• Sign Up

Vinca Alkaloid Toxicity


Vinca Alkaloid Toxicity

Article Author:
Rahul Arora
Article Editor:
Ritesh Menezes
Updated:
9/6/2020 1:00:38 PM
For CME on this topic:
Vinca Alkaloid Toxicity CME
PubMed Link:
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

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]

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]

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]

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.


References

[1] Loh K, Know the Medicinal Herb: Catharanthus roseus (Vinca rosea). Malaysian family physician : the official journal of the Academy of Family Physicians of Malaysia. 2008     [PubMed PMID: 25606134]
[2] Lee CT,Huang YW,Yang CH,Huang KS, Drug delivery systems and combination therapy by using vinca alkaloids. Current topics in medicinal chemistry. 2015     [PubMed PMID: 25877096]
[3] Gerullis H,Wawroschek F,Köhne CH,Ecke TH, Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience. Therapeutic advances in urology. 2017 Jan     [PubMed PMID: 28042310]
[4] Robey RW,Pluchino KM,Hall MD,Fojo AT,Bates SE,Gottesman MM, Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature reviews. Cancer. 2018 Jul     [PubMed PMID: 29643473]
[5] Huzil JT,Chen K,Kurgan L,Tuszynski JA, The roles of beta-tubulin mutations and isotype expression in acquired drug resistance. Cancer informatics. 2007 Apr 27     [PubMed PMID: 19455242]
[6] Di Cesare E,Verrico A,Miele A,Giubettini M,Rovella P,Coluccia A,Famiglini V,La Regina G,Cundari E,Silvestri R,Lavia P, Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules. Oncotarget. 2017 Mar 21     [PubMed PMID: 28160569]
[7] Bates D,Eastman A, Microtubule destabilising agents: far more than just antimitotic anticancer drugs. British journal of clinical pharmacology. 2017 Feb     [PubMed PMID: 27620987]
[8] Janumyan YM,Sansam CG,Chattopadhyay A,Cheng N,Soucie EL,Penn LZ,Andrews D,Knudson CM,Yang E, Bcl-xL/Bcl-2 coordinately regulates apoptosis, cell cycle arrest and cell cycle entry. The EMBO journal. 2003 Oct 15     [PubMed PMID: 14532118]
[9] Fletcher DA,Mullins RD, Cell mechanics and the cytoskeleton. Nature. 2010 Jan 28     [PubMed PMID: 20110992]
[10] Madsen ML,Due H,Ejskjær N,Jensen P,Madsen J,Dybkær K, Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review. Cancer chemotherapy and pharmacology. 2019 Sep;     [PubMed PMID: 31214762]
[11] Mora E,Smith EM,Donohoe C,Hertz DL, Vincristine-induced peripheral neuropathy in pediatric cancer patients. American journal of cancer research. 2016     [PubMed PMID: 27904761]
[12] Aminkeng F,Ross CJ,Rassekh SR,Brunham LR,Sistonen J,Dube MP,Ibrahim M,Nyambo TB,Omar SA,Froment A,Bodo JM,Tishkoff S,Carleton BC,Hayden MR, Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. The pharmacogenomics journal. 2014 Apr     [PubMed PMID: 23588107]
[13] Skiles JL,Chiang C,Li CH,Martin S,Smith EL,Olbara G,Jones DR,Vik TA,Mostert S,Abbink F,Kaspers GJ,Li L,Njuguna F,Sajdyk TJ,Renbarger JL, CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer. Pediatric blood     [PubMed PMID: 29115708]
[14] Grigorian A,O'Brien CB, Hepatotoxicity Secondary to Chemotherapy. Journal of clinical and translational hepatology. 2014 Jun     [PubMed PMID: 26357620]
[15] Hess D,Thürlimann B,Pagani O,Aebi S,Rauch D,Ballabeni P,Rufener B,Castiglione-Gertsch M,Goldhirsch A, Capecitabine and vinorelbine in elderly patients (> or =65 years) with metastatic breast cancer: a phase I trial (SAKK 25/99). Annals of oncology : official journal of the European Society for Medical Oncology. 2004 Dec     [PubMed PMID: 15550580]
[16] Moore DC, Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia. P     [PubMed PMID: 27990078]
