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

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 1

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 2

Our patient ID RS, 33 year-old male, 181 cm tall, weighing 76 kg, BSA 1.95 m 2 , admitted Aug 21 st 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 Stage IIIA B-cell lymphoma NYD which is FISH-negative for rearrangements Dx PMHx Hypertension (pre-dating cancer Dx) Non-contributory for cancer or CV risk FHx Doesn’t smoke, occasional EtOH, no illicits SHx 3

CNS/Psyc - Hyporeflexive in upper extremities , c/o numbness and tingling in fingers present since Aug 13 th - Upon advice from agency, reported to ER on Aug 16 th 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 As at home, plus… SMX/TMP 800/160 mg PO daily on Mon, Wed, Fri 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 Prednisone 100 mg PO BID days and spit QID 1 to 5 of cycle Day 1-4: Etoposide 72 mg/m 2 Ondansetron 4-8 mg PO q8h PRN Day 1-4: Doxorubicin 14 mg/m 2 Dimenhydrinate 25 mg PO q4-6h PRN Day 1-4: Vincristine 0.27 mg/m 2 Sennosides 17.2 mg PO BID PRN To be discharged home on Grastofil Day 5: Cyclophosphamide 1080mg/m 2 (G-CSF) 300 mcg SC daily starting day 6 of cycle, continuing until past Day 1 or 2: Rituximab 375 mg/m 2 nadir and ANC = or >5 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 CIPN 1,2 • 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 chemo 20 • Can be painful or non-painful • Compared to diabetic neuropathy or other non- cancer neuropathic pain, CIPN is poorly studied 3 10

Guidelines • ASCO guidelines 14 – “Moderate” recommendation for duloxetine (based on painful 21 CIPN data – Brief Pain Inventory) – Trial of TCA or gabapentinoid reasonable (based on non-CIPN data) • NCCN guidelines 15 – 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… Is any pharmacologic intervention… I More effective than placebo… C O To reduce subjective perception of symptoms and improve QOL… As shown in a RCT… S 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

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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 NNT = 3 for duloxetine in >50% Results 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 15

Revised PICO… In patients suffering from CIPN… P Is any pharmacologic intervention… I More effective than placebo… C O To reduce subjective perception of non-painful symptoms and improve QOL… As shown in a RCT… S T Over the course of chemo treatment? 16

(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

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PICO for trial 17 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 20

EORTC QLQ-CIPN20 18 • 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 reliability 19 • Minimum clinically meaningful difference unclear 18,19 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

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Efficacy results • NSS sensory and autonomic • SS for difference in motor – improvement in cramps and ability to hold pen drove results • Better improvement in upper extremities 24

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