Vincristine Induced Neurotoxicity in Cancer Patients - MedIND

Clinical Brief

Vincristine Induced Neurotoxicity in Cancer Patients Sunil Gomber, Pooja Dewan and Devender Chhonker Department of Pediatrics, University College of Medical Sciences, Delhi, India

ABSTRACT Ten out of 20 children, treated with usual doses of vincristine for various types of childhood cancers, developed neurotoxicity during treatment. Peripheral neurotoxicity (mixed motor-sensory 4/10, pure motor 3/10, pure sensory 3/10) was seen in the form of weakness of lower limbs, areflexia, neuropathic pain, or sensory loss. Autonomic neuropathy presented as constipation and urinary retention in 2 children, while 2 children developed encephalopathy in form of seizures, confusion, aphasia, and transient blindness. In children with severe neuropathy, vincristine administration was withheld/dose reduced till clinical improvement started, which took about 2-3 weeks time. Nerve conduction velocity showed motor-sensory axonal polyneuropathy. Electrophysiological abnormalities were found to persist even six months after clinical recovery in children with neurotoxicity. We found a relatively higher incidence of vincristine induced neuropathy in Indian children, which was probably due to coexistence of severe malnutrition in them. [Indian J Pediatr 2010; 77 (1) : 97-100] E-mail: poojadewan@ hotmail.com

Key words: Cancer; Childhood; Malnutrition; Neurotoxicity; Vincristine

Neurotoxicity is a known adverse effect of several chemotherapeutic drugs like vincristine, cisplatin, oxaliplatin, docetaxel, paclitaxel, and bortezomib. 1 Of these, vincristine is commonly used in pediatric cancer patients. Vincristine causes axonal degeneration due to microtubular disruption, and the consequent decreased axonal transport. 2 Vincristine induced neurotoxicity is dose-related and when administered at a dose of 1.4 mg/m2 at weekly intervals it is usually well-tolerated. We have noticed a spectrum of neural damage in 10 children (ALL: 5, NHL: 3, HD: 1, Neuroblastoma: 1), receiving treatment with vincristine in usual doses (1.4 mg/m 2) for different malignancies at our oncology centre over a period of two years. In this article, we intend to discuss the clinical course of these patients, alongwith a brief review of the literature on the subject. MATERIALS AND METHODS We studied the clinical records of all pediatric cancer patients who received vincristine during their treatment at our hospital during the period January 2006 to December 2007. A retrospective charting of patient’s

Correspondence and Reprint requests : Dr Pooja Dewan, D-II 65 Kaka Nagar, New Delhi 110 003, India. [DOI-10.1007/s12098-009-0254-3] [Received October 26, 2008; Accepted February 10, 2009]

Indian Journal of Pediatrics, Volume 77—January, 2010

age, sex, weight, clinical diagnosis, appearance of neurotoxic symptoms, number of doses and total dose of vincristine received, interventions done, progression of neurological symptoms, and time to recovery of neurotoxic symptoms, was done. All children were started on appropriate chemotherapy after obtaining an informed written consent from their guardians. Children with acute lymphoblastic leukemia, and lymphoblastic nonhodgkin’s lymphoma were put on MCP-841 protocol 3,4 and those with Hodgkin’s disease were started on monthly cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) alternately with COPP (cyclophosphamide, vincristine, prednisolone, procarbazine) 5. Children diagnosed as neuroblastoma received a combination of cisplatin, etoposide, vincristine, cyclophosphamide, and adriamycin 6 . Vincristine was given intravenously in a weekly dose of 1.4 mg/m2 in all children. Electrophysiological evaluation in the form of nerve conduction velocity (NCV) estimation was done in patients with motor weakness. Orthodromic fastest motor conduction was measured in the posterior tibial nerve between knee and ankle, and in the peroneal nerve in the two segments around the fibular head, and also in median and ulnar nerves, using TECA 26 gauge concentric needle electrodes. An informed written consent was obtained from the guardian of every child for using their child’s clinical data for publication. 97

98

Diagnosis

Weakness, areflexia b/l LL (1.2mg, 2nd dose) Depressed knee and ankle jerks (3.2mg, 4th dose)

2 ALL years, Female, 10.2

11 NHL years, (lymphoMale, blastic) 13.7

-

Weakness, areflexia b/l LL (5.6mg, 4th dose)

12 ALL years, Male, 12.4


-

Weakness (Power gr: 1/5), areflexia b/l LL (0.75mg, 2nd dose) Weakness, areflexia b/l LL (9.9mg, 9th dose)

Motor symptoms (timing, cumulative dose)



3½ ALL years, Male, 13.8

Age/ Sex/ BMI

Constipation (1.6mg, 2 nd dose)

-

-

-

Urinary retention (7.7mg, 7th dose)

-

Autonomic neuropathy (timing, cumulative dose)

