Methodological challenges of
studying CIPN during chemotherapy
MARCH 23, 2017
JENNIFER GEWANDTER, PHD, MPH
Presentation objectives
 Outline the design challenges and issues to consider when
designing a CIPN study during chemotherapy
 Summarize how published RCTs have addressed these
design challenges
 Propose topics for design discussion
Challenges
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Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges
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Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenge: Trial objectives
• Identify study objective:
 Primary prevention – initiate preventive treatment before chemotherapy
 Secondary prevention – initiate preventive treatment after start of chemotherapy but before
CIPN symptoms
 Tertiary prevention – initiate preventive treatment after detecting neuropathy signs or symptoms
in order to prevent worsening
 Symptomatic treatment – treatment of established CIPN symptoms
Published RCTs - Objectives
Systematic Review 38 RCTs of pharmacologic treatments published prior to November 2015
 Prevention Trials (36)
• 23 (61%) primary prevention (treatment initiated before or on the same day as chemotherapy)
• 10 (26%) exact timing of treatment initiation was not clear, but there was no indication that
CIPN symptoms appeared prior to treatment
• 1 (2.5%) “As close as possible to the beginning of chemotherapy”
• 1 (2.5%) “Ideally before the first cycle, but required to be before the second cycle”
• 1 (2.5%) “Within 4 days of the first dose of chemotherapy”
 2 (5%) symptomatic treatment trials
Challenges
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Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges: Eligibility
 Balance feasibility and generalizability with internal validity
All trials
 Patient characteristics
• Multiple cancer types
• Multiple chemotherapy types / agents / regimens
• Early stage vs. metastatic
• Diabetic / Alcoholic / HIV+ patients
• Prior exposure to neurotoxic treatments
• Concomitant treatments for neuropathy
Percentage of Trials (of 38)
Published RCTs – Cancer characteristics
40
35
30
25
20
15
10
5
0
 Included cancer stages
• 15 (40%) early and
advanced
• 8 (21%) advanced only
Percentage of Trials (of 38)
Published RCTs - Chemotherapy
characteristics
70
60
50
40
30
20
10
0
Platinum
Platinum or
taxane
Taxane
Vinca
alkaloid
Platinum,
taxane, or
vinca
alkaloid
 15 (40%) specifically stated that they included only 1 regimen
Bortezomib
Sagopilone
Published RCTs - Common exclusion
criteria
Percentage of Trials (of 38)
90
80
70
60
50
40
30
20
10
0
Pre-existing
neuropathy
Diabetes
"Neuropathy
treatments"
Previous
neurotoxic
chemo
Previous
chemo
Alcoholism
Minimum life
expectancy
Previous
radiation
therapy
Challenges: Eligibility
 Balance feasibility and generalizability with internal validity
All trials
Symptomatic treatment trials
 Patient characteristics

Definition of CIPN
• Multiple cancer types
• Assessment tool vs. clinician diagnosis?
• Multiple chemotherapy types / agents / regimens
• Who can administer assessment tool?
• Early stage vs. metastatic
• When to assess CIPN in relation to:
• Chemotherapy treatments
• Enrollment in the study
• Diabetic / Alcoholic / HIV+ patients
• Prior exposure to neurotoxic treatments
• Concomitant treatments for neuropathy
• Minimum severity required?
• Which symptom(s), sign(s)?
Published RCTs - Treatment trials: Inclusion
criteria
 CIPN-related inclusion criteria for the 2 symptomatic treatment trials
 Symptomatic treatment trial 1
• “Patients reporting a distressing acute neurotoxicity after administration of their
oxaliplatin-based chemotherapy”
 Symptomatic treatment trial 2
•
≥ 3 out of 10 pain, numbness, or tingling
Challenges



