Treating Non-painful Chemotherapy-induced Peripheral Neuropathy - - PowerPoint PPT Presentation

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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

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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

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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

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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
• n August 4 after cycle 3)

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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

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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

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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
• n prednisone
• 7. RS is experiencing excessive pill burden

secondary to taking lansoprazole without a compelling indication

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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

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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

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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

• ver the other

– “Choose an agent based on the clinician’s experience…titrate that agent to the maximal tolerated dose”

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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?

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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

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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…

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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

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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
• r composite Total Neuropathy Score

(grouping painful + non-painful together)

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PICO for trial17

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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

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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

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Efficacy results

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• 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

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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…”

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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

• n 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

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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

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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

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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

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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

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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

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Progress and resolution of

• ther 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

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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

• ther 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

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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

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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

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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.

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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.

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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.

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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.

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Thank You

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Appendix

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PICO for trial4

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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,

• xaliplatin, 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”

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Results

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Authors’ conclusions

• “…support the effectiveness of duloxetine

for CIPN due to oxaliplatin, paclitaxel, vincristine, and bortezomib in Japanese patients.”

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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
• ther trials – dose too low?
• Not adequately powered for subgroup

analysis

• Duloxetine use limited by drug interactions

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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
• f care in Japan for CIPN – vitamin B12
• No grade 2 or above AEs from duloxetine

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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

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Conclusions

• Hypothesis-generating
• Needs placebo-controlled trial whether
• ther neuropathic pain agents are

excluded

• Needs sample size for subgroup analysis

depending on chemotherapy drug received

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