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Vinca Alkaloid Toxicity
Introduction
Vinca alkaloids, which belong to a class of cell cycle phase M-specific anti-tubulin agents, were one of the first plant alkaloids to be developed for use as anti-cancer agents in humans. Vinca alkaloids derived from Vinca rosea or the periwinkle plant (Catharanthus roseus) include first-generation (vincristine, vinblastine), second-generation semi-synthetic derivatives (vinorelbine, vindesine), and third-generation (vinflunine). Some have also classified vinflunine as a second-generation agent.[1] Vinflunine is the newest vinca alkaloid and fluorinated anti-microtubule agent. The medication has been used to treat transitional cell urothelial bladder cancer. Vinflunine is reported to have a higher potency and lower frequency of adverse events when compared to the older vinca alkaloid agents.[2] Vinca alkaloids are usually combined with other agents (as part of multi-drug combination regimens) since they potentiate the anti-cancer effects. These are also known to be well tolerated with manageable adverse events.[3]
Examples of multidrug regimens include:
- CVP: cyclophosphamide, vincristine and prednisone
- CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone
- VCRT: vinblastine, cisplatin, radiation therapy
- CISCA/VB: cisplatin, doxorubicin, cyclophosphamide, vinblastine and bleomycin
- ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine
Toxicity from vinca alkaloids affects multiple organ systems, including the peripheral and central nervous, cardiovascular, hematologic, renal, and pulmonary systems. Neurotoxicity is the most commonly reported adverse event.
Etiology
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Etiology
Vinca alkaloids function as microtubule inhibitors, inhibiting the polymerization of tubulin, which is necessary for spindle formation during the M-phase of the cell cycle.[4] While they disrupt microtubular function at low doses, cell cycle arrest and apoptosis are seen at higher doses.[5] Cell cycle arrest has been attributed to phosphorylation of the pro-apoptotic B-cell lymphoma (BCL-2) protein and increased levels of BCL–2–associated X protein.[6] Microtubules are also involved in other essential cell cycle functions, such as transcellular transport, cellular motility, and stability of the cellular cytoskeleton; hence, their effects are seen in other crucial cellular functions.[7] Clinicians should avoid the concomitant use of these drugs with azole antifungals due to the increased risk of neurotoxicity, which has been known to present with seizures.[8] This is due to the inhibition of cytochrome P450 3A4, leading to decreased metabolism, as well as inhibition of p-glycoprotein, which usually transports xenobiotics out of a cell.[9] These mechanisms lead to increased serum concentrations of vinca alkaloids.
Epidemiology
Toxicity, via therapeutic dosing and overdose, occurs for all vinca alkaloids. Acute toxicity due to overdose has been reportedly most frequently with vincristine, which can occur with administration through incorrect route, incorrect dosing, confusing vincristine with vinblastine, and confusing different strength vials. Neurotoxicity, specifically peripheral neuropathy, is one of the most commonly reported adverse events of vinca alkaloids, with vincristine implicated in the majority of cases. Risk factors include smoking, pre-existing neuropathy, renal dysfunction, higher dosing, and specific gene mutations.[10] All vinca alkaloids are associated with the occurrence of the syndrome of inappropriate diuretic hormone (SIADH), with moderate to severe hyponatremia being reported in 11% for vincristine and higher for vinblastine. The onset of SIADH is variable and agent-dependent.[11]
Vincristine
Vincristine is used to treat Philadelphia chromosome-negative acute lymphoblastic leukemia, B-cell lymphoma, estrogen-receptor-negative breast cancer, glioma, colorectal cancer, multiple myeloma, and Wilm tumor. Neurotoxicity is the most common adverse event from vincristine. Signs and symptoms are known to emerge within 1 week of initiation.[12] The prevalence of vincristine-induced neuropathy is known to be 1.36% in younger populations and as high as 30% in the adult population.[13] The presence of pre-existent diabetic neuropathy and Charcot-Marie-Tooth disease type I correlate with a higher risk of developing sensorimotor polyneuropathy. The incidence of neurotoxicity is more common in Black patients and those receiving higher doses of vincristine during treatment. Lower expression of cytochrome (CYP) CYP3A4 and CYP3A5, responsible for the metabolism of vincristine, is associated with an increased risk of peripheral neuropathy.[9][14][15]Central nervous system toxicity also occurs with greater severity than the other vinca alkaloids.
