1. Methodological challenges of studying CIPN during chemotherapy
March 23, 2017
Jennifer Gewandter, PhD, MPH

2. 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

3. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

4. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

5. 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

6. 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

7. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

8. 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

9. Published RCTs – Cancer characteristics
Percentage of Trials (of 38)
Included cancer stages
15 (40%) early and advanced
8 (21%) advanced only

10. Published RCTs - Chemotherapy characteristics
Percentage of Trials (of 38)
15 (40%) specifically stated that they included only 1 regimen

11. Published RCTs - Common exclusion criteria
Percentage of Trials (of 38)

12. Challenges: Eligibility
Balance feasibility and generalizability with internal validity
All trials
Symptomatic treatment 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
Definition of CIPN
Assessment tool vs. clinician diagnosis?
Who can administer assessment tool?
When to assess CIPN in relation to:
Chemotherapy treatments
Enrollment in the study
Minimum severity required?
Which symptom(s), sign(s)?

13. 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

14. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

15. 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?

16. 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%)

17. 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

18. 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

19. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

20. Challenges: Primary endpoints - Prevention
Considerations
Neuropathy occurrence:
By end of chemo (Y/N)
Time to
Cumulative dosage to
Variability in timing of chemotherapy dosing (if multiple regimens allowed)
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
Dichotomous endpoint; potentially has lower power
Chemotherapy discontinuation:
Due to other causes
Due to neuropathy
Chemotherapy received:
Full course (Y/N)
Percentage of full course

21. Published RCTs: Primary endpoints – Prevention (18 identified)
Percentage of Primary Endpoints (of 18)
Severity

22. Challenges: Primary endpoints – Symptomatic treatment
Considerations
Severity
At one or multiple specified time points
Before or after a chemotherapy dose
Variability in timing of chemotherapy dosing (if multiple regimens allowed)
Chemotherapy discontinuation:
Due to neuropathy
Due to other causes
Percentage improvement in symptoms:
From experimental treatment initiation
Relative to previous chemotherapy dose (with no experimental treatment)
Dichotomous endpoint; potentially has lower power
After single or multiple chemotherapy doses

23. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

24. 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

25. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

26. Challenges: Primary analysis
Prevention Trials and some symptomatic treatment trials
All 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

27. 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

28. Challenges Trial objectives Eligibility Measurement Endpoints
Limited epidemiology and natural history
Analyses

29. 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.

30. 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

31. 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?

32. 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

33. Characterization of outcome measures reported in each publication
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%)

34. 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
16 (47%)
11 (32%)
2 (6%)
5 (15%)
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
15 (42%)
12 (33%)
6 (17%)
 1 (3%)

35. Published trials - disposition reporting
Percentage of articles (of 38)

36. 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

37. 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.

38. Published RCTs: Primary endpoints - Prevention
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%)
2 (10%)
2 10(%)
1 (5%)