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Chemotherapy- Induced Neuropathic Pain: Victories & Defeats

W. Clay Jackson, MD, DipTh UTHSC Palliative Medicine

@mydocjackson @aapainmanage

Disclosure I report that I have investments in Aspire Healthcare.

Feel the Burn �  Common

�  Meta-analysis (N>4,000)1

�  Incidence high at first; falls � 1 month 68% � 3 months 60% � 6 months 30%

�  Persistent (1-yr follow-up)2

�  Oxaliplatin 64% �  Docetaxel 45%

�  Problematic for treatment �  May lead to dose reduction

�  Problematic for survivors �  Adversely affects quality of life

1 Seretny M, et al. Pain 2014; 155(12):2461-70. 2 Ventzel L, et al. Pain 2016; 157(3): 560-8.

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A Fire with Many Fuels

� Disruption in microtubule-mediated axonal transport

� Axonal degeneration � Dorsal root ganglion (DRG) damage � Mitochondrial dysfunction � Release of inflammatory cytokines (sensitization)

Addington J, Freimer M. F1000Research 2016; 5: 1466.

The Commonest Offenders �  Platinum agents (sensory)

�  Oxaliplatin � ~90% affected at treatment1

� 10% residual at 2 yrs post treatment2

�  Multiple mechanisms for hyperexcitability3

� Prolong open phase of Na channels �  Transient receptor potential (TRP) channels increase

�  Taxanes (sensory) �  Multiple mechanisms for pathophysiology3

�  Induce axonal degeneration, secondary demyelination � Mitochondrial damage �  TRP upregulation in the DRG

1 Cersosimo RJ. Ann Pharmother 2005;39(1): 128-35. 2 Land SR, et al. J Clin Oncol 2007;25(16): 2205-11. 3 Addington J, Freimer M. F1000Research 2016; 5: 1466.

The Commonest Offenders �  Vinca alkaloids (sensory & motor)

�  Vincristine exhibits multiple effects (hypersensitivity, allodynia) � Microtubular dysfunction � Reduction in endomorphin-2

�  Thalidomide (sensory) �  Microvascular changes

�  Bortezomib (sensory) �  Multiple effects via 26S ribosome inhibition

� Microtubule polymerization disturbances � Vacuolation of DRG mitochondria �  TNF-� and ROS increase �  TRP channel activation

Addington J, Freimer M. F1000Research 2016; 5: 1466.

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Conditions Are Perfect… For Neuropathy

� Antecedent Type 2 DM (regardless of control) �  Taxane Tx (N=374; 81 had DM) incidence of CIPN1

� No DM 49% � DM < 5 yrs 53% � DM > 5 yrs 75%

� Genetic predisposition �  Vincristine Tx in ALL: CEP72 mutations predict

Grade 2-4 CIPN2

1 Kus T, et al. Support Care Cancer 2016; 24(3): 1175-9. 2 Diouf B, et al. JAMA 2015; 313(8): 815-23

Conditions are Perfect… For Neuropathy �  Functional vitamin deficiency

�  Normal B12 levels; elevated metabolites1 (methylmalonic acid MMA; homocysteine) � N=241; retrospective; PallCare service

�  Low vit B12: 17% �  High MMA: 38% �  High homocysteine: 23%

�  Role of vitamin D? (DPN studies) �  Poor emotional well-being

�  N=106; oxaliplatin CIPN; DUL vs. PBO2

�  Higher emotional functioning predicted DUL response (OR 4.03; P=0.050)

1 Solomon LR. Support Cancer Care 2016; 24(8): 3489-94. 2 Smith EM, et al. Eur J Cancer Care 2015; epub. doi: 10.1111/ecc.12421.

Assessing the Damage

� WHO system1

�  Grade 0 none �  Grade I paresthesias +/- decreased tendon

reflexes �  Grade 2 severe paresthesias; mild weakness �  Grade 3 intolerable paresthesias; motor loss �  Grade 4 paralysis

1 Miller AB, et al. Cancer 1981;47:207-14.

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Prevention? �  Guilongtongluofang1

�  Goshajinkigan (GJG)2,3

� N=45; colorectal cancer; FOLFOX; Grade 3 CIPN

� 10 courses �  GJG group 0% �  Control 12%

� 20 courses �  GJG group 33% �  Control 75%

1 LiuY, et al. Evid Based Complement Altern Med 2013:541217. 2 Kono, et al. Evid Based Complement Altern Med 2011:418481. 3 Nishioka, et al. Int J Clin Oncol 16;322-7.

A Legacy of Failure

� Alpha-lipoic acid (ALA) in platinum agents1

� Calcium +/- Magnesium before, after oxaliplatin2

� Glutathione in carboplatin, paclitaxel3

� Topical ketamine 2% and amitriptyline 4%4

1 Guo Y, et al. Support Care Cancer 2014; 22(5): 1223-31. 2 Loprinzi CL, et al. J Clin Oncol 2014; 32(10): 997-1005. 3 Leal AD, et al. Cancer 2014; 120(12): 1890-7. 4 Gewandter JS, et al. Support Care Cancer 2014; 22(7): 1807-14. 5 Majithia, et al. Support Care Cancer 2016; 24(3): 1439-47.

In total, of 15 studies approved by NCI, all agents failed except duloxetine.5

Decent Data for 1… Then Experience and Judgment (48 RCT’s)1

�  Duloxetine �  RCT: 60 mg daily2

�  Comparator trial at 40 mg daily vs. B123

�  Venlafaxine4

�  TCA’s1

�  Gabapentinoids1

�  Topical cream (ketamine, amitriptyline, baclofen)1

�  Physical Therapy (for propioception deficits) �  N=109; tx with taxanes or platinum; 19% falls5

�  CIPN pts at 5x risk of falls vs. age-matched controls6

�  Visual computer-feedback balance training (VCFBT) effective7

1 Hershman DL, et al. J Clin Oncol 2014; 32(18): 1941-67. 2 Smith EM, et al. JAMA 2013; 309(13): 1359-67. 3 Hirayama et al. Int J Clin Oncol 2015; 20(5): 866-71. 4 Aziz MT, et al. Ann Pharmacother 2014; 48(5): 626-32. 5 Tofthagen C, et al. Supp Care Cancer 2012; 20: 583-9. 6 Stubblefield MD, et al. JNCCN 2009; 7(Suppl 5): S1-26. 7 Cammisuli S, et al. Eur J Phys Rehabil Med 2016; epub.

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What About CAM?

� Mice and rats are in luck �  Acetyl-L-carnitine reduced paclitaxel peripheral

neuropathy1

�  Many other agents reduced vinca, platinum-IPN2

� Ginkgo biloba Green tea � Ocimum sanctum Matricaria chamomilia � Butea monosperma Walnut � Xylopia aethiopica Curcumin � Auraptenol Quercetin

1 Zheng H, et al. Exp Neurol 2011; 232(2): 154-61. 2 Cheng XL, et al. Frontiers in Pharmacology 2015; 6(234): 1-9.

What About CAM? � Humans have hope, too

�  Acupuncture-like TENS (ALTENS)1

� N=27; CIPN for mean 10 mos; modified Total Neuropathy Score (mTNS)

� Baseline 7.1 � 3 mos 3.6 � 6 mos 3.1

1 Wong R, et al. Integrative Cancer Therapies 2016; 15(2):153-164.

In sum… � CIPN is common, but gets better with time � The nosology of CIPN doesn’t match the clinical

phenomenology � CIPN is multifactorial, & treatments aren’t great � Duloxetine has good RCT evidence for efficacy � CAM, nutritional approaches may offer a path

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