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
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Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges: Measurement
All trials
 Variability in between-patient
symptom / sign presentation
•
•
•
•
•
•
•
•
Pain
Tingling
Cramping
Weakness
Numbness
Burning
Cold-induced symptoms
Impaired balance
 Primary outcome measure
• Clinically meaningful
• Sensitive to change
• Symptoms, signs, both?
• Does the treatment target specific
symptoms?
Published RCTs - Primary outcome measures
(22 identified)
 Clinician or patient reported symptom and/or function interference measure
• NCI-CTCAE (n=4; 18%)
• EORTC-CIPN20 (n=2; 9%)
• Other (n=6; 26%)
 Clinician reported symptom and sign composite
• TNS (n= 3; 14%)
• Other (n=2; 10%)
 Sign measure
• Vibration test (n=3; 14%)
• Composite of electrophysiology outcomes (n=1; 5%)
 Receipt of 6 cycles of chemotherapy without significant peripheral neuropathy or
impairments in electrophysiology (n=1; 5%)
Challenges: Measurement
 Severity of CIPN is dependent on
• Type of chemotherapy
• Cumulative dosage of chemotherapy
• Timing of the dosing regimen
• Time since last dose of chemotherapy
• Dose delays and discontinuations
• Scheduling of assessments
# of different chemotherapy
regimens included
Published RCTs – Timing of assessments
 Prevention trials (9 reported timing)
• Assessments made prior to chemotherapy doses (n=7; 78%)
• Assessments made on specified days after chemotherapy doses (n=2; 12%)
 Symptomatic treatment trial (1 reported timing)
• Assessments made on specified days after chemotherapy
doses
Challenges
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

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Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges: Primary endpoints - Prevention
Endpoints
Considerations
 Neuropathy occurrence:
• By end of chemo (Y/N)
• Time to
• Cumulative dosage to
 Neuropathy severity:
•
•
•
•
At specified cycle number
At specified time point after chemo initiation
At specified time point after chemo completion
Summary of multiple time points during chemo
 Chemotherapy received:
• Full course (Y/N)
• Percentage of full course
 Variability in timing of chemotherapy
dosing (if multiple regimens allowed)
 Dichotomous endpoint; potentially has
lower power
 Chemotherapy discontinuation:
• Due to other causes
• Due to neuropathy
Published RCTs: Primary endpoints – Prevention
(18 identified)
Percentage of Primary
Endpoints (of 18)
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
Occurrence
Time to
At completion Specific cycle Summary of
Occurrence
of chemo
multiple time
points
Severity
Specific time
point after
chemo
initiation
Specific time
point after
chemo
completion
Received 6
cycles (Y/N)
Challenges: Primary endpoints – Symptomatic
treatment
Endpoints
 Severity
• At one or multiple specified time points
Considerations
 Variability in timing of chemotherapy
dosing (if multiple regimens allowed)
• Before or after a chemotherapy dose
 Percentage improvement in symptoms:
• From experimental treatment initiation
• Relative to previous chemotherapy dose
(with no experimental treatment)
 After single or multiple chemotherapy doses
 Chemotherapy discontinuation:
• Due to neuropathy
• Due to other causes
 Dichotomous endpoint; potentially has
lower power
Challenges






Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges: Limited epidemiology and natural history
 Prevention Trials
• Limited literature on:
•
Neuropathy incidence rates by cancer and chemotherapy type
• Studies use inconsistent CIPN measurement tools
•
Rates of chemotherapy discontinuation due to neuropathy
 All Trials
• Limited literature on effects of CIPN symptoms on function and quality of life
Challenges






Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Challenges: Primary analysis
 All trials
 Prevention Trials and some
symptomatic treatment trials
• Accommodating missing data from
participants who discontinue the trial
• The neuropathy-causing agent (i.e.,
chemotherapy) is:
• Sometimes altered after randomization
• Can be affected by the treatment
• How to handle participants who
discontinue or delay chemotherapy
in the analyses
Published trials – handling of premature
discontinuation of chemotherapy
 Prevention trials:
• Excluded unless they reached a minimum cycle number or cumulative dosage of
chemotherapy (n=6)
• Excluded if didn’t complete the planned chemotherapy up until the time point of
assessment (n=2)
• Summary statistic prorated for #of chemotherapy cycles completed (n = 1)
 Symptomatic treatment trial:
• Discontinued chemotherapy before achieving responder status = non-responders
Challenges






