Neurological adverse reactions are the most common adverse reactions of chemotherapy, including central nervous system adverse reactions and peripheral nerve adverse reactions, which are dose-limiting adverse reactions of chemotherapy drugs. Adverse neurological effects may limit the further use of chemotherapy drugs and affect the long-term quality of life of patients. The incidence of chemotherapy-related neurological adverse reactions may be underestimated, and oncologists need to improve their awareness, early warning and ** capabilities. In order to guide clinical practice, the Tumor Support Professional Committee of the Chinese Anti-Cancer Association and the Clinical Chemotherapy Professional Committee of the Chinese Anti-Cancer Association have solicited opinions extensively, based on clinical evidence and combined with the clinical reality in China, and formulated this consensus on the prevention, diagnosis and comprehensive treatment of chemotherapy-related peripheral neuropathy, and the evidence-based medical evidence level, recommendation level and definition of the consensus are shown in Table 1 and Table 2.
oneOverview
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting adverse reaction associated with chemotherapy drugs, occurring in approximately 50% of 90% of chemotherapy patients, of which 30% to 40% will develop chronic neurological adverse effects. For example, in breast cancer patients who received docetaxel**, 42% of patients still had CIPN symptoms 2 years after **;Two years after receiving oxaliplatin in colorectal cancer patients, the incidence of CIPN was as high as 84%. In a survey of patients with malignant tumors, 47% of patients still had CIPN symptoms 6 years after the end of chemotherapy. Chemotherapy drugs that are known to cause CIPN include platinum (e.g., cisplatin, carboplatin, and oxaliplatin), vinblastine (e.g., vincristine), taxanes (e.g., paclitaxel and docetaxel), proteasomes, or angiogenesis inhibitors (bortezomib and thalidomide), and the dose thresholds, incidence, and clinical features of CIPN caused by different drugs are shown in Table 3. Other drug-related factors include the single dose administered, the cumulative dose of the drug and the duration of drug exposure, and other drug-drug interactions in the combination regimen.
The pathogenesis of CIPN has not been fully understood, and it is currently believed that multiple factors are involved in its occurrence, and the possible pathogenesis includes: (1) chemotherapy drugs act on sensory cell bodies and axons of the myelin cushion and dorsal root ganglia, release pro-inflammatory cytokines, activate the apoptosis signaling cascade, change the excitability of central and peripheral neurons, and lead to epineurial detachment;(2) Ion channel dysregulation;(3) microtubule disruption and axonal transport disorders;(4) Mitochondrial dysfunction and oxidative stress;(5) Abnormal multi-factor triggering of the immune system, including abnormal cytokine secretion and abnormal immune cell function, etc., leading to the development of neuroinflammation and sensitization of the sensory nervous system;(6) axonal degeneration;(7) Sensory neuron injury in the dorsal root ganglia.
Individual risk factors associated with the development of CIPN include diabetes, hypothyroidism, renal insufficiency, vitamin deficiencies, anemia, advanced age, obesity, alcoholism, smoking, severe fatigue, anxiety or depression, pro-inflammatory states (elevated pro-inflammatory factors interferon and interleukin-1 [IL-1] and decreased anti-inflammatory factor IL-10), and pre-existing neuropathy. In addition to individual risk factors, factors related to the type of chemotherapy drug, the duration of exposure to the drug, the regimen, and concomitant medications are also important risk factors for CIPN. In the future, we need to develop CIPN risk** models by further integrating genomics (genes involved in pharmacokinetics, ion channel function, neurological adverse effects, and DNA repair) and clinical data.
II. II. IIClinical manifestations of CIPN
CIPN is divided into sensory neuropathy, small fiber neuropathy, motor neuropathy and autonomic neuropathy, and its main clinical manifestations are detailed in Table 4.
CIPN can be divided into acute CIPN and chronic CIPN according to the course of the disease. Acute CIPN mostly occurs within a short period of time after the use of chemotherapy drugs, some can be reversed, and some develop into chronic CIPN, such as neurological adverse reactions that occur on the day of oxaliplatin infusion and within 1 2 days after infusion, mainly manifested as cold-induced distal paralysis, sensory impairment or pain, which are often reversed within 1 weekChronic CIPN persists during and after **. The severity of CIPN symptoms in the acute phase is related to the severity of chronic neuropathy and has a certain value. Symptoms of CIPN usually worsen as chemotherapy continues, and CIPN symptoms stabilize rapidly after chemotherapy ends, and then gradually lessen. It is important to note that neurological adverse effects caused by paclitaxel or oxaliplatin may worsen or change after stopping chemotherapy and persist for many years or even for life.
