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1
Treating Non-painful
Chemotherapy-induced
Peripheral Neuropathy (CIPN):
On Pins and Needles
Adam Mah, BSc (Pharm), 2018 ACPR Candidate
LMPS Adult Program
August 30th, 2017
2
Learning Objectives
• Be able to determine which patients would
best benefit from pharmacotherapy for
non-painful CIPN
• Be able to provide non-pharmacologic
recommendations for patients suffering
from non-painful CIPN
• Critically appraise the available evidence
for pharmacologic interventions to treat
non-painful CIPN
Our patient
ID RS, 33 year-old male, 181 cm tall, weighing
76 kg, BSA 1.95 m2, admitted Aug 21st
C/C Cycle 4 of 6 of dose-adjusted EPOCH-R
HPI Tolerated last cycle very well, minimal
nausea, ANC nadir 2.7, Plts nadir 86
Onco
Dx
Stage IIIA B-cell lymphoma NYD which is
FISH-negative for rearrangements
PMHx Hypertension (pre-dating cancer Dx)
FHx Non-contributory for cancer or CV risk
SHx Doesn’t smoke, occasional EtOH, no illicits
3
CNS/Psyc - Hyporeflexive in upper extremities, c/o numbness and
tingling in fingers present since Aug 13th
- Upon advice from agency, reported to ER on Aug 16th but
neurological exam was unremarkable.
- Can still type but abnormal writing was noted.
Difficulties with picking up small objects.
- Low mood and fatigue after last cycle.
HEENT No mucositis
Resp Chest clear to ascultation, equal air entry to bases
CV Normal S1/S2, no murmur
GI No masses, exam normal
GU No peripheral edema
Endo Not documented, no Hx of diabetes
Heme No lymphadenopathy
MSK Denies pain in fingers
Derm No rash
4
Labs and vitals
• Vitals: BP 120/80, HR 70, Temp 36.7,
RR 18, O2 sats 97% on RA
• Lytes: Na 137, K 3.9
• Renal: BUN 5.6, SCr 77, CrCl 105
• Tumour marker: LDH 565 (3x ULN) (281
on August 4 after cycle 3)
5
Meds at home Meds in hospital
SMX/TMP 800/160 mg PO daily on
Mon, Wed, Fri
As at home, plus…
Slow-K 32 mEq PO QID Dalteparin 5000 units SC QD
Amlodipine 10 mg PO QD Lansoprazole 30 mg PO QD only
when on prednisone
Magic mouthwash 20 mL swish
and spit QID
Prednisone 100 mg PO BID days
1 to 5 of cycle
Ondansetron 4-8 mg PO q8h PRN Day 1-4: Etoposide 72 mg/m2
Dimenhydrinate 25 mg PO q4-6h
PRN
Day 1-4: Doxorubicin 14 mg/m2
Sennosides 17.2 mg PO BID PRN Day 1-4: Vincristine 0.27 mg/m2
To be discharged home on Grastofil
(G-CSF) 300 mcg SC daily starting
day 6 of cycle, continuing until past
nadir and ANC = or >5
Day 5: Cyclophosphamide
1080mg/m2
Day 1 or 2: Rituximab 375 mg/m2
6
DTPs
1. RS is experiencing paresthesias and
numbing in upper extremities secondary
to vincristine
2. RS is at risk of N/V, abdominal discomfort
secondary to taking potassium
supplements
3. RS is experiencing excessive pill burden
secondary to potassium supplements
without a compelling indication
7
DTPs continued 4. RS is at risk of lymphoma progression secondary
to possibly inappropriate treatment of a
lymphoma not yet defined
5. RS is at risk of lymphoma progression secondary
to dose-reduction of vincristine from previous
cycle
6. RS is at risk of hypertension secondary to being
on prednisone
7. RS is experiencing excessive pill burden
secondary to taking lansoprazole without a
compelling indication
8
Goals of therapy for DTP#1
• Prevent escalation of symptoms
• Prevent delays or dose reductions in
curative chemotherapy
• Minimize symptoms of long-term chronic
peripheral neuropathy
• Improve QOL
• Preserve ADLs such as typing, buttoning
shirts, writing
• Minimize adverse drug reactions
9
Overview of CIPN1,2 • Disruption of axonal microtubule transport
– Same mechanism for painful + non-painful
• Platinums (~40%) 20, taxanes (42-70%)16,
vincristine (~20%) 20
• ↑ w/cumulative dosage
• ~68, 30% prevalence at 1, 6 months after
completing chemo20
• Can be painful or non-painful
• Compared to diabetic neuropathy or other non-
cancer neuropathic pain, CIPN is poorly studied3
10
Guidelines
• ASCO guidelines14 – “Moderate” recommendation for duloxetine (based on
painful21 CIPN data – Brief Pain Inventory)
– Trial of TCA or gabapentinoid reasonable (based on
non-CIPN data)
• NCCN guidelines15 – Insufficient evidence to recommend any treatment
over the other
– “Choose an agent based on the clinician’s
experience…titrate that agent to the maximal
tolerated dose”
11
PICO(ST)
P In patients suffering from non-painful
CIPN…
I Is any pharmacologic intervention…
C More effective than placebo…
O To reduce subjective perception of
symptoms and improve QOL…
S As shown in a RCT…
T Over the course of chemo treatment?
