# Guideline Resource Unit
Background There were an estimated 220,400 new diagnoses of cancer in Canada in 2018, and it is estimated that one in two Canadians will develop cancer in their lifetime. 1 For patients undergoing cancer treatment, chemotherapy-induced peripheral neuropathy (CIPN) is a common treatment-related side effect that can have a significant negative impact on quality of life 2 and is associated with higher healthcare costs and resource use. 3 CIPN is defined as the injury or degeneration of peripheral nerve fibers caused by exposure to a neurotoxic chemotherapy agent. Patients experiencing CIPN may experience sensory symptoms such as paresthesia, dysesthesia (numbness, tingling, abnormal touch sensations), cold sensitivity, hyperalgesia or allodynia in the hands or feet in a stocking-glove distribution, as well as pain. 4,5 Motor symptoms may include loss of strength, muscle cramps, and spontaneous movements. 6 The precise incidence and prevalence of CIPN varies according to the chemotherapeutic agent, dose, duration of exposure, and method of assessment, and there is likely significant underreporting. 5 Approximately two-thirds of patients experience CIPN in the first month following chemotherapy and half of these patients continue to experience CIPN after six months. 7,8 It is likely that the rate of CIPN will continue to rise as cancer treatments become more aggressive and patient survival rates improve. 9,10 The chemotherapy agents associated with the highest incidence are the platinum drugs (cisplatin, carboplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine) and bortezomib. 5,11,12 In addition, newer classes of medications, including molecular targeted chemotherapeutics and immune checkpoint inhibitors, continue to be associated with CIPN. 10 Management of CIPN can lead to chemotherapy dose reductions, modifications and/or premature treatment discontinuation, adversely affecting treatment outcomes.
The purpose of this guideline is to provide clinical practice recommendations to members of multidisciplinary healthcare teams who screen, assess, and manage adult patients with chemotherapy-induced peripheral neuropathy in their daily clinical practice. 

# Search Strategy
The PubMed database was searched for relevant studies, guidelines and consensus documents published up to December 2018. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: American Society of Clinical Oncology (ASCO), BC Cancer (BCC), and the National Comprehensive Cancer Network (NCCN).

# Target Population
The following recommendations apply to adult cancer patients with chemotherapy-induced peripheral neuropathy. 1.2 Prior to neurotoxic therapy, a baseline focused health assessment should be performed and recorded, identifying any pre-existing conditions that may predispose/exacerbate CIPN (see Table 1). 14,15 Since CIPN often progresses with dose accumulation, it is recommended that patients are actively assessed for signs and symptoms during chemotherapy, and intermittently thereafter. 5 The main goal of routine clinical assessment is to determine whether the patient is experiencing significant neuropathic symptoms that require intervention. 1.3 A valid quantitative measure should be used to assess the severity of motor symptoms, sensory symptoms, and pain. We recommend the use of the NCI-CTCAE v5 (Nervous System Disorders) and ESASr (Pain) tools regularly as needed at each appointment. Table 2 has been adapted from BC Cancer, 14 and summarizes these tools. 

# Recommendations

# Prevention
Although several agents have been investigated for their efficacy in the prevention of CIPN, these studies have not demonstrated reliable or conclusive evidence of benefit to clinical practice. Limiting factors include small sample size, lack of placebo-controlled groups, un-blinded study designs, and the harms outweighing the benefits. 5,9,11,23,24 There are therefore currently no agents that can be recommended as a standard of care for the prevention of CIPN in patients with cancer undergoing treatment with neurotoxic agents.
2.1 Ensure patients are aware of the following before starting a chemotherapy regimen:
- Specific neurotoxic effects that can be expected from their chemotherapy regimen.
- Awareness of potential risk factors for CIPN, including prior chemotherapy, diabetes, folate/vitamin B12 deficiencies, history of smoking, and decreased creatinine clearance. 5,7 - There are certain chemotherapy drugs such as paclitaxel and nab-paclitaxel that are associated with worsening of CIPN symptoms after completion of the last course of therapy. 25 - Platinum neuropathy can progress for several months after completion of chemotherapy and can lead to permanent damage or limitations. 25,26 - Signs and symptoms of platinum neuropathy (sensory, motor, autonomic) that should be reported to a health care provider when they are first noticed. - Strategies for self-care and personal safety.
The following agents are not recommended for the prevention of CIPN: 23,24 - Acetyl-L-carnitine (ALC)
- Amifostine 3 The efficacy of the following agents for the prevention of CIPN is inconclusive: 23,24 - N-acetylcysteine
- Carbamazepine - Glutamate - GSH for patients receiving cisplatin/oxaliplatin chemotherapy - Goshajinkigan (GJG) - Omega-3 fatty acids - Oxcarbazepine - rhuLIF - Vitamin E - Venlafaxine 2.

