What is Vinca Alkaloid Toxicity?
Vinca alkaloids are a type of medication that helps to stop cancer cells from growing. They were one of the first plant-based cancer treatments, made from a periwinkle plant called Vinca rosea, or Catharanthus roseus. There are three generations of these medicines: the first includes drugs called vincristine and vinblastine, the second has vinorelbine and vindesine, and the newest member of this group is vinflunine. Some think of vinflunine as a second-generation drug. It’s the latest version of this kind of medicine and is used to treat bladder cancer that has changed in certain ways.
Interestingly, vinflunine has been found to be more effective and has fewer side effects compared to the older versions. Vinca alkaloids often work better when they are used together with other cancer drugs. This is because they boost the cancer-fighting power of these medications. Plus, most people tolerate them well and are able to manage any side effects that might come up.
Here are some examples of combinations of cancer drugs that include vinca alkaloids:
- CVP: includes cyclophosphamide, vincristine and prednisone
- CHOP: includes cyclophosphamide, doxorubicin, vincristine and prednisone
- VCRT: consists of vinblastine, cisplatin, and radiation therapy
- CISCA/VB: contains cisplatin, doxorubicin, cyclophosphamide, vinblastine and bleomycin
- ABVD: includes doxorubicin, bleomycin, vinblastine, and dacarbazine
But just like any medication, vinca alkaloids can have side effects too. These side effects can affect the nervous system, heart and blood vessels, blood cells, kidneys, and lungs. The most common side effects are related to the nervous system.
What Causes Vinca Alkaloid Toxicity?
Vinca alkaloids are a type of drug that work by blocking a specific process in cells which is necessary for them to divide and multiply. This process involves the assembly of a structure called a spindle, which is crucial in cell division. This blocking action of the drug inhibits the growth of cells, which is particularly useful in cancer treatment where the aim is to stop the rapid multiplication of cancer cells.
At low doses, these drugs disrupt this cell division process, and at higher doses, they can stop the cell cycle completely and even trigger programmed cell death, or apoptosis. This process involves signaling proteins within the cell such as BCL-2 and BAX, which control cell death.
Microtubules, the structures that Vinca alkaloids target, are involved in many other key cell functions such as transportation of substances within the cell, cell movement and maintaining the cell’s shape and internal structure. Therefore, the effects of these drugs can be seen in various aspects of cell function.
It’s important to know that certain drugs, such as antifungals, shouldn’t be taken with Vinca alkaloids. This is because these combinations can increase the risk of nerve damage, which may even lead to seizures. The reason behind this is that antifungal drugs can hinder how the body metabolises Vinca alkaloids, and this can result in higher levels of these drugs in the blood.
Risk Factors and Frequency for Vinca Alkaloid Toxicity
Vinca alkaloids, a type of medicine, can cause toxicity in a couple of ways. This is especially true for vincristine, which is a type of vinca alkaloid, and it can lead to toxicity as a result of being given in the wrong way or wrong dosage. Side-effects from these drugs often include nerve damage, particularly peripheral neuropathy, with vincristine being the main medicine causing this. Factors increasing the risk of nerve damage are smoking, pre-existing nerve diseases, poor kidney function, higher dosage, and certain gene mutations. Additionally, all these drugs are connected with a condition called SIADH, with a moderate to severe low sodium level. The severity and onset of SIADH vary depending on the drug used.
- Vincristine: This is used to treat several types of cancer, including certain leukemias, lymphomas, breast cancer, brain tumours, bowel cancer, and multiple myeloma. Nerve toxicity is the main side effect and can appear within a week of starting treatment. The risk of nerve damage varies between age groups and pre-existing nerve diseases increase this risk. Interestingly, this side effect occurs more frequently in Black patients and in those receiving higher doses.
- Vinblastine: This is used to treat a variety of “liquid” cancers, including leukemias, lymphomas, breast cancer, and testicular cancer. Side effects include paralytic ileus, liver problems, and reduced blood cell production. The risk of severe infections due to low white blood cells is less than 10%, but severity can increase during some treatment regimens.
- Vindesine: This is used to treat solid tumors in children, as well as breast, kidney, and esophagus cancers. It can cause higher nerve toxicity compared to vincristine, and reduced white blood cell count is often the reason doctors have to limit its dose.
- Vinorelbine: This is used for advanced stages of breast and lung cancer. Side effects include mild to moderate nerve damage and constipation, nausea, and vomiting. Less frequent side effects are diarrhea and mouth ulcers.
- Vinflunine: This is a derivative of vinorelbine and is used to treat bladder cancer when other treatments have failed. Side effects include anemia, neutropenic fever, fatigue, and constipation. Nerve damage is reported but comparable to the control group.
