Incidence of this syndrome varies widely within patients and by type of chemotherapy. Typically, symptoms will initially present in the distal portion of the toes or fingers. Symptoms then gradually migrate proximally over time, in a symmetric “stocking and glove ” distribution. This type of neuropathy is usually a dose-dependent process , which occurs during chemotherapy treatment. There may be a “coasting effect ”, whereby symptoms progress for 2–6 months after cessation of treatment. Platinum agents are the most common source for CIPN, with reports of 50–100% incidence from the use of such agents. Taxane -induced CIPN may occur in a range of 15% to greater than 60%. Vinca-alkaloid agents have been shown to vary widely; Vincristine is similar to Cisplatin, with almost 100% incidence. Other Vinka-alkaloids may have less than 10% incidence [1]. More recent systematic reviews from 2014 suggest that the estimated prevalence of CIPN within the first month of chemotherapy may be as high as 68% [2].

There is considerable variation in the prevalence reported within the literature, depending on whether the data was patient- or clinician-reported; patient-reported outcomes were typically significantly higher [3]. Predisposing factors include treatment with multiple chemotherapy agents simultaneously or sequentially. Other factors include premorbid acquired or hereditary neuropathy, which may have been previously undiagnosed. Symptoms of CIPN typically improve within the first 3–6 months after cessation of treatment; however, recovery is often incomplete (20–35%). Rapid improvement of symptoms after chemotherapy cessation may be predictive of the overall prognosis for recovery of sensation and pain [1, 4]. However, permanent CIPN has been reported more than a decade after ending chemotherapy, often presenting with sensory symptoms in the lower extremities [5].

As for possible prevention, many of the treatments studied, which are described in later sections, have had disappointing results. A recent report in 2014, published by the American Society of Clinical Oncology (ASCO), included Clinical Practice Guidelines, which reviewed the available literature and concluded that no agents were recommended for the prevention of CIPN [6].

Mechanisms for CIPN: Platinum agents initially bind to DNA and then induce apoptosis of neurons within the dorsal root ganglion (DRG) of sensory nerves. A “coasting effect ” may occur due to the accumulation of platinum within the cell body, which generally results in symptoms long after treatment has been completed. Taxanes inhibit proper microtubule function within the mitotic spindle, thus interfering with axonal transport in a length-dependent manner. This occurs in both motor and sensory nerves and in a symmetrical distribution. Vinca-alkaloids also inhibit proper microtubule function, which interferes with axonal transport in both motor and sensory nerves in a symmetrical length-dependent pattern [1].

Signs: changes in gait pattern, falls, impaired pinprick sensation or proprioception, allodynia, myalgias, tremors, hyperpathia, orthostatic blood pressure.

Symptoms: numbness, tingling, burning, dysesthesias, paresthesias, cramping, autonomic symptoms including constipation, diarrhea, abnormal sweating, and dizziness have all been reported [7].

In current clinical practice, CIPN is often assessed using one of several common toxicity scales; however, these scales are limited as they rely predominantly on subjective patient reporting rather than objective quantitative testing [8].

Impairment of fine motor movements, dexterity, and coordination during tasks such as working, using a telephone, writing, ambulating, which may result in balance difficulty, gait dysfunction, impaired proprioception, self- care, mobility, and other routine daily activities or tasks.

Options include trialing an alternative chemotherapy agent with a lower neuropathy side effect profile, lowering the dose, or discontinuing the offending chemotherapy agent. A significant number of the treatment options are based on expert collective opinions, case reports, anecdotal evidence, and randomized clinical trials. Otherwise, they are extrapolated from known treatments for diabetic neuropathy, herpetic neuralgia, or other types of pain.

Exercise, PT, and OT with modalities such as aquatic therapy, paraffin wax baths, desensitization techniques, manual massage, myofascial release techniques, ice, superficial heat, TENS unit, biofeedback, cryotherapy, stretching, general exercise, and trigger avoidance [4, 9, 10, 15, 16].

Peripheral nerve block, ganglion block; secondary myofascial trigger point injection.

None.

Adaptive equipment, compression gloves, stockings, sleeves; adequate glucose control and monitoring of HgA1c levels; assessment of serum folate level, vitamin B12 level [17], and thyroid function for deficiency and need for supplementation; evaluation for undiagnosed chronic neuropathies such as Charcot Marie Tooth (CMT) , idiopathic forms, ETOH or toxin induced; evaluation of other comorbidities that cause or exacerbate neuropathy [10].

