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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 (Catharanthus roseus) consists of first-generation (vincristine, vinblastine), second-generation semi-synthetic derivatives (vinorelbine, vindesine), and third-generation (vinflunine). Vinflunine has also been classified by some as a second-generation agent. [1][2]
Vinflunine, the newest, third-generation, fluorinated, anti-microtubule agent, has been used in the setting of transitional cell urothelial bladder cancer. has been advocated to have a higher potency and lesser frequency of adverse events when compared to the older agents.[3] They are usually used in combination with other agents (as part of multi-drug combination regimens) since they have been shown to potentiate the anti-cancer effects. These are also known to be well tolerated with manageable adverse effects.[2] Vinca alkaloids are highly lipophilic and attain very high intracellular concentrations. Overproduction of P-glycoprotein, which is an efflux transporter protein, is a plausible mechanism of development of acquired drug resistance.[4] Mutations in beta-tubulin with overexpression of different isotypes may also correlate with the production of altered effects, leading to the development of drug resistance.[5]
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.[6] While they disrupt microtubular function at low doses, cell cycle arrest and apoptosis are seen at higher doses.[7] 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 (BAX) protein.[8] Microtubules are also involved in other essential functions of the cell cycle, such as transcellular transport, cellular motility, and stability of the cellular cytoskeleton; hence their effects may also be felt on other crucial cellular functions.[9]
Epidemiology
Vincristine
Neurotoxicity is the most common side effect of vincristine.[10] Signs and symptoms are known to emerge within a week of initiation.[11]
The prevalence of vincristine-induced neuropathy is known to be 1.36 percent in the pediatric population.[11]
The presence of pre-existent diabetic neuropathy and Charcot-Marie-Tooth disease type I correlate with a higher risk of developing sensorimotor polyneuropathy.[11]
Commoner in African Americans, dose-dependant.
The Incidence of peripheral neuropathy with the use of vincristine approaches 30 percent.
CYP 3A5 is involved in the metabolism of Vincristine. Lower expression of the CYP 3A5 gene slows down the metabolism of vincristine [12]. Delayed metabolism of vincristine has been associated with a higher incidence of Vincristine induced peripheral neuropathy. [13]
Vinblastine
Although paralytic ileus is known to be more common with the use of vincristine, research shows it to occur with a frequency of 2 to 4 percent in patients receiving vinblastine.[10]
Transient elevation of transaminases occurs in 5 to 10 percent of cases.[14]
Vinorelbine
Mild-moderate neuropathy and constipation.
Mild to moderate nausea and vomiting has been shown to occur in a third of patients on vinorelbine, whereas diarrhea and stomatitis are less frequent.[15]
Dose and duration dependant myelosuppression generally occurs 5 to 10 days after the administration of the drug and is known to subside after 1 to 2 weeks of cessation of use.[16] While there is documentation of the risk of febrile neutropenia in those receiving chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) schedule for Hodgkin lymphoma to be less than 10 percent by the national comprehensive cancer network guidelines, the incidence of grade iii/iv neutropenia is said to have been 20.9 percent.[17]
Pathophysiology
The microtubular apparatus plays a pivotal role in axonal transport and secretory function. The inhibitory action of these drugs on the microtubular apparatus is responsible for their neurotoxicity. [18]
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.[18]
History and Physical
Adverse Effects
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 to 45%.[19] Vincristine induced neurotoxicity is known to present with the sensory, motor, and autonomic symptoms [10]. Dose-limiting toxicity of vincristine, predominantly sensory presenting with painful dysesthesias, ataxia, foot drop, and cranial nerve palsy (affecting extraocular and laryngeal muscles).[20] Neurotoxicity is dose-dependent with a dose threshold of 2 to 6 mg/m^2 for the development of sensory symptoms.[21] Guidelines suggest that a single dose of vincristine should not exceed 2 mg to prevent neurotoxicity.[10] Peripheral neurotoxicity may present with areflexia as the initial complaint followed by paraesthesias.[20] Muscle cramps have been known to herald the onset of sensory symptoms.[22] While the sensory deficit may be reversible, the motor symptoms are known to be irreversible.[21] Posterior column involvement with the loss of joint position sense is an indication to stop the use of these drugs.[20] Vincristine has also shown to be associated with the development of acute motor axonal neuropathy, which must be distinguished from other forms of Guillain-Barre syndrome, particularly the acute inflammatory demyelinating polyneuropathy.[23] A severe peripheral neuropathy presenting with quadriparesis has also been reported with vincristine in patients with Guillain-Barre syndrome.[11] The family history of Charcot-Marie-Tooth disease is a contraindication to the use of vincristine.[24] Patients who develop signs of acute neurotoxicity with vincristine should undergo evaluation for this degenerative condition.[24] The worsening of neuropathy symptoms upon cessation of chemotherapy known as "coasting" is seen in 30% of patients.[25]