[17] Vakkalanka B,Link BK, Neutropenia and Neutropenic Complications in ABVD Chemotherapy for Hodgkin Lymphoma. Advances in hematology. 2011     [PubMed PMID: 21687649]
[18] LaPointe NE,Morfini G,Brady ST,Feinstein SC,Wilson L,Jordan MA, Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology. 2013 Jul     [PubMed PMID: 23711742]
[19] Marchettini P,Lacerenza M,Mauri E,Marangoni C, Painful peripheral neuropathies. Current neuropharmacology. 2006 Jul     [PubMed PMID: 18615140]
[20] Stone JB,DeAngelis LM, Cancer-treatment-induced neurotoxicity--focus on newer treatments. Nature reviews. Clinical oncology. 2016 Feb;     [PubMed PMID: 26391778]
[21] Starobova H,Vetter I, Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. Frontiers in molecular neuroscience. 2017     [PubMed PMID: 28620280]
[22] Haim N,Barron SA,Robinson E, Muscle cramps associated with vincristine therapy. Acta oncologica (Stockholm, Sweden). 1991     [PubMed PMID: 1659838]
[23] Brigo F,Balter R,Marradi P,Ferlisi M,Zaccaron A,Fiaschi A,Frasson E,Bertolasi L, Vincristine-related neuropathy versus acute inflammatory demyelinating polyradiculoneuropathy in children with acute lymphoblastic leukemia. Journal of child neurology. 2012 Jul     [PubMed PMID: 22241706]
[24] Chauvenet AR,Shashi V,Selsky C,Morgan E,Kurtzberg J,Bell B, Vincristine-induced neuropathy as the initial presentation of charcot-marie-tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study. Journal of pediatric hematology/oncology. 2003 Apr     [PubMed PMID: 12679647]
[25] Staff NP,Grisold A,Grisold W,Windebank AJ, Chemotherapy-induced peripheral neuropathy: A current review. Annals of neurology. 2017 Jun     [PubMed PMID: 28486769]
[26] McQuade RM,Stojanovska V,Abalo R,Bornstein JC,Nurgali K, Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments. Frontiers in pharmacology. 2016     [PubMed PMID: 27857691]
[27] Gomber S,Dewan P,Chhonker D, Vincristine induced neurotoxicity in cancer patients. Indian journal of pediatrics. 2010 Jan     [PubMed PMID: 19936661]
[28] Adams SC,Schondorf R,Benoit J,Kilgour RD, Impact of cancer and chemotherapy on autonomic nervous system function and cardiovascular reactivity in young adults with cancer: a case-controlled feasibility study. BMC cancer. 2015 May 18     [PubMed PMID: 25981952]
[29] Talebian A,Goudarzi RM,Mohammadzadeh M,Mirzadeh AS, Vincristine-induced cranial neuropathy. Iranian journal of child neurology. 2014 Winter     [PubMed PMID: 24665331]
[30] Magge RS,DeAngelis LM, The double-edged sword: Neurotoxicity of chemotherapy. Blood reviews. 2015 Mar;     [PubMed PMID: 25445718]
[31] Nagappa M,Bhat RR,Sudeep K,Mishra SK,Badhe AS,Hemavathi B, Vincristine-induced acute life-threatening hyponatremia resulting in seizure and coma. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2009 Jul-Sep     [PubMed PMID: 20040817]
[32] Grissinger M, Death and Neurological Devastation From Intrathecal Vinca Alkaloids. P & T : a peer-reviewed journal for formulary management. 2016 Aug     [PubMed PMID: 27504060]
[33] Samoon Z,Shabbir-Moosajee M, Vincristine-induced vocal cord palsy and successful re-treatment in a patient with diffuse large B cell lymphoma: a case report. BMC research notes. 2014 May 27     [PubMed PMID: 24886197]
[34] Patra PC,Mandal PK,Phukan A,Jitani A,Chakrabarti P, Vincristine Induced Reversible Vocal Cord Palsy in a Young Adult. Indian journal of hematology     [PubMed PMID: 30828171]
[35] Farruggia P,Tropia S,Cannella S,Bruno G,Oddo G,D'Angelo P, Vocal cord palsy after vincristine treatment in a child and the inefficacy of glutamic acid in the prevention of relapse: a case report. Journal of medical case reports. 2012 May 14     [PubMed PMID: 22584039]