12
Literature search • Embase (E), Medline (M), Pubmed (P)
• “peripheral neuropathy” [Title] AND
“chemotherapy” [Title] AND “non-painful”
[keyword] AND randomized controlled trial
– E = 1 (non-pharm); M = 0; P = 0
• “peripheral neuropathy” [Title] AND
“chemotherapy” [Title] AND “vincristine”
[keyword] AND randomized controlled trial,
published in last 3 years
– E = 13, M = 2, P = 3
13
15
Design Open-label RCT, crossover design
Treatment Duloxetine 20 mg/day x 1 week, then 40
mg daily for 3 wks, then crossover to
comparator after 2-4 wk washout
Comparator Vitamin B12 1.5 mg PO daily x 4 wks,
then crossover to intervention after 2-4
wk washout
Results NNT = 3 for duloxetine in >50%
reduction in VAS scores for numbness
Limitations - Small sample size (n = 34)
- 41% of pts were taking pregabalin
- No reporting of outcomes for
crossover period
Revised PICO…
16
P In patients suffering from CIPN…
I Is any pharmacologic intervention…
C More effective than placebo…
O To reduce subjective perception of
non-painful symptoms and improve
QOL…
S As shown in a RCT…
T Over the course of chemo treatment?
(Broader) Literature search
• “peripheral neuropathy” [Title/Abstract] AND
“chemotherapy” [Title/Abstract] AND randomized
controlled trial AND human subjects, published
in last 3 years
– E = 18, M = 8, P = 67
17
Lit search filtering
• Some were murine studies and review
papers
• Some were prophylaxis against CIPN
• Case study of lacosamide for severe CIPN
• Some non-pharm interventions
• Some only used either Brief Pain Inventory
or composite Total Neuropathy Score
(grouping painful + non-painful together)
18
PICO for trial17
20
P N = 208; N = 150 for final analysis. Patients
suffering from numbness, tingling, or pain
associated with chemotherapy for at least 1 month
I Compounded gel containing 0.76% baclofen, 3.1%
amitriptyline, 1.5% ketamine in PLO gel, apply
1.31 g to each affected area (up to 4 areas) BID
C Identical appearing placebo gel, apply 1.31 g to
each affected area (up to 4) BID
O Primary: change in EORTC QLQ-CIPN20
instrument score for CIPN
S Multicentre, DB RCT
T 4 weeks
EORTC QLQ-CIPN2018 • QOL measure – questionnaire items
assess some ADLs (driving, opening jars)
• Sensory (9), motor (8), and autonomic (3)
measures
– 4-point Likert scale linearly convert to 0-100
• Positive results so far in terms of validity
and reliability19
• Minimum clinically meaningful difference
unclear18,19
21
Patient characteristics
• Pts who had received or currently
receiving neurotoxic chemotherapy
• Had numbness, tingling or pain for at least
1 month
• Exclusions: Life expectancy <4 months,
SCr >1.5x ULN, neuropathy spread to
more than hands or feet, Hx of non-chemo
peripheral neuropathy or CAD, no
concurrent anticonvulsant or TCA allowed
22
Efficacy results
24
• NSS sensory and autonomic
• SS for difference in motor – improvement in
cramps and ability to hold pen drove results
• Better improvement in upper extremities
Safety results
• Adverse events were similar in each arm
– Mild constipation in 18-22%
– Mild dry mouth in 17-22%
• No grade 2 or above adverse events
25
Authors’ conclusions
• “As there are no other known effective
treatments…the signal of potential benefit
provided by these data warrant further
study of this combination of topical
baclofen, amitriptyline, and ketamine,
specifically evaluating a higher dose of the
agents…”
26
Authors’ limitations
• Doses of agents in gel may have been low
– Study RPh initially recommended amitriptyline
4.6%, ketamine 2.3%, baclofen 2.3% based
on clinical experience
• Overall effect size not large
• Hands may have seen larger effect
because of rubbing action
• 25% of participants did not provide
sufficient data to be analyzed
27
Strengths
• Well-designed trial with clear documented
reasons for dropout
• Took into account QOL for outcomes
• Trended towards benefit for sensory
• No serious ADRs
• Public funding
28
Other limitations
• BID application – too infrequent?
