Group SOCRA 9/2005 L. Messett Radiation Therapy
  21. 21. 0022 Protocol Objectives • Assess the Feasibility of Adequate Target Coverage and Major Salivary Gland Sparing in Patients With Oropharygeal Cancer Treated With IMRT Techniques. • Determine the Rate and Pattern of Locoregional Tumor Recurrence. • Determine the Nature and Prevalence of Acute and Late Side Effects (Using RTOG Scales) and Their Relationship to Local Dose. Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  22. 22. Dry Mouth Syndrome (Xerostomia) • Determines Nature and Prevalence of Acute and Late Side Effects (Using RTOG Scales) • Determines Relationship to Local Dose Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  23. 23. RTOG Head & Neck Form 0022 • Form Design Weakness Identified: Dry Mouth/Xerostomia AE Not Captured on the Majority of CRFs Sent to RTOG • Corrected Form Improves Data Collection Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  24. 24. Revised FS Form for Study 0022 Form Now Includes Hard Coded Element: “Dry Mouth”
  25. 25. Accurate Analysis of Adverse Effects Needed Which Treatment(s) Might Provide the Best Outcome to Preserving Salivary Gland Function? • 0022 IMRT • 0244 Salivary Gland Transfer • Radio-protectors: Pilocarpine/Amifostine Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  26. 26. RTOG 0421 Phase III Trial for Locally Recurrent, Previously Irradiated Head and Neck Cancer: Concurrent Re-irradiation and Chemo. vs. Chemo. Only Eligibility • Recurrent or Second Primary SCC of the Oral Cavity, Oropharynx, Hypopharynx, Larynx or Recurrent Neck Metastases With Unknown Primary • Measurable Disease • Patients Must Be Surgically Inoperable • No Signs of Carotid Exposure • Must Have Had Prior Radiation to the Head and Neck 45 to 75 Gray Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  27. 27. 0421 Study Shows Why Baseline Data Is Important Patients in 0421 Study Have Had at Least 45 and up to a Maximum of 75 Gray Adverse Event Collection at Baseline & Careful Long Term Screening is Key for this Study Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  28. 28. Differentiating Between a Baseline Symptom and A New One Can Be Challenging. Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  29. 29. Collect Baseline Dysphagia Example: Study Form 0421 I1 CRF Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  30. 30. RTOG Head & Neck Study 0234 Mild Moderate • Chemotherapy • Radiotherapy • C-225 (Cetuximab) • Recognition and Grading of Erbitux Rash Severe Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  31. 31. Criteria Problems RTOG Head & Neck Study 0234 • Proper Grading Needed to Capture Skin Rash • Some Reports Suggest the More Severe the Rash, Perhaps the Better Outcome and Survival Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  32. 32. CTC Terms Relevant for Grading EGFRi Rash Mild Mod Severe Disabling Pruritus/itching* 1 Mild of Localized 2 Intense or Widespread 3 Intense or Widespread And Interfering With ADL Macular or Papular Severe, Generalized EruptioN or Erythema With Erythroderma or Pruritus or Other Macular, Papular or Associated Symptoms; Vesicular Eruption; Localized Desquamation or Desquamation Covering Other Lesions Covering < > 50% Bsa 50% of Body Surface Area (Bsa) Rash/desquamation* Macular or Papular Eruption or Erythema Without Associated Symptoms Rash/acne/acneiform * Intervention Not Indicated Intervention Indicated Nail Changes* Discoloration; Ridging (Koilonychias); Pitting 4 - Partial or Complete Loss of Interfering With ADL Nail(s); Pain in Nail Bed(s) Rash: Dermatitis Associated With Radiation: − Select: − Chemo Radiation − Radiation 1 Faint Erythema or Dry Desquamation Radiation Therapy Oncology Group 2 Moderate to Brisk Desquamation Erythema; Patchy Moist, Mostly Confined to S kin Folds And Creases; Moderate Edema Generalized, Exfoliative, Ulcerative, or Bullous Dermatitis Associated With Pain, Disfigurement, Ulceration, or Desquamation 3 Moist Desquamation Other Than Skin Folds And Creases; Bleeding Induced by Minor Trauma or Abrasion SOCRA 9/2005 - - 4 Skin Necrosis or Ulceration of Full Thickness Dermis; Spontaneous Bleeding From Involved Site L. Messett
  33. 33. Early And Late Effects Are Pivotal in Deciding New Standards of Care • Randomized Trials Needed to Estimate the Benefits of Combined or Single Therapies • Accurate Data Can Answer Whether Added Toxicity Provides Additional Benefits • Definitive Data Needed Before Therapies Become an Accepted Community Standard for a Patient Population Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  34. 34. RTOG Plan of Action  Provide Clear Definitions for Grading AEs Not Clearly Defined in CTCAE 3.0  Provide a Check List to Use for Patient Assessments  Use More Hard Coded Elements on CRFs  Provide Protocol Specific Instruction for Assessments  Add Question to the Case Report Forms to Capture Base Line Information. E.G. 0421 Forms Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  35. 35. What You Can Do ... • Review the Protocol Become Familiar With the Expected AEs for All Modalities Used • Create a Checklist for Consistent Patient Assessment • If Documentation is Lacking Ask the Person Assessing the Patient for More Information or an Addendum. • Follow Your Patient After Treatment Is Over to Capture the Late Effects Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett
  36. 36. Thank You! Radiation Therapy Oncology Group SOCRA 9/2005 L. Messett

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