Vinblastine
Vinblastine is used to treat various liquid cancers, such as leukemia, Hodgkin and non-Hodgkin lymphoma, breast cancer, and testicular carcinoma. Paralytic ileus is more common when using vincristine. Research shows the condition occurs with a frequency of 2% to 4% in patients receiving vinblastine.[16] Transient elevation of transaminases occurs in 5% to 10% of cases.[17] Myelosuppression occurs with increased severity as compared with vincristine. The risk of febrile neutropenia is apparent in those receiving chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) scheduled for Hodgkin lymphoma to be less than 10% by the National Comprehensive Cancer Network guidelines, the incidence of grade III/IV neutropenia is said to have been 20.9%.[18]
Vindesine
Vindesine has been used for treating pediatric solid tumors, blast-crisis, as well as breast, renal, and esophageal carcinomas. The severity of neurotoxicity is reported to be higher with vindesine as compared with vincristine. The dose-limiting effect is often myelosuppression, leading to leukopenia.[19]
Vinorelbine
Vinorelbine is used for advanced breast cancer and advanced non-small cell lung cancer. Vinorelbine is associated with mild to moderate neuropathy and constipation. Further, mild to moderate nausea and vomiting occur in a third of patients on vinorelbine, whereas diarrhea and stomatitis are less frequent.[20]
Vinflunine
Vinflunine is a derivative of vinorelbine, used for the treatment of bladder cancer that has failed platinum-based treatment. In the CURVE trial, adverse events included anemia, neutropenic fever, fatigue, and constipation. Peripheral neuropathy is reported but had occurred similarly to the control group.[21]
Pathophysiology
The microtubular apparatus plays a pivotal role in axonal transport and secretory function. The normal function of the microtubule apparatus involves polymerization and depolymerization of individual α and β subunits. Vinca alkaloids bind to specific sites on the β-subunit and prevent propagation of the microtubule. The inhibitory action of these drugs on the microtubular apparatus is responsible for their anti-cancer effects and toxicity. Vinca alkaloids penetrate the blood-brain barrier poorly due to their large size and significant protein binding. As a result, effects on the peripheral nervous system predominate over central nervous system actions.[22]
Overproduction of P-glycoprotein by cancer cells may lead to resistance to various anti-cancer drugs, including vinca alkaloids.[23] Mutations in β-tubulin with overexpression of different isotypes may also correlate with the production of altered effects, leading to developing drug resistance.[24]
Toxicokinetics
Current data suggest that vinca alkaloids exhibit a triphasic clearance. The initial 2 phases are similar for all agents, with rapid distribution and uptake into peripheral tissues. The terminal phase depends on the agent in question, as this phase is dependent on tissue sequestration. All vinca alkaloids bind plasma proteins. Distribution into peripheral tissues also depends on the contained cells' tubulin content.[25] All vinca alkaloids are metabolized by the CYP3A isozyme and undergo majority hepatobiliary elimination with almost no renal clearance.[26]
Capping the single maximum dose to 2 mg, irrespective of the body surface area, has been suggested to minimize the probability of occurrence of acute neurotoxicity.[16] The use of vincristine mini bags is an alternative to prevent inadvertent intrathecal administration, which can be potentially lethal.[27] Developing liposomal formulations may allow for more than the single recommended dose of 2 mg.[28]
History and Physical
When evaluating a patient with vinca alkaloid toxicity, obtain historical information concerning the patient's medical history, cancer history, and current chemotherapy regimen. Also, information concerning the patient's most recent treatment, the amount, and the route of administration must be obtained. Questions should be directed to help determine the organ systems involved, the onset time, and the severity of symptoms.