ThreeDiagnosis of CIPN
The diagnostic criteria for CIPN have not been established to date, and its incidence and severity are often underestimated due to non-reporting and inadequate physician evaluation. The best assessment methods are a combination of clinical assessment tools (Common Terminology Criteria for Adverse Events) and patient-reported outcome measures, including EORTC QLQ-C30 scale, EORTC CIPN20 scale and EORTC CIPN20 scale, QLQ-CIPN20 scale, as well as drug-specific adverse reaction assessment scales, such as specific scales in the cancer patient quality of life assessment scale system (taxane and oxaliplatin neuro-adverse effects special evaluation scale). )。 All of these assessment tools have some diagnostic value, and there is no evidence to show which assessment tool is clearly superior. A comprehensive neurological examination is recommended prior to administration to assess baseline neurological status and identify patients at higher risk for CIPN.
It is recommended to use a cotton swab or wooden stick to assess the sensation of touch, hot and cold objects to assess the sensation of temperature, and the tuning fork test to assess the sensation of vibration. Electromyography (EMG) may provide additional information for clinical evaluation, such as a gradual decrease in the amplitude of sensory nerve action potentials and impaired nerve conduction velocities, suggesting axonal compromise. However, traditional nerve conduction parameters often do not reflect patient symptoms and are not suitable for monitoring CIPN severity during the ** process. In addition, although there was an improvement in clinical symptoms and functional recovery, there was no significant improvement in indicators of neurophysiological assessment. Other assessment tools, such as somatosensory potentials, can help determine whether the proximal sensory nerve is damaged. In microfiber neuropathy, all tests based on standard neurophysiology may be normal, and only a biopsy can be used as the gold standard for diagnosis. Quantitative sensory testing (QST) measures the detection threshold of sensory stimuli to quantify changes in nociceptive stimuli, thermal stimuli, and vibration perception. In breast cancer patients, QST results correlate with patient-reported CIPN degree and can be used to detect changes in CIPN symptoms and assess CIPN** effects. There are currently no definitive biomarkers that can be used to diagnose and monitor CIPN. Preclinical studies have shown that individual-specific genetic variants affect the regulation of genes involved in processes such as drug pharmacokinetics, ion channel function, neurological adverse effects, and DNA repair, thereby affecting the development and severity of CIPN.
Recommendation 1
1) There are no definite diagnostic criteria for CIPN, and some clinical assessment tools have some diagnostic value (Level of evidence: Quality, level of recommendation: weak recommendation
2) Diagnosis should focus on identifying the symptoms that have the greatest impact on the patient's quality of life, first distinguishing between neuropathic pain and simple functional impairment. If pain is the main cause of deterioration in quality of life, medications are indicated**Dysfunction without severe pain is suitable for physiotherapy. When pain and dysfunction occur at the same time, the combination of ** is a reasonable choice (Level of evidence: Quality, level of recommendation: weak recommendation
FourCIPN prevention and **
a) Prevention of CIPN
Studies have evaluated the effectiveness of anticonvulsants (pregabalin), antidepressants, B vitamins, calcium-magnesium minerals, and other chemoprotective agents for the prevention of CIPN, but there is no reliable or definitive evidence of clinical benefit. As a result, there is no high-level evidence or guideline consensus recommending its use for CIPN prophylaxis. Adjusting the dose of chemotherapy drugs may help reduce severe CIPN without affecting the efficacy. In terms of non-pharmacological prophylaxis, the results of a randomized controlled study of acupuncture for the prevention of paclitaxel-induced CIPN in 63 patients showed no benefit from acupuncture for the prevention of CIPN compared with non-acupuncture. Therefore, this consensus does not recommend acupuncture for the prevention of CIPN. It should be noted that the sample size and follow-up time of the above-mentioned acupuncture prevention of CIPN are limited, and the expert group encourages clinical studies based on clear clinical endpoints in highly selective populations. In a meta-analysis of 2,250 patients receiving paclitaxel chemotherapy, cryo** was shown to be safe and potentially effective in preventing CIPN using cryotaxel and surgical glove compression** (sensory neuropathy: RR 0.).65，p<0.00001；Motor neuropathy: RR 018，p＝0.04)。Another small, single-arm study suggested that surgical glove compression** prevented and reduced nab-paclitaxel-induced peripheral neuropathy and reduced the incidence of CIPN. Therefore, this consensus suggests the use of cryotyping** and surgical glove compression** for the prevention of taxane-induced peripheral neuropathy. Preclinical studies have suggested promising clinical applications of compounds targeting mitochondrial dysfunction, oxidative stress pathways, restoring microtubule stability, preventing axonal degeneration, and nerve fiber demyelination, such as the use of pifitaline-L, HDAC6 inhibitors, metformin, antioxidants, and peroxynitrite decomposition catalysts for the prophylaxis of CIPN**.