Autonomic neuropathy, which presents with constipation, ileus, and abdominal cramps, may require pre-emptive laxatives.[26] Autonomic symptoms may also lead to bladder atony, which manifests as urinary retention, polyuria, and dysuria.[27]
Autonomic effects on the cardiovascular system may present as arterial hypertension or hypotension and orthostatic hypotension.[28] The onset of mild autonomic symptoms is known to predate the development of peripheral neuropathy.[29]
Central Nervous System
Acute or subacute encephalopathy, seizures, visual loss can occur with the administration of these drugs.[20] 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 (SIADH).[30] The latter is known to be more common in patients who have been receiving intravenous hydration and may present with encephalopathy and generalized seizures.[31] The intrathecal use of these drugs, which is not advisable, shows correlations with ascending myelopathy, coma, and death.[32]
Jaw pain with a neuropathic component, which is non-responsive to traditional pain medications has been reported with the use of vincristine. There is a hypothesis that this pain results from the fifth cranial nerve (trigeminal nerve) involvement.[29]
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.[33][34] 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 as a result of recurrent laryngeal nerve involvement.[33] 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.[35]
Hematological Toxicity
Vincristine is usually a bone marrow sparing agent.[36] Reports exist of dose-limiting hematological toxicity of vinblastine.[37] Leucopenia is more common than thrombocytopenia. Anemia is not known to be that common. Vinorelbine and vindesine are also known to cause bone marrow toxicity.[36]
Renal Toxicity
Vinblastine and its active metabolite desacetylvinblastine, vincristine, and vindesine have a low renal excretion (between 10 to 15%).[2] No dose adjustment has been advised for vinca alkaloids as a class. However, it is a recommendation that the dose of vinorelbine is reduced by 50% in patients undergoing hemodialysis due to an increased risk of adverse effects.[38]
Hepatic Toxicity
Since vincristine is primarily metabolized in the liver, dose adjustments are recommended with hepatic dysfunction with hyperbilirubinemia, particularly in cases with an elevation of the direct bilirubin fraction.[14] Both vincristine and vinblastine are known to cause hepatic sinusoidal obstruction syndrome (hepatic veno-occlusive disease) in predisposed individuals, namely those with higher doses of radiation, concurrent use of dactinomycin, and cyclophosphamide and children.[39][40] Re-exposure to the offending drug has been achieved successively without the re-occurrence of these symptoms and a reduction in the dosing of the alkylating agent or dactinomycin has been advised.[39][41]
Pulmonary Toxicity
Acute dyspnoea and bronchospasm may occur with the concurrent use of vincristine and vinblastine with mitomycin-C.[42]
Gastrointestinal Toxicity
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.[21]
Cardiovascular Toxicity
Apart from the cardiovascular autonomic effects which present as disturbances in the hemodynamic parameters, these drugs have also correlated with cardiac ischemic pain presenting with electrocardiographic abnormalities and myocardial infarction.[43]
Local Effects
Vincristine and vinblastine are known to act as vesicants and cause chemotherapy-associated extravasation.[44]
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.[45]
Other Rare Adverse Effects
Alopecia is a rare adverse effect of these drugs.[46]
Evaluation
There are various tools used for the evaluation of chemotherapy-induced peripheral neuropathy namely the "Common Terminology Criteria for Adverse Events" (CTCAE) developed by the National Cancer Institute, the "European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire C30" (EORTC QLQ-C30), and the "Chemotherapy-Induced Peripheral Neuropathy-20 Questionnaire" (CIPN20).[47][48][49][50][51] No tools specific for neurotoxicity caused by vinca alkaloids exist, although various risk factors predisposing to neurotoxic adverse events have been identified (as outlined above).
Both nerve conduction studies and electromyography are expected to demonstrate symptoms of an axonopathy but are not performed routinely due to the costs involved. An indirect laryngoscopic examination in patients presenting with hoarseness of voice will likely demonstrate reduced mobility of the affected vocal cord.
SIADH is known to be present with symptoms of hypovolemic hyponatremia and may require determination of urine and plasma osmolarity for its diagnosis.