Peripheral Nervous System
The incidence of peripheral neuropathy, which presents in a typical glove and stocking distribution and proceeds from a distal to a proximal fashion with vincristine, is known to range between 35% and 45%.[29] Vincristine-induced neurotoxicity is known to present with sensory, motor, and autonomic symptoms. Dose-limiting toxicity of vincristine, predominantly sensory, presents with painful dysesthesias, ataxia, foot drop, and cranial nerve palsy (affecting extraocular and laryngeal muscles). Neurotoxicity is dose-dependent, with a 2 to 6 mg dose threshold for developing sensory symptoms. Guidelines suggest a single dose of vincristine should not exceed 2 mg to prevent neurotoxicity. Peripheral neurotoxicity may present with areflexia as the initial complaint, followed by paraesthesias. Muscle cramps herald the onset of sensory symptoms.[30] While the sensory deficit may be reversible, the motor symptoms are known to be irreversible. Posterior column involvement with the loss of joint position sense is an indication to stop using these drugs. Vincristine is associated with acute motor axonal neuropathy development, which must be distinguished from other forms of Guillain-Barre syndrome, particularly acute inflammatory demyelinating polyneuropathy.[31] A severe peripheral neuropathy presenting with quadriparesis has also been reported with vincristine in patients with Guillain-Barre syndrome.[12] The family history of Charcot-Marie-Tooth disease is a contraindication to the use of vincristine. Patients who develop signs of acute neurotoxicity with vincristine should undergo evaluation for this degenerative condition.[32] The worsening of neuropathy symptoms upon cessation of chemotherapy, known as "coasting," is seen in 30% of patients.[13]
Autonomic neuropathy, which presents with constipation, ileus, and abdominal cramps, may require pre-emptive laxatives.[33] Autonomic symptoms may also lead to bladder atony, which manifests as urinary retention, polyuria, and dysuria.[34] Autonomic effects on the cardiovascular system may present as arterial hypertension or hypotension and orthostatic hypotension.[35] The onset of mild autonomic symptoms is known to predate the development of peripheral neuropathy.[36] Capping the single maximum dose of vincristine to 2 mg, irrespective of the body surface area, has been suggested as an option to minimize the probability of acute neurotoxicity occurrence.[16] Using vincristine mini bags is an alternative to prevent inadvertent intrathecal administration, which can be potentially lethal.[27]
Central Nervous System
Acute or subacute encephalopathy, seizures, and visual loss can occur when administering these drugs, typically in the setting of overdose or delayed elimination.[37] Other less frequent side effects include transient cortical blindness with posterior reversible encephalopathy syndrome, unilateral or bilateral optic neuropathy, ataxia, visual hallucinations, tremors, parkinsonism, and syndrome of inappropriate antidiuretic hormone secretion.[38] The latter is more common in patients receiving intravenous hydration and may present with encephalopathy and generalized seizures.[39] Accidental intrathecal administration is associated with ascending myelopathy, coma, and death.[40]
Jaw pain with a neuropathic component, which is non-responsive to traditional pain medications, has been reported with the use of vincristine. A hypothesis exists that this pain results from the fifth cranial nerve (trigeminal nerve) involvement.[36] Vincristine-induced vocal cord palsy, which is a potentially reversible phenomenon and subsides with the cessation of the drug, has also been reported in the literature.[41] The involvement of the vocal cords, which presents with hoarseness of voice, could present as unilateral or bilateral but has been reported to be more common on the left side. While bilateral involvement is known to localize to the vagal nucleus neurologically, unilateral involvement is known to occur due to recurrent laryngeal nerve involvement.[42] Higher doses, preexisting hepatic dysfunction, neuropathic illness, history of hypersensitivity to the drug, and co-administration of other cancer chemotherapy agents and non-chemotherapy drugs such as mitomycin–C, allopurinol, azathioprine, phenytoin, isoniazid, and itraconazole has also shown a predisposition to an increased risk of vocal cord palsy.[43] Seizures, as a direct effect, can occur in severe toxicity, particularly in acute overdoses.[44]
Hematological Toxicity
Vincristine is usually a bone marrow-sparing agent. Reports exist of dose-limiting hematological toxicity of vinblastine.[45] Leukopenia is more common than thrombocytopenia, and anemia is not as common. Vinorelbine and vindesine are also known to cause bone marrow toxicity.[46]
Renal Toxicity
Vinblastine and its active metabolite desacetylvinblastine, vincristine, and vindesine have low renal excretion (10% to 15%).[3] No dose adjustment has been advised for vinca alkaloids as a class. However, the dose of vinorelbine should be reduced by 50% in patients undergoing hemodialysis due to an increased risk of adverse events.[47]
Hepatic Toxicity
Since vincristine is primarily metabolized in the liver, dose adjustments are recommended for hepatic dysfunction with hyperbilirubinemia, particularly in cases with an elevation of the direct bilirubin fraction.[17] Both vincristine and vinblastine are known to cause hepatic sinusoidal obstruction syndrome (hepatic veno-occlusive disease) in children or predisposed individuals, namely those with higher doses of radiation and concurrent use of dactinomycin and cyclophosphamide.[48][49] The adverse events include jaundice, anasarca, weight gain, and right upper quadrant pain.