Recommendation 2
1) Anticonvulsants, antidepressants, vitamins, minerals and other chemoprotective agents can be considered for the prevention of CIPN, and adjusting the dose and interval of chemotherapy drugs and the interval of use can help reduce the occurrence of severe CIPNLevel of evidence: Quality, level of recommendation: weak recommendation
2) Cryotyping** prevents and reduces the incidence of certain chemotherapeutic agents (e.g., taxanes)-induced CPIN (Level of evidence: Quality, level of recommendation: Strong recommendation
3) Surgical glove compression** prevents and reduces the incidence of nab-paclitaxel-induced CIPN (Level of evidence: Quality, level of recommendation: weak recommendation
b) CIPN**
CIPN-related neurological symptoms include both pharmacological and non-pharmacological, and medications are further divided into systemic and topical medications. Adjusting the dose and interval of chemotherapy and use is currently an effective way to limit severe CIPN.
Systemic medications**
Recommendations for systemic medications** are derived from studies of other types of neuropathic pain or low-quality evidence, including antiepileptic drugs, antidepressants, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, tricyclic antidepressants, and opioids, all of which are symptomatic** medications. The existing guidelines only recommend duloxetine as a first-line agent for cipn neuropathic pain. Systemic drugs** should be titrated slowly from a low starting dose until the dose is optimal and controllable for adverse effects, with attention to the impact of concomitant medications. Preclinical studies of monoclonal antibodies against certain CIPN-specific pathologic molecules, such as interleukin 6 and matrix metalloproteinase 9 monoclonal antibodies, have shown potential efficacy.
Serotonin reuptake inhibitors and norepinephrine reuptake inhibitors:Duloxetine has shown clear efficacy for peripheral neuropathy other than CIPN, and duloxetine is recommended for CIPN**. In 231 patients with CIPN with neuropathic pain, the pain level was significantly reduced after 5 weeks of duloxetine use (30 mg daily for duloxetine in week 1 and 60 mg daily for 5 weeks) compared with placebo. Among the 156 CIPN patients with neuropathic pain, duloxetine (30 mg d) was more than venlafaxine (37.)5 mg d) is more effective in reducing symptoms of chemotherapy-induced peripheral and motor neuropathy. However, it is important to note the interaction of duloxetine with other drugs metabolized by the liver. Small case reports have shown that venlafaxine is more effective than placebo for CIPN.
Aminobutyric acid (GABA) receptor blockers:Pregabalin is a novel GABA receptor blocker that has shown promising efficacy in CIPN neuropathic pain**. In a randomized clinical study of 82 patients with paclitaxel-induced peripheral neuropathy with neuropathic pain, pregabalin (150 mg d)** and duloxetine (60 mg d)** both showed good efficacy in relieving neuropathic pain, but duloxetine (38.)1%) is lower than pregabalin (92.).5%)。
Tricyclic antidepressants:Two randomized placebo-controlled trials of amitriptyline were negative, including a randomized, double-blind, placebo-controlled study evaluating the efficacy of low-dose amitriptyline in 44 patients with CIPN and neuropathic pain** for 8 weeks (starting at 10 mg daily, gradually increasing the dose to 50 mg daily if tolerated, followed by a stable dose for 4 weeks), and amitriptyline did not improve neuropathic pain symptoms. In addition, the results of a phase study of cisplatin-induced peripheral neuropathy (N 51) showed only a modest benefit from nortriptyline, but the difference was not statistically significant.