[36] Cooling L,Bombery M,Hoffmann S,Davenport R,Robertson P,Levine JE, The impact of recent vincristine on human hematopoietic progenitor cell collection in pediatric patients with central nervous system tumors. Transfusion. 2014 Aug     [PubMed PMID: 24527786]
[37] Bordbar MR,Bazrafshan A,Karimi M, Successful Management of Vinblastin Overdose with Exchange Transfusion: A Case Report. Iranian journal of pediatric hematology and oncology. 2015     [PubMed PMID: 26131351]
[38] Launay-Vacher V,Oudard S,Janus N,Gligorov J,Pourrat X,Rixe O,Morere JF,Beuzeboc P,Deray G, Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer. 2007 Sep 15     [PubMed PMID: 17634949]
[39] Ortega JA,Donaldson SS,Ivy SP,Pappo A,Maurer HM, Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Childrens Cancer Group, the Pediatric Oncology Group, and the Pediatric Intergroup Statistical Center. Cancer. 1997 Jun 15     [PubMed PMID: 9191535]
[40] Sulis ML,Bessmertny O,Granowetter L,Weiner M,Kelly KM, Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma. Journal of pediatric hematology/oncology. 2004 Dec     [PubMed PMID: 15591910]
[41] Choi A,Kang YK,Lim S,Kim DH,Lim JS,Lee JA, Severe Hepatic Sinusoidal Obstruction Syndrome in a Child Receiving Vincristine, Actinomycin-D, and Cyclophosphamide for Rhabdomyosarcoma: Successful Treatment with Defibrotide. Cancer research and treatment : official journal of Korean Cancer Association. 2016 Oct     [PubMed PMID: 27034141]
[42] Ki KD,Lee JM,Lee SK,Tong SY,Huh CY,Ryu JK,Kim KY, Pulmonary toxicity after a quick course of combinatorial vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy in cervical cancer. Journal of Korean medical science. 2010 Feb     [PubMed PMID: 20119577]
[43] Csapo M,Lazar L, Chemotherapy-Induced Cardiotoxicity: Pathophysiology and Prevention. Clujul medical (1957). 2014     [PubMed PMID: 26528012]
[44] Dorr RT, Antidotes to vesicant chemotherapy extravasations. Blood reviews. 1990 Mar     [PubMed PMID: 2182147]
[45] Biswal SG,Mehta RD, Cutaneous Adverse Reactions of Chemotherapy in Cancer Patients: A Clinicoepidemiological Study. Indian journal of dermatology. 2018 Jan-Feb     [PubMed PMID: 29527024]
[46] Middleton J,Franks D,Buchanan RB,Hall V,Smallwood J,Williams CJ, Failure of scalp hypothermia to prevent hair loss when cyclophosphamide is added to doxorubicin and vincristine. Cancer treatment reports. 1985 Apr     [PubMed PMID: 3995509]
[47] Atkinson TM,Ryan SJ,Bennett AV,Stover AM,Saracino RM,Rogak LJ,Jewell ST,Matsoukas K,Li Y,Basch E, The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2016 Aug     [PubMed PMID: 27260018]
[48] Aaronson NK,Ahmedzai S,Bergman B,Bullinger M,Cull A,Duez NJ,Filiberti A,Flechtner H,Fleishman SB,de Haes JC, The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute. 1993 Mar 3     [PubMed PMID: 8433390]
[49] Guzelant A,Goksel T,Ozkok S,Tasbakan S,Aysan T,Bottomley A, The European Organization for Research and Treatment of Cancer QLQ-C30: an examination into the cultural validity and reliability of the Turkish version of the EORTC QLQ-C30. European journal of cancer care. 2004 May     [PubMed PMID: 15115469]
[50] Cavaletti G,Cornblath DR,Merkies IS,Postma TJ,Rossi E,Frigeni B,Alberti P,Bruna J,Velasco R,Argyriou AA,Kalofonos HP,Psimaras D,Ricard D,Pace A,Galiè E,Briani C,Dalla Torre C,Faber CG,Lalisang RI,Boogerd W,Brandsma D,Koeppen S,Hense J,Storey D,Kerrigan S,Schenone A,Fabbri S,Valsecchi MG, The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings. Annals of oncology : official journal of the European Society for Medical Oncology. 2013 Feb     [PubMed PMID: 22910842]
