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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 30 th , 2017

Treating Non-painful Chemotherapy-induced Peripheral Neuropathy (CIPN… · 2017-09-06 · 2. Argyriou AA, Bruna J, Marmiroli P et al. Chemotherapy-induced peripheral neurotoxicity

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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

14

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

19

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

23

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

Thank You

41

Appendix

42

43

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

Results

46

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

Conclusions

• Hypothesis-generating

• Needs placebo-controlled trial whether

other neuropathic pain agents are

excluded

• Needs sample size for subgroup analysis

depending on chemotherapy drug

received

51