Signs and Symptoms of Vinca Alkaloid Toxicity
When assessing a patient with vinca alkaloid toxicity, it’s important to look into the patient’s medical and cancer history, as well as their current chemotherapy treatment. We also need to understand details about their most recent treatment episode, like the method of administration and dosage amount. Key symptoms can suggest what organ systems are affected and help gauge the severity and onset of symptoms.
Peripheral Nervous System
Vinca alkaloids like vincristine can often result in nerve damage, with symptoms affecting the sensory, motor and autonomic systems. One might experience tingling sensations, difficulties with balance, foot drop and more. Notably, these symptoms can become quite serious, including quadriparesis (partial paralysis of all four limbs) in severe cases. If a patient shows signs of intense nerve symptoms, eliminating vincristine and considering genetical conditions becomes necessary.
- Sensory symptoms: painful sensations or tingling, ataxia, foot drop
- Motor symptoms: cranial nerve palsy
- Autonomic symptoms: constipation, abdominal cramps, bladder atony, arterial hypertension or hypotension, and orthostatic hypotension
Central Nervous System
These drugs can also induce symptoms like memory problems (acute or subacute encephalopathy), seizures, and vision loss. Jaw pain and abnormal vocal cord function are other notable side effects. Severe toxicity can trigger seizures, particularly if the drug is administered excessively.
Hematological and Renal Toxicity
These drugs can also affect the blood and kidneys. Vincristine is typically not harmful to the bone marrow, but associated drugs can lead to blood disorders. Notably, renal complications are rare, as these drugs are not significantly excreted through the kidneys.
Hepatic and Pulmonary Toxicity
Vinca alkaloids can harm the liver, especially in patients with increased bilirubin levels. While pulmonary complications are relatively rare, they can occur if vinca alkaloids are used alongside mitomycin-C, leading to acute breathing difficulties and bronchospasm.
Gastrointestinal, Cardiovascular and Local Toxicity
Vinca alkaloids can cause mouth sores and paralytic ileus in the stomach and intestines. They can also lead to disturbances in heart function and can damage the skin when injected. It can cause hair loss in rare cases.
Testing for Vinca Alkaloid Toxicity
The tests your doctor orders aim to check for damages caused to body organs (known as end-organ toxicity). These tests include a full blood count, a basic metabolic panel, a liver function test, and a coagulation panel. The tests check for conditions such as leukopenia (a low number of white blood cells), anemia (a low red blood cell count), thrombocytopenia (a low number of platelets), any irregularities in body salts and kidney function, liver dysfunction, and coagulopathy (a condition that affects the blood’s ability to clot).
An electrocardiogram (a test that measures the electrical activity of the heartbeat) and a troponin test (a test to detect any damage to the heart) may be performed if there’s a concern for reduced blood supply (myocardial ischemia). Tests to determine the levels of the drug vinca alkaloids in body fluids (such as blood and cerebrospinal fluid that surrounds the brain and spinal cord) can be used to help predict the severity of the drug’s toxicity. Remember, higher levels generally link to more severe toxicity.
Advanced imaging techniques can help rule out other possible causes of your symptoms.
Signs of the syndrome of inappropriate antidiuretic hormone can be present, with symptoms of low blood volume and low sodium levels in the blood (hypovolemic hyponatremia). This condition may be diagnosed by measuring the concentration of particles in your urine and blood (urine and plasma osmolarity). Hepatic venous-occlusive disease, a condition associated with decreased or absent blood flow in the liver vein, can be detected using liver function tests and duplex ultrasonography, a type of imaging test. The diagnosis can be supported using the Seattle and Baltimore criteria. Significantly increased levels of bilirubin in the blood (hyperbilirubinemia with a serum bilirubin level exceeding 2 mg/dL) have been regarded as a primary diagnostic symptom.
The effect of chemotherapy on the nerves (chemotherapy-induced peripheral neuropathy) can be evaluated using various tools. These tools measure the adverse effects of chemotherapy treatments, as well as your quality of life. Although there are no tools designed specifically for neurotoxicity caused by vinca alkaloids, there are identified risk factors.
Medical tests like nerve conduction studies and electromyography, used to test the nerves and muscles, might indicate symptoms of axonopathy, a nerve disease. However, these tests are not routinely performed due to their cost. For patients with a hoarse voice, your doctor might order an indirect laryngoscopic examination, a procedure that involves a long, flexible scope to visually check the vocal cords, which will show if the affected vocal cord’s movement is reduced.
Treatment Options for Vinca Alkaloid Toxicity
Certain medications and treatments can help manage the syndrome of inappropriate antidiuretic hormone (which can cause low sodium levels in your blood). These include limiting fluid intake, having a saline solution, and using a type of medication known as loop diuretics.
Neutropenia, a condition characterized by a low number of white blood cells, can be treated with a medication known as a granulocyte colony-stimulating factor. For seizures, benzodiazepines are often the first line of treatment. To spot neurological symptoms early, regular check-ups and patient education strategies are key. Also, the dosage of some medications may need adjusting, or alternative treatments may need considering if side effects are too severe.