Jaw pain (1mg), each time thereafter

-

Jaw pain (1.1mg, 1 st dose, each time thereafter) Jaw pain (1.1mg, 1 st dose, each time thereafter), Pain both thighs (5.6mg, 4th dose) -

-

Back pain (0.75mg, 2nd dose)

Sensory symptoms (timing, cumulative dose)

Not done

MSAN b/l CPN

-

Generalized voltage suppression in b/l CPN

MSAN, Absent conduction b/l CPN

Electrophysiology (NCV)

-

-

Seizure, transient MSAN b/l CPN visual loss (3.2mg, 4 th dose) Fundus, CSF examination, and MRI (brain): normal

-

-

Agitation, delusions, aphasia (9.9mg, 9th dose) MRI (brain) CSF and fundus: normal -

-

Encephalopathy

Transient jaw pain

VCR withheld till improvement, subsequent doses halved

VCR withheld*

VCR withheld till improvement

-

VCR withheld till recovery, subsequent doses halved

VCR withheld till recovery, subsequent doses halved

Countermeasure to alleviate VIN

-

Generalized voltage suppression in b/l CPN, but amplitude improved

Amplitude improved in b/l CPN

Electrophysiology 6 months later

-

Light Amplitude perception 1 improved in week after b/l CPN withholding VCR, normal vision after 3 weeks. No further seizures. -

-

Weakness Amplitude improved improved in b/l within 3 CPN weeks of withholding VCR

Transient jaw pain

Improved after 2 weeks of withholding VCR

Gradual, complete recovery over 6 months

Clinical

Change in adverse effect profile

TABLE 1. Clinical features, Electrophysiological Findings and Outcome of Pediatric Cancer Patients Suffering from Vincristine Induced Neuropathy (VIN)

Sunil Gomber et al


Decreased voltage in b/l CPN but amplitude improved

Improvement within 2 weeks of withholding VCR Transient jaw pain


UL: upper limbs, LL: lower limbs, CPN: common peroneal nerve, b/l: bilateral, MSAN: motor sensory axonal neuropathy, VCR: vincristine *Expired due to febrile neutropenia and septicemia

Jaw pain (0.8mg, 1 st dose), each time thereafter

Sensory loss left thigh (2.2mg, 2nd dose)

Mixed axonal neuropathy with decreased voltage in b/l CPN

-

Absent conduction VCR withheld* in b/l CPN, decreased amplitude in b/l median and ulnar nerves Weak gag reflex (9mg, 10th dose)

Weakness, areflexia b/l UL and LL (9mg, 10 th dose), nasal regurgitation, nasal twang in voice 12 HL Weakness, years, (Relapsed) areflexia Male, b/l LL 14.2 (2.2mg, 2nd dose) 10 NBL years, Male, 11.5

dose)


Electrophysiology (NCV) Encephalopathy Autonomic neuropathy (timing, cumulative Sensory symptoms (timing, cumulative dose) Motor symptoms (timing, cumulative dose) Diagnosis

VCR withheld till recovery

Electrophysiology 6 months later Clinical

Countermeasure to alleviate VIN

Change in adverse effect profile

RESULT

Age/ Sex/ BMI

TABLE 1 (Contd). Clinical features, Electrophysiological Findings and Outcome of Pediatric Cancer Patients Suffering from Vincristine Induced Neuropathy (VIN)

Vincristine Induced Neurotoxicity in Cancer Patients

Twenty pediatric cancer patients (males: 17, females: 3) admitted in the oncology unit of a tertiary care hospital in Delhi, who received vincristine during treatment were reviewed. The children ranged from two mths to twelve yr in age. Seven children were diagnosed to have acute lymphoblastic leukemia (ALL); three children suffered from lymphoblastic non hodgkin’s lymphoma (NHL), six children from hodgkin’s disease (HD), two children from neuroblastoma, and two children from langerhan’s cell histiocytosis (LCH). Table 1 summarises the clinical features of neurotoxicity in our patients. None of our patients had evidence of central nervous system infiltration, derangement of liver function, pre-existing neuropathy, diabetes mellitus or megaloblastic anemia. Only two children had received cranial radiation at the time of appearance of neurological abnormalities. Children on MCP-841 protocol received prophylaxis with ketoconazole (58 mg/kg/d) and cotrimoxazole during induction and consolidation phases of treatment. The neuropathy was severe enough to warrant withholding treatment with vincristine in six patients, in three of whom the subsequent doses of vincristine were halved. All patients showed complete clinical improvement on modifying treatment, and there was no re-emergence of symptoms after restarting vincristine. Two children (cases 2 and 8) succumbed to other complications of disease. NCV, done in 6/10 patients, all having grade III/IV neuropathy, was reported as mixed motor-sensory axonal neuropathy in bilateral common peroneal nerves in all. In one patient (case 8) there was also axonopathy of bilateral ulnar and median nerves. Changes in nerve conduction velocity, however, persisted even six months after the clinical recovery of neurotoxic symptoms. The remaining 10 children (ALL:1, NHL:1, HL:5, LCH:2, Neuroblastoma:1) who did not develop neurotoxicity, were comparable with respect to age (mean age: 8.1 years) and sex distribution with the children who developed neurotoxicity. These children were found to have significantly higher weight for age (mean: 67.6 ± 6.5%) compared with the children who developed neurotoxicity (mean 41.3 ± 6.8%) (P=0.03).

