Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 20  |  Issue : 2  |  Page : 135-139

Vinca alkaloid-induced peripheral neuropathy in Zaria, North Western Nigeria: A case report


Department of Haematology and Blood Transfusion, Ahmadu Bello University/Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State, Nigeria

Date of Web Publication17-Jul-2019

Correspondence Address:
Dr. Benjamin Augustine
FMCPath, Department of Haematology and Blood Transfusion, Ahmadu Bello University/Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomt.jomt_16_18

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  Abstract 


Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common occurrence among patients who have received neurotoxic chemotherapy for hematological and other malignancies.
Case Presentation We report a case of a 28-year-old man with Hodgkin lymphoma, who received cumulative doses of vinblastine and vincristine among his combination regimen and subsequently developed severe neurotoxicity, which led to withholding of cytotoxic chemotherapy, and the patient eventually succumbed to the disease.
Discussion The incidence of CIPN varies considerably for each chemotherapeutic agent when administered alone or in combination, but often ranges from 30% to 40% of patients. Sensory complaints are often the first symptoms and are far more common than motor or autonomic symptoms, and may interfere with treatment, by limiting therapeutic options, doses, or warrant the early cessation of chemotherapy, thereby potentially impacting negatively on patient survival.
Conclusion Our case report therefore emphasizes the need for clinicians and hemato-oncologist to be more alert to CIPN, which is a debilitating adverse effect of these commonly used, first-line agents.

Keywords: Chemotherapy-induced peripheral neuropathy, Hodgkin lymphoma, vinca alkaloid


How to cite this article:
Augustine B, Abdulrahman FM, Yahaya G, Adebayo A, Obiako RO, Muktar HM. Vinca alkaloid-induced peripheral neuropathy in Zaria, North Western Nigeria: A case report. J Med Trop 2018;20:135-9

How to cite this URL:
Augustine B, Abdulrahman FM, Yahaya G, Adebayo A, Obiako RO, Muktar HM. Vinca alkaloid-induced peripheral neuropathy in Zaria, North Western Nigeria: A case report. J Med Trop [serial online] 2018 [cited 2020 Jul 11];20:135-9. Available from: http://www.jmedtropics.org/text.asp?2018/20/2/135/262751




  Introduction Top


Hematological malignancies are common conditions occurring globally. In addition to other modalities of management, chemotherapeutic agents are the mainstay in the management of these conditions with good response rates. The chemotherapeutic agents belong to a variety of compounds that differ in nature, chemical structures, mechanisms, and sites of action, and this has led to improved survival for these patients.

Despite the beneficial effects of these drugs in the management of hematological and other malignancies, they are associated with adverse reactions that can be life threatening. A common and often overlooked complications of these agents is the occurrence, both during and after treatment, of chemotherapy-related side effects,[1] and one of the well-established debilitating side effect is peripheral neurotoxicity,[2] which has come to be known as chemotherapy-induced peripheral neuropathy (CIPN).[3]

The first case report of sensory neuropathy secondary to a chemotherapeutic agent cisplatin was published over 30 years ago.[4] Chemotherapeutic combinations with the most neurotoxic side effects include those that contain vinca alkaloids, platinum drugs, bortezomib, and/or taxanes.[5],[6],[7],[8],[9]

The incidence of CIPN varies considerably for each chemotherapeutic agent when administered alone or in combination.[10] For vincristine, cisplatin, oxaliplatin, and paclitaxel, estimates for the occurrence of CIPN are as high as 60% to 90%.[11] Although the incidence of this adverse reaction varies, the development of both short and long-term CIPN is highly dependent on factors such as the chemotherapeutic combination, duration of exposure, cumulative dose, dose intensification, patient-related factors such as age, excessive alcohol consumption, assessment methods, and preexisting comorbidities predisposing to neuropathy such as diabetes, vitamin B12 deficiency, or hypothyroidism.[7],[8],[9],[12],[13] The overall incidence of CIPN is estimated to be approximately 38% in patients treated with multiple agents.[8]

Chemotherapeutic agents are the mainstay among the diverse modalities for managing both hematologic and other malignancies in our environment with attendant adverse drug reactions. Currently, there is no reported prevalence of CIPN in our setting, most likely due to underdocumentation and reporting and inadequate diagnostic facility, hence this reports to stimulate a high index of suspicion in patients on chemotherapeutic agents.