Anticonvulsants:Although gabapentin has been shown to be effective in polyneuropathy, data on CIPN are very limited. A phase randomized, double-blind, placebo-controlled study (N 115) showed no improvement in either pain intensity or sensory neuropathy. Due to insufficient evidence and serious adverse effects, carbamazepine is generally not recommended for neuropathic pain and occasionally for trigeminal neuralgia.
Opioids:The use of oxycodone during chemotherapy reduces the incidence of CIPN-related pain. The German Society of Neurology recommends opioids as a third-line option for neuropathic pain.
Non-opioid pain relievers:Non-opioid analgesics such as NSAIDs, analgin, or paracetamol have limited efficacy in neuropathic pain, and a variety of potential adverse effects may occur. However, NSAIDs are effective in reducing swelling and pain when chronic venous insufficiency causes swelling of the hands and feet, causing increased tissue pressure, resulting in peripheral nerve damage and neuropathic pain.
Recommendation 3
1) Duloxetine (60 mg d) can be used as a first-line drug for neuropathic pain caused by **CIPN (Level of evidence: Quality, level of recommendation: Strong recommendation
2) Pregabalin (150 mg d) can be used as the preferred drug for neuropathic pain associated with taxane-related peripheral neuropathy (Level of evidence: Quality, level of recommendation: Strong recommendation
3) As a posterior line option, CIPN can use non-opioids (non-steroidal anti-inflammatory drugs) and/or opioids for pain relief based on clinical experience, noting comorbidities and the impact of concomitant medications (Level of evidence: Quality, level of recommendation: Strong recommendation
Topical medications** include patches and various gel formulations. Lidocaine patches can be used for postherpetic neuralgia and other localized neuropathic pain, including CIPN. Lidocaine patches may be recommended as a second-line option for **CIPN, especially if oral medications are not tolerated.
The capsaicin patch (179 mg) is approved in the EU as a single agent or in combination with other drugs for the analgesia of localized peripheral neuropathic pain**. Guidelines from the German Neurological Association recommend capsaicin patch (179 mg) as a second-line** for any type of neuropathic pain, with comparable efficacy to oral medications, good tolerability and safety, and low incidence of systemic adverse effects. Subgroup data from 15 patients in the QuEPP study support the efficacy of capsaicin patches in CIPN. In two open-label, single-center, small-sample studies, high-dose capsaicin patches were effective in reducing CIPN pain. The use of low-dose preparations (<1%) or the use of capsaicin for ** non-painful polyneuropathy is not recommended. In a study of 51 patients, 1% menthol gel topical** significantly reduced CIPN-related pain, improved function, and reduced pain sensitivity.
Testimonial 4
For localized peripheral neuropathic pain, topical** regimens such as capsaicin patch (179 mg), lidocaine patch, other patches, and gel preparations should be preferred (Level of evidence: Quality, level of recommendation: Strong recommendation
Non-pharmacological**
Acupuncture:As an adjunct method, acupuncture is safe and effective and has a low incidence of adverse reactions. In a randomized controlled trial, researchers evaluated the feasibility and safety of acupuncture intervention in patients with moderate to severe CIPN in breast cancer patients, and the results showed that 8 weeks of acupuncture intervention compared with usual care significantly improved CIPN neuropathological symptoms in patients with mild and moderate breast cancer, and no serious adverse reactions were observed. However, in the future, reasonable clinical design, including appropriate sample size, adequate follow-up time, and clear study endpoint indicators, is needed to establish a CIPN gold standard acupuncture program.
Frozen ** and pressed **:The efficacy of cryotropel-induced peripheral neuropathy with cryotherapy and compression has been reported and is well tolerated and safe. Clinical trials have also shown that compression** with surgical gloves is safe and potentially effective**.
Other**:The use of auricular patches (including acupuncture points on the shenmen, liver, spleen, and fingers or toes)** can reduce CIPN-related symptoms. Home physiotherapy for CIPN symptoms may improve CIPN pain in breast cancer patients, and whole-body exercise during chemotherapy is necessary to maintain sensory function.
Recommendation 5
CIPN non-pharmacological exercises** include functional exercises, acupuncture, auricular patches, cryotyping** and compression**, etc., and functional exercises can be started as early as possible in the early stage of chemotherapy, and TCM acupuncture, auricular patches, cryotyping** and compression** can improve and alleviate CIPN-related symptoms and reduce the occurrence of functional impairment (Level of evidence: Quality, level of recommendation: weak recommendation