This type of neuropathy has proven difficult to manage and to treat. Many drugs have been tested, which include anticonvulsants, antidepressants, and compounded creams. Most randomized controlled trials testing a wide variety of drugs, with different mechanisms of action, have not proven to be efficacious [10]. Gabapentin was not effective in treating oxaliplatin-induced CIPN in a Phase 3 randomized, double blind placebo-controlled crossover trial in 2007 [18]. However, there is growing evidence that serotonin and norepinephrine dual reuptake inhibitors (SNRIs) may be effective in treating neuropathic pain [19]. First-line treatments for some clinicians include amitriptyline, duloxetine, and pregabalin with some basis stemming from trials or consensus statements [20–22].

Trials by Goldstein et al. (2005) and Wernicke et al. (2006) have demonstrated that duloxetine is an effective form of treatment for painful diabetic neuropathy. However, the best evidence for the use of duloxetine for CIPN came more recently through a phase 3 randomized placebo-controlled trial of 231 patients by Smith et al. in 2013 [23]. This study demonstrated that patients with painful CIPN, who used duloxetine as compared to placebo for 5 weeks, resulted in a greater reduction in pain (59% versus 38%). Additionally, their results suggested that patients who received platinum-based drugs experienced more benefit from duloxetine than those who were treated with taxane-based drugs.

This data led to the development of the American Society of Clinical Oncology Guidelines in 2014, which gave a moderate recommendation for the treatment of CIPN with duloxetine. However, the guidelines also recommended clinicians to provide education and to inform patients of the limited scientific evidence for the treatment of CIPN, potential side effects, and cost of the use of medications, such as tricyclic antidepressants, gabapentin, and pregabalin [6].

Just as other areas of medicine, genetic susceptibility has been explored for CIPN to attempt more individualized treatment based on genetic status. This may aid clinicians in prescribing more effective treatment in the future [24, 25].

Significant morbidity after surgical treatment for breast cancer has been well-documented. Some figures in the literature report that up to 68% of women will experience some level of impairment, which can involve shoulder pain, rib pain, decreased range of motion, lymphedema, and neuropathy [26]. The incidence of post-mastectomy pain syndrome (PMPS) has been reported to range from 30 to 70% [8, 27–30]. According to the International Association of Study for Pain (IASP), post-mastectomy pain syndrome (PMPS) is pain of neuropathic origin, which is likely caused by peripheral neuropathy, often involving the intercostobrachial nerve [31, 32]. The lateral cutaneous branch of the second intercostal nerve is often resected during mastectomy and this nerve is reported to be injured in 80–100% of cases with axillary dissection. Tumor involvement or radiation fibrosis in the brachial plexus may also result in or contribute to PMPS [33]. Some evidence suggests that post-operative pain may also influence the development of chronic post-mastectomy pain [34]. This syndrome occurs following procedures performed to treat breast cancer, such as breast conserving surgery, breast reconstruction, or tumor enucleation [27, 29, 35]. However, this syndrome has also been reported in patients with only sentinel node biopsies, with sparing of the intercostobrachial nerve [8, 35, 36].

Recently, a cohort study by Couceiro et al. in 2014 examined the prevalence and associated risk factors of 250 women treated surgically for breast cancer. The results demonstrated a strong association of post-mastectomy pain syndrome (PMPS) in patients undergoing quadrantectomy with axillary lymphadenectomy, in patients with a prior history of headache, and in patients less than 50 years of age [37].

Pain, scar tissue formation, altered joint motion, venous/lymphatic congestion, neuropathy, plexopathy, and tendonosis are all possible etiologies, which may lead to rotator cuff impingement, adhesive capsulitis, complex regional pain syndrome, lymphedema, axillary web syndrome, contracture, and many other disorders.

Signs: scapular dyskinesia, glenohumeral restriction, loss or restricted range of motion, impingement syndrome, rotator cuff tendonosis

Symptoms: arthralgias, chest wall pain, shoulder pain, scapular pain, cervicalgia, intercostal brachalgia, axillary or arm swelling

Impairment in activities of daily living (ADLs, instrumental ADLs), ambulation, posture; restriction with spine or joint range of motion and/or flexibility; difficulty with self-care, driving, dressing, working, exercise; symptoms including arm fatigue, pain at rest, pain with wearing clothing, and sensitivity to temperatures.

A significant proportion of treatment options are based on expert collective opinions, meta-analyses, case reports, anecdotal experience, small randomized clinical trials, or extrapolated from evidence of treatments for diabetic neuropathy, chemotherapy-induced neuropathy, herpetic neuralgia, or other types of pain.