Hepatic veno-occlusive disease is expected to present with symptoms of jaundice, anasarca, weight gain, and decreased or absent blood flow in the hepatic vein on duplex ultrasonography.[52] Both the Seattle criteria and Baltimore criteria have been useful in the diagnosis of hepatic veno-occlusive disease. Hyperbilirubinemia with a serum bilirubin level exceeding 2 mg percent has been positioned as the sine qua non in the diagnosis, whereas transfusion refractory thrombocytopenia is an addition in a recent modification of the diagnostic criteria.[52]
Treatment / Management
Regular surveillance and patient education strategies are necessary for the early recognition of neurological symptomatic adverse events.[10] 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.[53] While researchers have studied a multitude of neuroprotective and neurostimulatory strategies, there is a glaring lack of robust scientific evidence supporting their use. Both pyridostigmine and pyridoxine have shown to improve the rate of recovery of vincristine-induced peripheral neuropathy, whereas the role of glutamic acid in the treatment of this condition has been a subject of pre-clinical studies.[10][54] 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.[55] About 55 to 66% of pediatric patients presenting with vincristine-induced bilateral vocal cord palsy require airway protective strategies in the form of tracheostomy.[33](A1)
Secondary preventive strategies aimed at mitigating the impact of these adverse effects on the patient's quality of life can be beneficial. Patient and caregiver education, lifestyle interventions, physical therapy, and occupational therapy approaches, along with avoiding risk factors that predispose to a neurological insult, can also improve outcomes.[56] It is important to recognize the risk of long term neurotoxicity and recommend rehabilitative approaches that mitigate the impact of this neurological insult on the patient's quality of life.[11] Physical therapy can provide benefits for the amelioration of motor symptoms.[57]
Fluid deprivation, supplementation with 3% hypertonic saline, and use of loop diuretics are the recommendations for the management of SIADH.[31](B3)
Clinicians should avoid concomitant use of these drugs with azole antifungals is to be avoided due to the risk of neurotoxicity, which has been known to present with seizures.[58]
Given the low incidence of febrile neutropenia, no recommendations exist for growth factor support along with ABVD chemotherapy in Hodgkin's lymphoma (during the first 3 or 4 cycles of ABVD chemotherapy.[59]
Defibrotide is a viable treatment option in the management of hepatic veno-occlusive disease.[60]
Flushing of the veins after injection is advisable to minimize inflammation. Extravasations of vinca alkaloids have shown an association with skin ulceration occurring up to after 24 hours after the administration of these agents, for which hyaluronidase and corticosteroids can provide viable treatment options. Urgent surgical consultation and immediate debridement are necessary for severe cases.[61][62](B2)
The development of liposomal formulations may allow for the administration of more than the single recommended of 2 mg.[63]
Differential Diagnosis
Constipation - Electrolyte abnormalities (hypokalemia), reduced oral intake, opioid-induced constipation, and peritoneal carcinomatosis may be considered in the differential diagnosis.[64]
Pertinent Studies and Ongoing Trials
Clinical trials examining the effect of putative neuroprotective agents such as glutamine, acetyl-L-carnitine, vitamin B12, and vitamin B6 against vincristine-induced neuropathy are underway.
Prognosis
While 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.[10]
Vincristine-induced vocal cord palsy is generally reversible with complete recovery expected within 6 to 9 months.[33]
Complications
Long term sequelae of neuropathy have been reported in patients even after many years (nine) after cessation of treatment with vincristine, and a negative impact on the quality of life adds to the long-lasting morbidity associated with its use.[10]
Deterrence and Patient Education
The importance of timely recognition of signs and symptoms of neuropathy along with measures to prevent their impact on the patient's quality of life cannot be overemphasized.
Enhancing Healthcare Team Outcomes
Considerable caution is necessary for the handling and administration of vinca alkaloids. Vincristine is a drug with considerable toxicity and a relatively narrow therapeutic index.
Neurotoxicity and extravasation need to be anticipated in the acute setting.
Capping the single maximum dose to 2 mg, irrespective of the body surface area has been suggested as an option to minimize the probability of occurrence of acute neurotoxicity.[10] The use of vincristine mini bags is an alternative to prevent inadvertent intrathecal administration, which can be potentially lethal.[65]
Pharmacists and cancer care nurses should be well trained in the use of vincristine. The ready availability of Expertise and training in administering vincristine are essential in any unit providing chemotherapy services.
The role of physical and occupational therapists in preventing functional deterioration due to the potentially disabling impact of chemotherapy-induced neuropathy should not be ignored.
The utility of various drugs in the prevention of chemotherapy-induced peripheral neuropathy is an object of ongoing research. The recognition and management of positive signs of neuropathic pain which might be associated with a reasonable impairment of quality of life fall within the purview of cancer pain and palliative medicine specialists.
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