• PLO gel compounds require vigorous
application
• Majority had already completed treatment
• Majority had >6 month duration of
symptoms
• Snapshot – symptoms may wax/wane
• Different pharmacy = different
compounding competency
29
Recommendation + rationale
• Recommend 0.76% baclofen, 3.1%
amitriptyline, 1.5% ketamine in PLO gel,
apply TID to affected areas, start now
• Efficacy
– Motor symptoms most bothersome for RS
– ↓vincristine, but will receive 2 more cycles of
curative daEPOCH-R – avoid further dose ↓
– RS’s motor functioning still good enough to
vigorously apply PLO gel base compound
30
Recommendation + rationale
• Safety
– ADRs were similar to placebo and ECOG = 0
– TID chosen over BID – similar PLO-base
compounds (like diclofenac) applied up to
QID, assess TID administration at next cycle
• Adherence
– Has private drug plan from work
– Vigorous application – addressed in Efficacy
– Requires compounding pharmacy
31
Non-pharmacologic measures
• Selfguided online CBT: no better than standard of care; useful if comorbid Ψ condition and patient willing. Low-harm
intervention5
• Neurofeedback: studied in patients who
had completed treatment and were cured,
showed to be better than waitlist8
• Acupuncture9, exercise12, electrical
stimulation10 = more trials needed
32
Progress and resolution of
other DTPs • Slow-K was discontinued after Aug 22nd (day 2)
• Subsequent CT head/neck showed treatment
response for RS
• Evening BP was 126/84 on Aug 22nd and 130/84
mm Hg (on target) on Aug 23rd (day 3)
• Lansoprazole was continued after discussion
with Medical as it was short-term use (only
during admission as per before) – RS did not
exhibit any subjective symptoms of GERD
33
Monitoring - efficacy
Parameter Who
monitors
Change Timeframe to
reassess
Picking up
small objects
RPh, RN,
MD
Able to without dropping
them or without difficulty
Next cycle (Sept 11th)
Numbness
and tingling
in extremities
RPh, RN,
MD
Improvement on EORTC
QLQ-CIPN20 scale or
other validated scale
Next cycle (Sept 11th)
Pain in
extremities
RPh, RN,
MD
No appearance Next cycle (Sept 11th)
LDH RPh, MD Decrease from 565 U/L Next cycle (Sept 11th)
Nausea and
vomiting
RPh, RN,
MD
Decrease from baseline, or
maintenance at baseline
Ongoing daily
34
Monitoring - safety Parameter Who
monitors
Change Timeframe to
reassess
Constipation RPh, RN,
MD
Appearance; usage of PRN
sennosides
Ongoing daily
Drowsiness,
somnolence
RPh, RN,
MD
Appearance Next cycle (Sept 11th)
Dry mouth RPh, RN,
MD
Appearance Next cycle (Sept 11th)
Potassium RPh, MD Decrease to <3.5 mmol/L Day of discharge
(Aug 25th)
Blood
pressure
RPh, RN,
MD
Increase to >140/>90 mm
Hg
Ongoing daily
GERD
symptoms
RPh, RN.
MD
Presence of acid reflux,
water brash
Ongoing daily
35
What about prophylaxis?
• B-complex vitamins6
– Small (n=71) trial, B group vitamin PO BID
showed SS benefit over placebo for total
neuropathy score (TNS) only at 32 weeks
• Glutamic acid (in vincristine patients)13
– Small (n=87) trial, showed less loss of
Achilles tendon reflex but NSS for
development of moderate-severe
paresthesias
36
References 1. Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol
1986;1(6):421.
2. Argyriou AA, Bruna J, Marmiroli P et al. Chemotherapy-induced peripheral
neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol 2012;82(1):51-77.
3. Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of
chemotherapy-induced peripheral neuropathy in survivors of adult cancers:
American Society of Clinical Oncology clinical practice guideline. J Clin Oncol
2014;32(18):1941.
4. Hirayama Y, Ishitani K, Sato Y et al. Effect of duloxetine in Japanese patients with
chemotherapy-induced peripheral neuropathy: a pilot randomized trial. Int J Clin
Oncol 2015;20:866-71.
5. Knoerl R, Yang J, Barton DL et al. Selfguided online cognitive behavioral strategies
for chemotherapy-induced peripheral neuropathy (CIPN): a multi-center, single
blind, randomized, waitlist controlled trial. J Clin Oncol 2017;35(15):S1.
6. Schloss JM, Colosimo M, Airey C et al. A randomised, placebo-controlled trial
assessing the efficacy of an oral B group vitamin in preventing the development of
chemotherapy-induced peripheral neuropathy (CIPN). Support Care Cancer
2017;25:195-204.
37
References 7. Hertz DL, Roy S, Motsinger-Reif AA et al. CYP2C8*3 increases risk of neuropathy in
breast cancer patients treated with paclitaxel. Ann Oncol 2013;24(6):1472-78.