  Case report Top


We report a case of a 28-year-old man, a tile layer, who was diagnosed in our facility with lymphocyte-depleted Hodgkin lymphoma (HL) and Ann Arbor stage IIIS,E in November 2013. Admitting hematological parameters were as follows: Packed Cell Volume (PCV) of 0.27 L/L, white blood cell 11.2 × 109/L, with an absolute count of lymphocytes 7.4 × 109/L, granulocytes 2.8 × 109/L, and monocytes 1.0 × 109/L; platelets count was 369 × 109/L. Bone marrow examination was essentially normal with no marrow disease involvement. Routine screening for tuberculosis was negative.

Standard regimen for Hodgkin Lymphoma (HL), Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) was commenced a month after presentation at the following doses: intravenous (IV) adriamycin 45 mg (on days 1 and 15), IV bleomycin 18 mg (on days 1 and 15), IV vinblastine 11 mg (on days 1 and 15), and IV dacarbazine 67 mg (on days 1 and 15). Supportive therapies included allopurinol tablet at 300 mg daily, hematinics, prophylactic antimalarials in the form of paludrin, and antifungal prophylactics, which were commenced before chemotherapy and continued throughout the cycle. The patient also received subcutaneous erythropoietin at a dose of 4000 IU twice weekly.

By day 20 of the first cycle of ABVD, the patient had made significant clinical improvement with significant reduction in lymphadenopathies at all initial sites. He was discharged home and subsequently followed-up as an outpatient.

During the sixth cycle, significant events were those of complaints of numbness and tingling sensations in both hands and feet, which subsequently were resolved before the commencement of the seventh cycle.

A year after the commencement of chemotherapy, patient complained of increasing swellings in all lymph node regions. Examination revealed generalized lymphadenopathy for which a repeat biopsy was scheduled. However, the patient was lost to follow-up for 2 years, after which he presented again with a history of ongoing generalized lymphadenopathy. Repeat lymph node biopsy confirmed the same disease for which the patient was recommenced on ABVD. Having exceeded the therapeutic dose of adriamycin and to avoid its toxicity, the patient was switched to cyclophosphamide, vincristine, procarbazine, and prednisolone (COPP),[20] which included vincristine rather than vinblastine. The patient received a total of three cycles of COPP.

During the third cycle of COPP, the patient complained of worsening numbness in both the lower limbs, progressive weakness, and pains in the hands and legs with associated inability to walk. He also complained of abdominal distention and constipation, with a history of urinary and fecal incontinence. There was also associated right-sided facial and truncal sweating with feeling of dryness of the opposite side of the body. Neurological examination showed a conscious and alert man, oriented in time place and person, but with flaccid quadriparesis. (He had muscle strength of 2/5 in all limbs and absent tendon reflexes with a sensory level between L1and L2 was noticed.)

A diagnosis of CIPN was made (likely due to the vinca alkaloids).

Chemotherapy was withheld and he was continued pyridoxine at 100 mg twice daily and vitamin B12 at 1000 μg daily. Unfortunately, the patient died of disease progression after 10 days.


  Discussion Top


CIPN is a well-known debilitating side effect of many chemotherapeutic agents either used alone or in combinations.