[51] Smith EML,Zanville N,Kanzawa-Lee G,Donohoe C,Bridges C,Loprinzi C,Le-Rademacher J,Yang JJ, Rasch model-based testing of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) using Alliance for Clinical Trials in Oncology (Alliance) A151408 study data. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2019 Jul     [PubMed PMID: 30460399]
[52] Mohty M,Malard F,Abecassis M,Aerts E,Alaskar AS,Aljurf M,Arat M,Bader P,Baron F,Bazarbachi A,Blaise D,Ciceri F,Corbacioglu S,Dalle JH,Dignan F,Fukuda T,Huynh A,Masszi T,Michallet M,Nagler A,NiChonghaile M,Okamoto S,Pagliuca A,Peters C,Petersen FB,Richardson PG,Ruutu T,Savani BN,Wallhult E,Yakoub-Agha I,Duarte RF,Carreras E, Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone marrow transplantation. 2016 Jul     [PubMed PMID: 27183098]
[53] Ichikawa M,Suzuki D,Inamoto J,Ohshima J,Cho Y,Saitoh S,Kaneda M,Iguchi A,Ariga T, Successful alternative treatment containing vindesine for acute lymphoblastic leukemia with Charcot-Marie-Tooth disease. Journal of pediatric hematology/oncology. 2012 Apr     [PubMed PMID: 22246157]
[54] Boyle FM,Wheeler HR,Shenfield GM, Glutamate ameliorates experimental vincristine neuropathy. The Journal of pharmacology and experimental therapeutics. 1996 Oct     [PubMed PMID: 8859020]
[55] Bradfield SM,Sandler E,Geller T,Tamura RN,Krischer JP, Glutamic acid not beneficial for the prevention of vincristine neurotoxicity in children with cancer. Pediatric blood & cancer. 2015 Jun     [PubMed PMID: 25545757]
[56] Tofthagen C,Visovsky CM,Hopgood R, Chemotherapy-induced peripheral neuropathy: an algorithm to guide nursing management. Clinical journal of oncology nursing. 2013 Apr     [PubMed PMID: 23538249]
[57] Jung M,Rein N,Fuchs B, [Physical Therapy for Chemotherapy-induced Peripheral Neuropathy in Pediatric Oncology]. Klinische Padiatrie. 2016 Nov     [PubMed PMID: 27846661]
[58] Pana ZD,Roilides E, Risk of azole-enhanced vincristine neurotoxicity in pediatric patients with hematological malignancies: old problem - new dilemma. Pediatric blood & cancer. 2011 Jul 15     [PubMed PMID: 21265011]
[59] Sureda A,Domingo-Domenech E,Gautam A, Neutropenia during frontline treatment of advanced Hodgkin lymphoma: Incidence, risk factors, and management. Critical reviews in oncology/hematology. 2019 Jun     [PubMed PMID: 31092364]
[60] Tang C,Lindsay J,Gill A,Kerridge I, Defibrotide Use in Vincristine-induced Hepatic Sinusoidal Obstruction Syndrome. Clinical lymphoma, myeloma & leukemia. 2017 Aug     [PubMed PMID: 28842141]
[61] Gilbar PJ,Carrington CV, The incidence of extravasation of vinca alkaloids supplied in syringes or mini-bags. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2006 Jun     [PubMed PMID: 16984750]
[62] Bertelli G,Dini D,Forno GB,Gozza A,Silvestro S,Venturini M,Rosso R,Pronzato P, Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results. Journal of cancer research and clinical oncology. 1994     [PubMed PMID: 8207052]
[63] Mao W,Wu F,Lee RJ,Lu W,Wang J, Development of a stable single-vial liposomal formulation for vincristine. International journal of nanomedicine. 2019     [PubMed PMID: 31296986]
[64] Müller-Lissner S, [Constipation - pathophysiology, diagnostics, treatment]. Deutsche medizinische Wochenschrift (1946). 2019 Aug     [PubMed PMID: 31416107]
[65] Nurgat ZA,Smythe M,Al-Jedai A,Ewing S,Rasheed W,Belgaumi A,Ahmed SO,Ashour M,Al Agil A,Siddiqui K,Aljurf M, Introduction of vincristine mini-bags and an assessment of the subsequent risk of extravasation. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2015 Oct     [PubMed PMID: 24821691]