Pulmonary Toxicity
Acute dyspnea and bronchospasm may occur with the concurrent use of vincristine and vinblastine with mitomycin-C.[50]
Gastrointestinal Toxicity
Vinca alkaloids are associated with the development of oral-mucosal ulcerations and paralytic ileus. Vinorelbine and its metabolites are associated with chemotherapy-induced autonomic neuropathy, which may present with constipation and urinary retention through activation of the muscarinic receptors.[51]
Cardiovascular Toxicity
Apart from the cardiovascular autonomic effects, which present as disturbances in the hemodynamic parameters (eg, hypotension, tachycardia), these drugs have also correlated with cardiac ischemic pain presenting with electrocardiographic abnormalities and myocardial infarction.[52]
Local Effects
Vincristine and vinblastine are known to act as vesicants and cause chemotherapy-associated extravasation.[53] Recommendations include caution against the intramuscular, subcutaneous, and intraperitoneal use of vinca alkaloids. A bolus injection is recommended whenever possible due to the risks associated with local administration. Local reactions related to the injection include erythema, pain, and discoloration.[54]
Other Rare Adverse Events
Alopecia is a rare adverse event of these drugs.[55]
Evaluation
Testing should be directed at evaluating for end-organ toxicity. A complete blood count, basic metabolic panel, liver function tests, and coagulation panel should be obtained to assess leukopenia, anemia and thrombocytopenia, electrolyte abnormalities and kidney function, liver dysfunction, and coagulopathy. An electrocardiogram and troponin testing should be performed if a concern for myocardial ischemia is apparent. Although generally not readily available, vinca alkaloids can be obtained. Testing of bodily fluids such as blood and cerebral spinal fluid can be used as a potential prognostication tool, as higher levels are associated with more severe toxicity. Advanced imaging should be used to explore other potential differentials.
Syndrome of inappropriate antidiuretic hormone is known to be present with symptoms of hypovolemic hyponatremia and may require determination of urine and plasma osmolarity for diagnosis. Hepatic venous-occlusive disease is associated with decreased or absent blood flow in the hepatic vein on duplex ultrasonography. Liver function tests are usually abnormal. The Seattle and Baltimore criteria have been useful in diagnosing hepatic veno-occlusive disease. Hyperbilirubinemia with a serum bilirubin level exceeding 2 mg/dL has been positioned as the sine qua non in the diagnosis. In contrast, transfusion refractory thrombocytopenia is an addition to a recent modification of the diagnostic criteria.[56]
Various tools are used to evaluate chemotherapy-induced peripheral neuropathy, namely the "Common Terminology Criteria for Adverse Events" developed by the National Cancer Institute, the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire C30, and the Chemotherapy-Induced Peripheral Neuropathy-20 Questionnaire.[57][58][59][60][61] No tools specific for neurotoxicity caused by vinca alkaloids exist, although various risk factors predisposing to neurotoxic adverse events are identified.
Both nerve conduction studies and electromyography are expected to demonstrate symptoms of axonopathy, but they are not routinely performed due to the costs involved. An indirect laryngoscopic examination in patients with hoarseness of voice will likely demonstrate reduced mobility of the affected vocal cord.
Treatment / Management
Fluid restriction, supplementation with 3% hypertonic saline, and use of loop diuretics are the recommendations for managing syndrome of inappropriate antidiuretic hormone.[39] Neutropenia can be treated with a granulocyte colony-stimulating factor.[62] Seizures are treated primarily with benzodiazepines. Regular surveillance and patient education strategies are necessary to recognize neurological symptomatic adverse events early. Modification of the administered dose, use of alternative treatment (substitution of vincristine with vindesine is advisable in patients with Charcot-Marie-Tooth disease), and cessation of chemotherapy in case of severe, life-threatening toxicities seem to be the most effective strategies to control the adverse effects.[63] (B3)
While researchers have studied many neuroprotective and neurostimulatory strategies, more robust scientific evidence is needed to support their use. Both pyridostigmine and pyridoxine improve the rate of recovery of vincristine-induced peripheral neuropathy. In contrast, the role of glutamic acid in treating this condition has been a subject of pre-clinical studies.[16][64] A double-blind, randomized control trial to assess the efficacy of glutamic acid in the prevention of vincristine-induced neurotoxicity reportedly showed a negative outcome.[65] About 55% to 66% of pediatric patients presenting with vincristine-induced bilateral vocal cord palsy may need airway protection and, in severe cases, tracheostomy.[42](A1)
Secondary preventive strategies to mitigate the impact of these adverse effects on the patient's quality of life can be beneficial. Patient and caregiver education, lifestyle interventions, physical and occupational therapy approaches, and avoiding risk factors predisposing to a neurological insult can also improve outcomes.[66] The risk of long-term neurotoxicity should be recognized, and rehabilitative approaches should mitigate the impact of this neurological insult on the patient's quality of life.[12] Physical therapy can provide benefits for the amelioration of motor symptoms.[67] Defibrotide is a viable treatment option in the management of hepatic veno-occlusive disease.[68] Surgical, interventional radiology, and hepatic consultation should be obtained to assist with management.