Other strategies like neuroprotective and neurostimulatory measures are being researched, but more solid scientific evidence is needed to validate their use. Two substances, pyridostigmine and pyridoxine, have been found to improve the rate of recovery from vincristine-induced peripheral neuropathy, a side effect of certain chemotherapy drugs which causes nerve damage. However, the effectiveness of glutamic acid, another substance, in treating this condition is still being investigated.
More than half of children patients with vincristine-induced bilateral vocal cord palsy, a condition which causes the vocal cords to become paralyzed, may need treatment to protect their airways. This could involve a medical procedure known as a tracheostomy in extreme cases.
Secondary preventive strategies can help lessen the impact of these side effects on a patient’s quality of life. Education for patients and their caregivers, lifestyle changes, physical and occupational therapies, and avoiding elements that could lead to a neurological condition can help improve outcomes. It’s important to be aware of the risk of long-term neurotoxicity (harm to the nervous system), to manage this impact on the patient’s quality of life. Physical therapy can also improve motor symptoms.
A medication called defibrotide is a good treatment option in the management of hepatic veno-occlusive disease, a condition that can cause blockage of small veins in the liver. In certain cases, surgical and medical consultation may be required for treatment management.
To minimize inflammation, it’s recommended to flush the veins after an injection. Extravasations of a group of compounds known as vinca alkaloids, which are used in certain chemotherapy treatments, may result in skin ulcers. This can be treated with a compound called hyaluronidase and corticosteroids. In severe cases, immediate medical attention and surgical removal of damaged skin area may be necessary. In accidental cases where vinca alkaloids are administered into the spinal fluid, it’s considered a neurosurgical emergency and swift consultation with a neurosurgeon is necessary.
If a patient has severe toxicity, removal of these substances from their blood outside the body, known as extracorporeal removal, should be considered. Because vinca alkaloids bind quickly to proteins and distribute rapidly in the body, methods other than traditional dialysis may be better. For adults, a treatment known as plasmapheresis, and for children, a process called exchange transfusion have been successful in lowering the concentration of chemical substances in the blood.
What else can Vinca Alkaloid Toxicity be?
Peripheral neuropathy, a condition that affects the nerves outside your brain and spinal cord, can be caused by a variety of factors. However, understanding someone’s current medical treatments can often assist in figuring out the cause. Several anti-cancer drugs can be linked to peripheral neuropathy. Some examples include ixabepilone from the group of drugs called epothilones, paclitaxel and docetaxel from the group called taxanes, and oxaliplatin and cisplatin from the platinum-based antineoplastics.
When it comes to the syndrome of inappropriate antidiuretic hormone, a condition where your body makes too much antidiuretic hormone that issues orders to your kidneys, several causes can be considered:
- Tumors, particularly small cell lung carcinoma
- Problems in the brain, like a stroke or a brain bleed
- Medication side effects, from drugs like carbamazepine and selective serotonin reuptake inhibitors
If someone is experiencing constipation or something called ileus, where the intestine doesn’t move food along properly, there could be a few different causes to look into:
- Imbalance of body salts, particularly low potassium
- Reduced intake of food and drink
- Constipation caused by opioid medications
- Peritoneal carcinomatosis, which is cancer spread to the tissue covering organs in your belly
What to expect with Vinca Alkaloid Toxicity
The side effects from acute toxicity, which can include stomach discomfort, blood disorders, or heart-related issues, may remain for several days after stopping the vinca alkaloids treatment. Early detection is important to manage these side effects. Mild symptoms related to peripheral neuropathy, which is nerve damage often causing weakness, numbness and pain, caused by Vincristine, another type of drug, usually improve over a period of weeks to months and do not have any long-term effects.
However, severe symptoms may continue to cause distress for months to years without fully going away. On the bright side, Vincristine-induced vocal cord palsy, a condition that impairs the ability to speak, is generally temporary. Complete recovery from this can be expected within 6 to 9 months.
Possible Complications When Diagnosed with Vinca Alkaloid Toxicity
Some people have reported long-term nerve damage effects even many years after stopping the treatment with Vincristine. This can adversely affect their quality of life, adding to their long-term illness or disability.
- Long-term nerve damage
- Effects years after stopping vincristine treatment
- Negative impact on quality of life
- Increase in long-term illness or disability
Preventing Vinca Alkaloid Toxicity
Chemotherapy drugs, specifically those called Vinca alkaloids, can often cause significant side effects. It’s really important for patients undergoing cancer treatment to tell their doctor about any and all symptoms they are experiencing. Being aware of these symptoms early on can help limit any negative effect on their daily life and stop symptoms from getting worse. If such side effects are not identified early, it might lead to issues such as imbalances in body salts (electrolytes), liver damage (hepatotoxicity), serious infections, seizures, and nerve damage (peripheral neuropathy).