8. Prinsloo S, Novy D, Driver L et al. Randomized controlled trial of neurofeedback on
chemotherapy-induced peripheral neuropathy: A pilot study. Cancer
2017;123(11):1989.
9. Greenlee H, Crew KD, Capodice J et al. Randomized sham-controlled pilot trial of
weekly electroacupuncture for the prevention of taxane-induced peripheral
neuropathy in women with early stage breast cancer. Breast Cancer Res Treat
2016;156(3):453-64.
10. Smith TJ, Coyne PJ, Parker GL et al. Pilot trial of a patient-specific cutaneous
electrostimulation device (MC5-A Calmare) for chemotherapy-induced peripheral
neuropathy. J Pain Symptom Manage. 2010;40(6):883-91.
11. Doxorubicin. In: Lexi-Drugs [database on the Internet]. Hudson (OH): LexiComp,
Inc; 2017 [cited 24 Aug 2017]. Available from: http://online.lexi.com/action/home.
12. Streckmann F, Kneis S, Leifert JA et al. Exercise program improves therapy-related
side-effects and quality of life in lymphoma patients undergoing therapy. Ann Oncol
2014;25(2):493-9.
13. Jackson DV, Wells HB, Atkins JN et al. Amelioration of vincristine neurotoxicity by
glutamic acid. Am J Med 1988;84(6):1016.
38
References 14. Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of
chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American
Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014;32(18)1941.
15. Stubblefield MD, Burstein HJ, Burton AW et al. NCCN Task Force Report:
Management of Neuropathy in Cancer. JNCCN 2009;7:S5.
16. Paclitaxel. In: Lexi-Drugs [database on the Internet]. Hudson (OH): LexiComp, Inc;
2017 [cited 24 Aug 2017]. Available from: http://online.lexi.com/action/home.
17. Barton DL, Wos EJ, Qin R et al. A double-blind, placebo-controlled trial of a topical
treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.
Support Care Cancer 2011;19(6):833-41.
18. Postma TJ, Aaronson NK, Heimans JJ, EORTC Quality of Life Group. et al. The
development of an EORTC quality of life questionnaire to assess chemotherapy-
induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer. 2005; 41(8):1135–
1139.
19. Lavoie Smith EM, Barton DL, Qin R et al. Assessing patient-reported peripheral
neuropathy: the reliability and validity of the European Organization for Research and
Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res 2013;22(10):2787-
99.
39
References
20. Seretny M, Currie GL, Sena ES et al. Incidence, prevalence, and predictors of
chemotherapy-induced peripheral neuropathy: A systematic review and meta-
analysis. Pain 2014;155(12):2461-70.
21. Smith EM, Pang H, Cirrincione C et al. Effect of duloxetine on pain, function, and
quality of life among patients with chemotherapy-induced painful peripheral
neuropathy: a randomized clinical trial.
40
PICO for trial4
44
P Patients suffering from non-painful and
painful CIPN
I Duloxetine 20 mg/day x 1 week, then 40 mg
daily for 3 wks, then crossover to
comparator after 2-4 wk washout
C Vitamin B12 1.5 mg PO daily x 4 wks, then
crossover to intervention after 2-4 wk
washout
O Reduction in VAS scores for numbness and
pain (separately)
S Single-centre, open-label RCT
T During or after chemotherapy
Patient characteristics
• Age 25-75 eligible (median 61 duloxetine,
64 VB12), had received paclitaxel,
oxaliplatin, vincristine, or bortezomib
• N = 34; 14 of which received R-CHOP
• 14 were taking pregabalin at study entry
• Exclusions: non-chemo PN, depression,
suicidal ideation, bipolar, EtOH abuse,
“abnormal renal or liver function”
45
Authors’ conclusions
• “…support the effectiveness of duloxetine
for CIPN due to oxaliplatin, paclitaxel,
vincristine, and bortezomib in Japanese
patients.”
47
Authors’ limitations
• Concede that CIPN risk could be linked to
genotype (e.g. CYP2C8*3 allele for
paclitaxel7)
• Cite efficacy of duloxetine 60 mg daily in
other trials – dose too low?
• Not adequately powered for subgroup
analysis
• Duloxetine use limited by drug interactions
48
Strengths
• Showed subjective benefit (NNT = 3) for
50% or greater reduction in numbness
despite background pregabalin in 14
patients
• Compared intervention to what is standard
of care in Japan for CIPN – vitamin B12
• No grade 2 or above AEs from duloxetine
49
Other limitations
• Small sample size, open-label
• Pregabalin dose changes allowed
• Unclear which patients responded –
pregabalin or no pregabalin?
• Timing of entry into trial was erratic
• No QOL measures
• Did not do statistical analysis on 2nd
treatment period
50