Flushing the veins after injection is advisable to minimize inflammation. Extravasations of vinca alkaloids have shown an association with skin ulceration up to 24 hours after administering these agents, for which hyaluronidase and corticosteroids can provide viable treatment options. Urgent surgical consultation and immediate debridement are necessary for severe cases.[69][70] Intrathecal administration of vinca alkaloids is a neurosurgical emergency, and prompt neurosurgical consultation may limit morbidity and mortality. Cerebral spinal fluid aspiration, irrigation, and intrathecally administrating folinic acid, glutamic acid, and pyridoxine have been reported with variable results.[71][72][73](B2)
Extracorporeal removal should be considered in patients with severe toxicity. Due to rapid distribution and high protein binding, other methods than hemodialysis may be beneficial. Plasmapheresis in adults and exchange transfusion in children successfully decrease serum concentrations of vincristine.[74][75](B3)
Differential Diagnosis
Peripheral neuropathy can occur due to various etiologies, but historical information about current treatment helps narrow a diagnosis. Peripheral neuropathy is associated with other anti-cancer medications, such as epothilones (ixabepilone), taxanes (paclitaxel, docetaxel), and platinum-based antineoplastics (oxaliplatin and cisplatin). The differential for syndrome of inappropriate antidiuretic hormone includes neoplasm (eg, small cell lung carcinoma), central nervous system pathology (eg, stroke, hemorrhage), and drug-associated (eg, carbamazepine, selective serotonin reuptake inhibitors).[76][77] Electrolyte abnormalities (hypokalemia), reduced oral intake, opioid-induced constipation, and peritoneal carcinomatosis may be considered in the differential diagnosis for constipation or ileus.[78]
Pertinent Studies and Ongoing Trials
Randomized clinical trials examining the effect of putative neuroprotective agents such as glutamine, acetyl-L-carnitine, and vitamins B12 and B6 against vincristine-induced neuropathy have been performed. Glutamine was studied in the pediatric and adolescent population and was associated with improved sensory function and reported quality of life.[79] In a pilot study of Chinese patients with cancer, acetyl-L-carnitine was associated with improved sensory function and decreased fatigue.[80] Another study looked at vitamins B12 and B6 to prevent peripheral neuropathy in neurotoxic chemotherapy agents and found no difference in the prevention of neuropathy compared to controls, but decreased severity was a potential benefit.[81]
Prognosis
Acute toxicity effects, such as gastrointestinal distress, hematologic toxicity, or cardiovascular effects, may last several days after discontinuation of the vinca alkaloid and depend on rapid identification. Mild symptoms of vincristine-induced peripheral neuropathy generally subside over weeks to months with no residual deficits. Severe symptoms may persist for months to years without complete resolution. Vincristine-induced vocal cord palsy is generally reversible, with complete recovery expected within 6 to 9 months.[42]
Complications
Long-term sequelae of neuropathy have been reported in patients many years after cessation of treatment with vincristine, and a negative impact on the quality of life adds to the long-lasting morbidity.[16]
Deterrence and Patient Education
Vinca alkaloid chemotherapeutic agents are associated with significant toxicity. As a patient, reporting adverse effects during cancer treatment is important. Early identification of symptoms is crucial to reduce the potential impact on quality of life and prevent worsening symptoms. Delayed diagnosis may lead to electrolyte derangements, hepatotoxicity, severe infection, seizures, and peripheral neuropathy.
Enhancing Healthcare Team Outcomes
Vinca alkaloids, commonly used in cancer treatment, pose a risk of toxicity that clinicians must be vigilant about. These chemotherapeutic agents, including vincristine and vinblastine, can lead to severe neurotoxicity if not carefully administered. Recognizing early signs such as neuropathic pain, muscle weakness, and constipation is crucial. Dose adjustment and careful administration via central venous access can help mitigate toxicity risks. Regular neurological assessments and close monitoring of patients during and after infusion are essential to identify and manage potential complications promptly. Clinicians should also be aware of drug interactions and adjust treatment plans accordingly. Through heightened awareness, meticulous administration, and proactive management, healthcare providers can optimize the benefits of Vinca alkaloids while minimizing the risk of toxicities, ensuring safer and more effective cancer therapy.
Apart from the oncologist, the care team comprising nurses, nurse practitioners, physician assistants, pharmacists, technologists, physical and occupational therapists, and other physicians may also play a direct or indirect role in the treatment process. Therefore, monitoring patients for adverse effects is imperative. This can help minimize the morbidity and mortality resulting from vinca alkaloid treatment. The occurrence of neurotoxicity and extravasation should be anticipated in the acute setting. If an adverse effect is identified, the care team must work together to modify the treatment plan or institute appropriate treatment.
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