In our case, the patient was initially treated with ABVD, with vinblastine as the vinca alkaloid in this regimen. The initial symptoms were those of numbness and tingling sensations in the hands and feet, which were mild and subsequently resolved. These symptoms are common with the vinca alkaloid and had been variously reported by several authors.[1],[3],[7],[8],[16],[19] The patient’s symptoms were noticed after a cumulative dose of 132 mg of vinblastine by the sixth cycle of chemotherapy. This is also in keeping with reports that the severity and incidence of CIPN are related to factors such as chemotherapeutic agent used, cumulative dose, and duration of therapy.[20] Vinblastine neuropathy have been reported as rare and mild. During the third cycle of COPP, symptoms of worsening numbness in both lower limbs were of significant concern to the patient. There was also associated progressive weakness and pains in the hands and legs with associated inability to walk, abdominal distension and constipation, urinary and fecal incontinence, and right-sided facial and truncal sweating with feeling of dryness of opposite side of the body. These symptoms are those of a mixed sensorimotor polyneuropathy with involvement of the autonomic nervous system. Our patient’s onset and severity of polyneuropathy was dose dependent and occurred after receiving 6 m g of vincristine. These scenarios are characteristic of the clinical profile of vincristine neurotoxicity that is said to be dose dependent and occurring after administration of 4 mg of the drug.[1],[2],[7],[15],[16] Vincristine is known to be more neurotoxic than vinblastine, and this was evident in our patient whose neuropathy worsened on vincristine. Other factors that may have contributed to the worsening of neuropathy in our patient was the coadministration of prophylactic antifungal agent. This has been reported as a factor that can worsen CIPN in cancer patients receiving chemotherapeutic agents. Our case report shows that there is a relationship between cumulative dose of vinca alkaloid and onset of neurotoxicity. Neurotoxic symptoms were noted during the sixth cycle with vinblastine and also during the third cycle with vincristine.[1]

CIPN symptoms may interfere with treatment, by limiting therapeutic options for patients, warrant a dose reduction, or lead to the withdrawal of chemotherapy, thereby potentially impacting negatively on patient survival. In the aftermath of treatment, it can have a significant impact on quality of life in survivors by directly interfering with activities of daily living, functionality, and behavior of cancer patients.[14] Verbalization of frustration feelings is common as a consequence of social role impairment, of distress due to functional skills changes, and dismay and loss of objectives due to the need to give up some activities.[1],[15]

Peripheral sensory nerves have their cell bodies in the dorsal root ganglion, which lie outside the protective mechanisms of the central nervous system. The pathophysiology of CIPN is generally described as symmetric and bilateral axonopathy and preferentially takes place in dorsal root ganglia, sensory neurons, satellite cells, and Schwann cells. These sites are therefore particularly susceptible to injury.[16]

Although the precise pathophysiology is not clearly understood, different mechanisms have been proposed for different classes of anticancer agents.[1],[2] The most common mechanisms proposed are alterations of the structural integrity and/or the functionality of mitochondria nuclear DNA damage, altered axonal transport, microtubule changes, dysfunctions in sodium (Na+), calcium (Ca2+) and potassium (K+) channels, and modifications of peripheral vascularization.[3]

Various forms of CIPN exist, depending on the agent used; a pure sensory and painful neuropathy can occur with cisplatin, oxaliplatin, and carboplatin or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system can also occur with vincristine, docetaxel, and paclitaxel, presenting with motor dysfunction such as foot drop.[5],[7],[13] CIPN symptoms, in general, appear in the beginning of the treatment, between the first and third cycles, with severity peak approximately in the third month of therapy.[1]

Sensory complaints are often the first symptoms,[16] and are far more common than motor or autonomic symptoms. Classically, most chemotherapy drugs that cause CIPN do so in a symmetric, distal, and length-dependent manner, presenting as nonpainful sensory symptoms such as bilateral paresthesias (“pins and needles”), dysesthesias, and numbness in the hands and feet and tingling. These symptoms then spread proximally to affect both lower and upper extremities in a characteristic “glove and stocking” distribution and present with pain that is burning, shooting, or like electric shock.[8],[13] These are typically associated with a reduction or absence of deep tendon reflexes.[5],[15] This may also lead to impairment of perception of touch, vibration, and proprioception. These sensory symptoms are often reported in 90% of CIPN cases.[1],[6],[17]

Motor symptoms, in general, manifest as distal weakness (such as feet weakness), including foot drop,[18] gait and balance disorders, and difficulties with fine movements (writing, buttoning and unbuttoning clothes, cutting, and sewing).[1]

Autonomic symptoms include reduced heart rate, postural hypotension, and mild-to-moderate constipation. Cases of paralytic ileus and megacolon, as well as erectile dysfunction, incontinence, and urinary retention,[1],[3],[7],[16],[19] have also been documented; less commonly, ocular palsies and vocal cord paralysis may develop.[15],[19]