DISCUSSION Our results show a surprising higher incidence of vincristine induced neurotoxicity, compared to 99

Sunil Gomber et al earlier estimates by a few authors, which range between 3 and 13%.7,8 This may partly be accounted for the fact that all of our patients who developed neurotoxicity were severely malnourished with the weight for age as well as body mass indices being below the 3rd centile for age for all children, using standards recommended by World Health Organization.9 This is supported by the fact that the group of children who developed neurotoxicity had significantly higher weight for age compared to the children who developed neurotoxicity. Malnutrition is known to predispose to neurotoxicity.10,11 Further susceptibility to neurotoxicity may be associated with certain micronutrient deficiencies, which needs to be explored.12,13 Based on these findings in a small group, it may be difficult to make significant suggestions. It would be pertinent to asssess the possibility of enhanced genetic or environmental susceptibility of Indian children to the neurotoxic effects of vincristine in a larger study. A study to see the effect of malnutrition and micronutrient deficiencies on susceptibility to chemotherapy related toxicity is also needed. Until then, proper monitoring by frequent clinical examination can help in early detection of neural symptoms, and, avoidance of permanent disability in these children. The neurotoxicity in our patients has been attributed to vincristine, as the neurological symptoms could be temporally linked to its administration. Further, withholding vincristine or modification in its dose alone led to improvement in the neurological symptoms. We did not modify the dose of intrathecal methotrexate, though intrathecal administration was temporarily withheld in patients who had seizures and altered sensorium. Also central neurotoxicity has been reported with high dose intrathecal methotrexate and cytosine arabinoside 7,8, which were not given to any of our patients. Electrophysiological studies done in our patients showed axonal neuropathy characteristic of vincristine induced neuropathy. MRI done in two of our patients showed no evidence of leukoencephalopathy, sinus vein thrombosis, infarcts or hemorrhage, all of which are reported more commonly with the use of methotrexate and Lasparaginase. Areflexia was the earliest clinical sign noticed in our patients. The peroneal nerves were the commonest peripheral nerves to be involved, though

100

cavus deformity or foot drop were not seen. Severe or life threatening (vide supra) neurotoxicity was noticed in six patients. Very rare manifestations like seizures and blindness were also recorded in one patient each. Contributions: SG and PD designed the study. DC and PD collected the data. SG, PD and DC performed clinical evaluation of patients. PD and SG drafted the manuscript. SG gave critical comments. All authors approved the final draft. Conflict of Interest : None. Role of Funding Source : None.

REFERENCES 1. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002; 249: 9-17. 2. Rosenthal S, Kaufman S. Vincristine neurotoxicity. Ann Med 1974; 80:733-737. 3. Advani S, Pai S, Venzon D et al. Acute lymphoblastic leukemia in India: an analysis of prognostic factors using a single treatment regimen. Ann Oncol 1999; 10: 167-176. 4. Magrath I, Shanta V, Advani S et al. Treatment of acute lymphoblastic leukemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period. Eur J Cancer 2005; 41: 1570-1583. 5. Loeffler M, Diehl V, Pfreundschuh M et al. Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin’s disease. J Clin Oncol 1997; 15:2275. 6. Ritchey M. Pediatric Urologic Oncology. In Campbell MF, Walsh PC, Retik AB, ed. Campbell’s Urology. 8th ed. Philadelphia; Saunders, 2002; 2469-2475. 7. Ray M, Marwaha RK, Trehan A. Chemotherapy related fatal neurotoxicity during induction in acute lymphoblastic leukemia. Indian J Pediatr 2002; 69: 185-187. 8. Ochs JJ. Neurotoxicity due to central nervous system therapy for childhood leukemia. Am J Pediatr Hematol Oncol 1989; 11: 95-105. 9. Centers for Disease Control and Prevention National Health and Nutrition Examination survey: http://www.cdc.gov/nchs/ about/major/nhanes/growthcharts/clinical_charts.htm 10. Kumar N. Nutritional neuropathies. Neurol Clin 2007; 25: 209-255. 11. Weber GA, Sloan P, Davies D. Nutritionally induced peripheral neuropathies. Clin Podiatr Med Surg 1990; 7: 107128. 12. Robson D, Welch E, Beeching NJ, Gill GV. Consequences of captivity: health effects of far East imprisonment in World War II. QJM 2008. [Epub ahead of print] 13. Madhusudanan M, Menon MK, Ummer K, Radhakrishnan K. Clinical and etiological profile of tropical ataxic neuropathy in Kerala, South India. Eur Neurol 2008; 60: 2126.
