Cancer treatment aims to cure or alleviate the symptoms of the disease. One of the most used options, are potential neurotoxic drugs, which, in an attempt to achieve this purpose, can cause side effects that vary among patients depending on multiple factors, and may differ in intensity and duration.
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common side effect of many drugs in cancer treatments: its global incidence varies from 50-90% depending on the drug. Therefore, it is a potentially dose-limiting side effect of several commonly used cytotoxic chemotherapy agents.
CIPN is one of the most common reasons for cancer patients to drop out of treatment. For some people, symptoms can be alleviated by decreasing the drug dose or temporarily suspending it, reducing pain, which leads to dose reduction or even premature interruption of treatment[1-3]. But for other patients, symptoms remain for months, years or even indefinitely after treatment, potentially affecting the patient's function and quality of life[2-4].
The main clinical factor influencing the occurrence of CIPN is the type of cancer, which is what determines the use of a neurotoxic drug. Solid tumors, including colorectal, breast, gynecological, testis, lung, and hematological malignancies, represent the most common cancers treated with neurotoxic chemotherapy.
The main pharmacological classes that can cause CIPN include classic cancer drugs such as platinum compounds (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine and vinblastine), proteasome inhibitors (bortezomib), epothilones (ixabepilone), other chemotherapeutic agents (eribulin, thalidomide and lenalidomide), as well as the recently introduced immunological checkpoint inhibitors.
The CIPN is generally associated with the dosage, both in the amount and in the number of administrations, and with the infusion time of the medication[3-5]. Some drugs have dose-dependent toxicity and others have, instead, idiosyncratic non-dose-dependent toxicities. It is also associated with risk factors such as diabetes, obesity, chronic use of alcohol or a history of smoking, and preexisting peripheral neuropathy (PN)[2,5].
These drugs are effective in killing cancer cells by acting against markedly different but well-identified cellular targets (tubulin, proteasome, cancer-related vessels, etc). However, its neurotoxicity mechanisms are much less known and this is one of the main limitations in the discovery of effective treatments capable of preventing CIPN or limiting its severity.
Chemotherapy treatments lead to several changes in cell structure and function, such as the loss of sensory terminals in the skin. They also lead to changes in membrane receptors and ion channels, intracellular signaling, neurotransmission, excitability and metabolism. All these factors can negatively influence glial and neuronal cell phenotypes, contributing to the development of CIPN.
CIPN symptoms are mainly sensitive, such as paresthesia, dysesthesia and pain, especially in the hands and feet[4,5,7]. However, motor symptoms such as weakness and autonomic neuropathy may also be present.
These sensory and sometimes motor changes can affect the patient's quality of life due to the significant loss of functional abilities to the point where a dose reduction or interruption of therapy is necessary, an action that can negatively impact the time of oncologic disease progression and even patient survival[1,2]. Also, unfortunately, CIPN is not always reversible. Although recovery from induced PN after treatment interruption is common, recovery in some patients may take months or even 2 years, and some patients will never fully recover their neurological functions[2,3].
The Brazilian National Cancer Institute (INCA) summarizes and classifies neurotoxicities in symptoms that affect the Peripheral Sensory Nervous System, namely:
Grade 1: mild paresthesias, reduced reflexes;
Grade 2: moderate paraesthesia, reduced sensitivity;
Grade 3: intolerable paraesthesia, marked reduction in sensitivity;
Grade 4: lack of reflexes and sensitivity.
The development of accurate and sensitive assessment tools for CIPN is essential to allow clinical monitoring during treatment, follow-up of long-term results and measurement of toxicity. As with all treatment toxicities, a balanced approach between patient reporting, physical examination, and physician description is required.
There are several tools available to assess PN and neuropathic pain, but there is no consensus on the ideal method[9,10]. Among the most used tools for screening neuropathic pain is the Douleur Neuropathique en 4 (DN4) questionnaire. DN4 comprises seven symptom items and three clinical examination items. This questionnaire showed a sensitivity of 83% and a specificity of 90% when compared to the medical diagnosis.
Electroneuromyography (ENMG) can be used as a complementary diagnostic test, where it is expected to find a predominantly sensory, peripheral and symmetrical neuropathy pattern[11,12]. However, conventional ENMG does not detect fine-fiber neuropathy and thus may not identify cases of CIPN restricted to them, which in general only present with pain. There are other limiting factors, such as the fact that it is uncomfortable and high costly, and is performed only by specialists in clinical neurophysiology.
The treatment of CIPN is still limited, in part due to the complexity of its mechanisms, which are not yet fully understood[5,7]. So far, only duloxetine is recommended by the American Society of Clinical Oncology (ASCO).
Opioids, which are one of the mainstays of chronic pain treatment, provide only limited relief for CIPN, in addition, they present a risk of dependence.
In the absence of an effective drug solution, dose modification (reduction or discontinuation depending on the degree of PN) remains the gold standard for the management of CIPN[2,3]. Immediate adherence to the dose reduction algorithm is important to limit the severity of PN and to increase the chances of reversibility.
The combination of the trend towards an increased incidence of cancer in the future, with an estimated number of cases reaching approximately 29.5 million in 2040, associated with earlier diagnosis, greater availability of chemotherapy protocols and greater survival, will lead to a greater number of cancer survivors, who will live longer, but a considerable number of them will be affected by CIPN. These numbers underscore the importance of recognizing the CIPN and offering neuroprotective and modifying strategies for the disease in its early stages and/or to prevent its onset, and new symptomatic treatments once it has been established.