The vinca alkaloids are useful first-line agents in the treatment of HL and non-HL among other hematological malignancies. They act by causing mitochondrial damage, impairment of β-tubulin assembly, axonal swelling, and damage to myelinated and unmyelinated fiber; this leads to severe alterations in axonal microtubules, thereby inhibiting the mitotic spindle movements necessary for cellular reproduction.[16] The resultant peripheral neuropathy can affect both small fiber axons (temperature, pin prick) and large fiber sensory axons (vibration, proprioception).[10] They include vincristine, vinblastine, and the semisynthetic form vinorelbine. Vincristine, a first-generation vinca alkaloid, has the greatest use because of its efficacy and relative lack of myelotoxicity, cardiac toxicity, and nephrotoxicity; it is, however, the most neurotoxic of the vinca alkaloids and a mainstay in the treatment of lymphomas in combination with other chemotherapeutic agents.[7],[16]

It has been estimated that 35% to 45% of patients treated with vincristine develop neuropathy. The onset and severity of peripheral neuropathy following its administration is dose dependent and usually occurs at the dose of 4 to 10 mg. Sensory signs are the earliest, presenting as a mixed sensory/motor polyneuropathy, usually as myalgia and distal paresthesias, and decrease in ankle jerks.[2],[16] Fortunately though, neurotoxic symptoms of vincristine are reversible after discontinuation of the treatment. Symptomatic recovery of vincristine neuropathy may take as long as 40 months.[16] However, off-therapy worsening of neurotoxic symptoms and signs might unexpectedly occur (“coasting”).[3],[7],[10],[19] Azole-based antifungal agents may also exacerbate vincristine-induced neuropathy. Accordingly, it is recommended that azole-based agents be avoided during vincristine administration.[15]


  Conclusion Top


CIPN still remains a clinically significant and potentially adverse effect of cancer therapy even with commonly used first-line agents. Our case report therefore emphasizes the need for clinicians managing patients with hematological and other malignancies with chemotherapeutic agents to be more alert to this debilitating adverse effect.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994;35:304–11.  Back to cited text no. 12
    
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Majithia N, Temkin SM, Ruddy KJ, Beutler AS, Hershman DL, Loprinzi CL. National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons. Support Care Cancer 2016;24:1439-47.  Back to cited text no. 14
    
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Park SB, Goldstein D, Krishnan AV, Lin CS-Y, Friedlander ML, Cassidy J, Park SB, Goldstein D, Krishnan AV, Lin CS-Y, Friedlander ML, Cassidy J et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 2013;63:419-37.  Back to cited text no. 15
    
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Author Forman. Peripheral Neuropathy. In: Victor A. Levin (Ed). Cancer of the Central Nervous System. [book on the internet]. 2nd Edition. London: Oxford University Press, 2002: Part VI, Chapter 17, Symptoms Secondary to Cancer and its Treatment. p.395-412.pdf. Available at: http://www.socneuro-onc.org>Files. [Accessed June 17, 2017].  Back to cited text no. 16
    
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Silva A, Wang Q, Wang M, Ravula SK, Glass JD. Evidence for direct axonal toxicity in vincristine neuropathy. J Peripher Nerv Syst 2006;11:211-6.  Back to cited text no. 17
    
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Grisold W, Cavaletti G, Windebank AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-Oncology 2012;14:iv45-iv54. doi:10.1093/neuonc/nos203. Available from: https://academic.coup.com/neuro-oncology/article/14/suppl4/iv45/1046884 [Accessed June 17, 2017]  Back to cited text no. 18
    
19.
Argyriou AA, Kyritsis AP, Makatsoris T, Kalofonos HP. Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature. Cancer Manag Res 2014;6:135-47.  Back to cited text no. 19
    
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Suresh P, Kapoor R, Kapur BN. Severe neurotoxicity due to vinblastine in Hodgkin lymphoma. South Asian J Cancer 2014;3:147-8.  Back to cited text no. 20
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