# Exercise
- There is a growing body of evidence to suggest a protective effect of exercise and physical activity on CIPN, particularly for patients treated with taxanes, platinum drugs, or vinca alkaloids. 27-30 - More information is required regarding the optimal types of training (i.e., balance, strength, endurance) and recommended duration of exercise regimens; referral to a rehabilitation specialist is appropriate for patients who are experiencing changes in strength or mobility.

# Rehabilitation
Cancer patients with CIPN often present with significant functional deficits, particularly as their neuropathy worsens. The most common deficits include decreased balance, gait abnormalities, muscle weakness, fine motor difficulties, and sensory loss, which can lead to an increased risk of falls, difficulties with performing activities of daily living (ADL), and safety concerns. 4 Rehabilitation specialists such as occupational therapists and physical therapists have a critical role in providing therapeutic interventions, education, and practical advice to help patients correct and manage their symptoms and improve their quality of life. 4, Guideline Resource Unit

# CIPN rehabilitation referral criteria:
- Grade 2 CIPN according to NCI-CTCAE version 5 criteria (see Table 2; moderate pain and symptoms impacting instrumental ADLs such as preparing meals, shopping, managing money) and/or; - Subsequent to an unsuccessful trial of initial pharmacologic therapy options (see Figure 1).

# Assessments and outcome measures:
- General: quantitative sensory testing is a method of objectively quantifying and assessing sensory impairment. Is not sufficiently reliable to be used alone for decision making, but may be used as an adjunct to clinical assessment (monofilament protective sensation testing, reflex testing, vibration sensation testing, temperature testing, manual muscle testing of affected area). 4 - Upper extremity specific: grip strength, DASH, functional task assessment, fine motor outcome measure (e.g., Jebsen Hand Function Test). - Lower extremity specific: balance testing/assessment (Berg, TUG, FAB, mini-BEST), Gait assessment (Winters-Stone 2017). 35 - Canadian Occupational Performance Measure: 36 o Individualized measure of a patient's perception of problems encountered in occupational performance. Aims to provide high quality, occupation-focused, evidence-based, patientcentered practice. - General assessment of ADL. 

# Pharmacological Management
Figure 1 outlines the recommended pharmacologic treatment approach for patients with painful established CIPN. The goals of pharmacologic therapy are:
- a reduction of pain by 30% or greater - improved function (e.g., increased tolerance for walking and standing), mood, and sleep - minimal or tolerable adverse effects Good Practice Point: Guiding Principles for Administering Pharmacologic Therapy
- Titrate each agent up to usual minimum effective dose; if well tolerated and helpful, continue to titrate to the optimal dose. - If an agent is ineffective and/or poorly tolerated, discontinue and consider an alternate agent.
- If an agent is only partially effective but well tolerated, continue it and add an additional agent or agents from a different class. - Intractable pain may require treatment with some combination of agents such as anticonvulsants, antidepressants, and opioid analgesics. Opioids should be used with caution in patients with cancer that has been cured or is under long-term control. - Individual patients and responses will vary, and every pain syndrome is unique, therefore the lack of evidence does not preclude reasonable attempts at symptom management.
4.1 For patients with CIPN symptoms that require pharmacological intervention, duloxetine is the only agent that has been shown in a well-designed randomized clinical trial to be effective in alleviating CIPN, 42 and is therefore the only recommended first-line medication. A subgroup analysis within the same trial suggested that duloxetine may be most effective for patients receiving platinum agents such as oxaliplatin compared to taxanes such as paclitaxel. 42 The recommended dosing is 30 mg per day for the first week, and 60 mg per day thereafter, if well tolerated.
The efficacy of the following agents is inconclusive for treatment of CIPN, but because their efficacy has been established for other forms of neuropathic pain and based on limited treatment options, it is reasonable to consider these agents either in addition to duloxetine, or if duloxetine is not effective or well-tolerated. Patients should be informed of the limited scientific evidence and counseled on the potential harms and benefits. 24 - Anticonvulsants (gabapentin or pregabalin)
- Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine, or imipramine)
- Referral to a specialized pain management service is recommended for discussion of other add-on or alternative options not described above. 
Additional Criteria: Review articles, case reports with <30 patients, and studies that did not report on the outcomes of interest were excluded from the final review were not included in the final review.