Trial objectives
Eligibility
Measurement
Endpoints
Limited epidemiology and natural history
Analyses
Considerations for designing eligibility criteria
 Goal - establish recommendations for eligibility criteria related to the following:
• Localized or metastatic cancers or both
• One or multiple cancer types
• One or multiple chemotherapy types / agents / regimens
• Diabetic / Alcoholic / HIV+ patients
• Prior exposure to neurotoxic treatments
• Concomitant treatments for neuropathy
• Others?
 Recommendations may be different for different study objectives.
Considerations for Endpoints
 Goal – Create a list of recommended endpoints
• Discuss the advantages and disadvantages of different endpoints
• Create a roadmap of future research to support our recommendations
Considerations for analyses
 Goal – create recommendations regarding how to handle participants who
prematurely discontinue chemotherapy
• Discuss the following possibilities:
• Include all participants as randomized regardless of chemotherapy received
• Remove participants who don’t receive a minimum cumulative dosage of
chemotherapy
• Adjust for the amount of chemotherapy received
 Which of these are reasonable as primary analyses or only as sensitivity analyses?
Acknowledgements
•
•
•
•
Robert Dworkin, PhD
Roy Freeman, MD
Shannon Smith, PhD
Lynn Gauthier, PhD
•
•
•
•
•
•
•
•
Rachel Kitt, BS
Guido Cavaletti, MD
Mike McDermott, PhD
Nimish Mohile, MD
Supriya Mohile, MD
Gordon Smith, MD
Mohamed Tejani, MD
Dennis Turk, PhD
Characterization of outcome measures
reported in each publication
N (%)
Considering all reported outcome measures
Symptom measures only
Symptom and sign measures
Symptom measures and electrophysiology outcomes
Sign measures only
Symptom measures and objective function measures (e.g., pegboard test)
Symptom and sign measures and electrophysiology outcomes
15 (40%)
6 (16%)
5 (13%)
2 (5%)
2 (5%)
2 (5%)
Timing of experimental treatments and
assessments
N (%)
Frequency of treatment (of the 34 (89%) articles that reported it)
Daily or multiple times daily
On the same day as each chemotherapy dose
Daily for a specified number of days following each chemotherapy dose
Other
Timing of assessment (of the 36 (95%) articles that reported it)
At particular cycle numbers (but not every cycle)
Every cycle
At specified weeks post chemotherapy initiation
After participant receives a pre-specified cumulative dosage of chemotherapy
Biweekly for some measures only at study endpoint for other measures
16 (47%)
11 (32%)
2 (6%)
5 (15%)
15 (42%)
12 (33%)
6 (17%)
2 (6%)
1 (3%)
Percentage of articles (of 38)
Published trials - disposition reporting
70
60
50
40
30
20
10
0
# completed the
study
# discontinued
chemo
(neuropathy)
# discontinued
chemo
(other reasons of
unspecified)
Safety considerations
Challenge:
• Administering an experimental treatment in conjunction with chemotherapy – possible
affects on chemotherapy efficacy.
• CIPN efficacy studies likely won’t be powered to detect differences in chemotherapy
efficacy.
Can we provide any recommendations for standards for monitoring this safety concern?
When should experimental treatments only be used in advanced cancer patients?
• Considering available preclinical and clinical data and theoretical mechanisms
Published RCTs: Primary endpoints –
Acute treatment
 100% relief of acute neuropathy symptoms (days 2-5 post chemotherapy doses)
on the NPSI
• Included multiple chemotherapy cycles and not clear if 100% relief was
required at multiple cycles or last cycle
• If a participant discontinued chemotherapy before reaching 100% response,
they were counted as not achieving relief.
Published RCTs: Primary endpoints - Prevention
N (%)
Primary endpoints (of the 19 (51%) prevention articles that identify a primary endpoint)
Occurrence of a grade 2 neuropathy using the NCI-CTCAE
Occurrence of neuropathy measured using another measure
Vibration threshold at completion of chemotherapy
Severity of neuropathy measured by the EORTC-CIPN20 or electrophysiology composite score after
specific number of chemotherapy cycles
AUC of neuropathy severity during chemotherapy measured by the EORTC-CIPN20 (sensory subscale)
Severity of neuropathy measured using the FACT/NTX at a specific time point after initiation of
chemotherapy
Severity and occurrence of neuropathy 1 month after completion of chemotherapy, measured by the
TNS (both identified as primary)
Severity of author-developed symptom/sign composite score 3 months after completion of
chemotherapy
Response, defined as receipt of 6 cycles of chemotherapy without significant peripheral neuropathy or
impairments in electrophysiology
Neuropathy free interval, defined by the time receiving chemotherapy before the occurrence of
bilateral paresthesia rated as 3 or higher on a 0 – 10 NRS
4 (20%)
3 (15%)
3 (15%)
2 (10%)
2 10(%)
1 (5%)
1 (5%)
1 (5%)
1 (5%)
1 (5%)