Japanese Journal of Clinical Oncology 30:515-518 (2000)
© 2000 Foundation for Promotion of Cancer Research
Vincristine-induced Dysphagia Suggesting Esophageal Motor Dysfunction: A Case Report
Division of Medical Oncology, Department of Medicine, Veterans General Hospital–Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan
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ABSTRACT |
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Transient esophageal motor dysfunction with dysphagia was observed in a 62-year-old man receiving vincristine-containing chemotherapy for non-Hodgkin’s lymphoma. Neurological examinations, including muscle strength of extremities, deep tendon reflexes and cranial nerves, were normal. However, the patient complained of severe numbness in the fingertips and toes. The results of esophagogram and esophagoscopy were unremarkable. However, a significantly prolonged esophageal transit time was observed. Vincristine was considered as the causative agent. Empirical vitamin and metoclopramide were prescribed for his neurological symptoms but there was no improvement. The symptoms of dysphagia subsided spontaneously 2 weeks later. However, prompt recurrence of severe dysphagia was observed again after administration of the second and third courses of treatment, which again disappeared upon discontinuation of the drug. Peripheral nerves and the gastrointestinal tract are often affected by vincristine. Common gastrointestinal tract symptoms of vincristine neuropathy may be colicky abdominal pain and constipation. However, vincristine-induced esophageal motor dysfunction with dysphagia is uncommon but generally reversible. The oncologist and chemotherapist should be aware of this complication.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The first chemotherapeutic drug group to be recognized as having neurotoxicity was the Vinca alkaloids, especially vincristine. Vincristine is widely used in the treatment of leukemia and lymphoma (1). Vincristine exerts its cytotoxic effects by binding to a specific site on tubulin and preventing polymerization of tubulin dimmers, disrupting the formation of microtubules and therefore disrupting the process of mitosis in cancer cells (2). Vincristine also disrupts microtubule function in neuronal axons. Electrophysiologic studies of vincristine neuropathy indicate distal axonal dysfunction. Nerve conduction testing shows that sensory nerves are most affected (3).
Peripheral neuropathy is the most common adverse effect of vincristine. However, the neurological injury can also occur in the central or autonomic nervous systems (4,5). The most common and initial manifestations of neurotoxicity induced by vincristine are depression of the deep tendon reflexes and parasthesias of the distal extremities. Loss of the Achilles tendon reflex and numbness of the fingertips are common (4,5). Motor dysfunction and gait disorders are initially manifested as lower extremity weakness. Foot drop may occur and, if vincristine is continued, weakness to the point of parasthesias may develop (4,5). The severity of neurotoxicity from vincristine is usually dose dependent (6). Depending on the severity of the neuropathy, recovery may take weeks or months and residual minor abnormalities sometimes persist (4,5). Empirical vitamin therapy is usually ineffective (7).
The gastrointestinal tract is often affected by vincristine and the earliest symptoms may include colicky abdominal pain, constipation and adynamic ileus. These symptoms can occur in up to 30–40% of patients receiving vincristine (8). However, severely impaired motility of the esophagus with dysphagia induced by vincristine is uncommon in clinical practice (9–12). Here we report on a patient who developed transient esophageal motor dysfunction with dysphagia after receiving a single dose of vincristine-containing chemotherapy for malignant lymphoma.
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CASE REPORT |
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A 62-year-old male patient presented with severe dysphagia for 2 days. He denied any previous symptoms related to swallowing. Two weeks earlier, the patient had undergone excisional biopsy of enlarged cervical lymph node. The pathology revealed malignant lymphoma, diffuse large B-cell type. A chest radiograph and computerized tomography (CT) scan of the chest showed no abnormalities, but a CT scan of the abdomen showed several enlarged lymph nodes over the retroperitoneum. Bone marrow biopsy was done and revealed no anomalies. Three days prior to this episode, the patient had received one course of combination chemotherapy, which included 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin and 2 mg vincristine administered by intravenous injection, plus prednisolone 60 mg/m2 given orally for 5 days (the CHOP regimen). The patient tolerated the treatment well and was discharged the following day. The patient also had a history of hypertension and received regular calcium-channel blocker treatment. The patient had no prior history of diabetes mellitus. Furthermore, the patient had no prior history of tobacco, ethanol or herb use and no potential occupational and hobby exposures to neurotoxic agents.
On physical examination, the vital signs and body temperature were normal. Breathing sound was clear and the abdomen was normal. Neurological examinations, including muscle strength of extremities, deep tendon reflexes and cranial nerves, were normal. However, severe numbness of fingertips and toes were complained of. Serum electrolytes and fasting blood sugar were normal, as was renal function. The results of the esophagogram and the esophagoscopic examination were unremarkable (Figs. 1 and 2. Esophageal manometry was suggested to the patient, but he refused owing to prior uncomfortable experience during esophagoscopy. A CT scan of the brain was normal, as was the chest radiograph. However, the esophageal transit time examined at the Nuclear Medicine Department of our hospital during this episode revealed 15.4 s (normal range: 5.2–6.4 s, from oropharynx to body of the stomach), which was significantly prolonged. Vincristine was considered to be the causative agent. A nasogastric tube was inserted for diet feeding. Metoclopramide 20 mg every 6 h and thiamine 100 mg every 8 h were given intravenously. However, the clinical symptoms and signs of dysphagia were not improved. The patient suffered from severe dysphagia for at least 2 weeks and the only food he could eat was a clear liquid diet.
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Two weeks later, the symptoms and signs of dysphagia improved gradually, so the nasogastric tube was removed. He began to eat a soft diet and was rapidly shifted to a regular diet. The esophageal transit time study was performed again and was approximately normal (6.8 s). The patient was discharged without recurrence of symptoms. Unfortunately, prompt recurrence of severe dysphagia occurred again after administration of the second and third courses of vincristine-containing chemotherapy, which again disappeared upon discontinuation of the drug. Therefore, vincristine-induced esophageal motor dysfunction with dysphagia was highly suspected.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Vincristine causes a mixed sensory and motor peripheral neuropathy by a mechanism not well understood. As an anti-neoplastic agent, it disrupts the microtubules of the mitotic spindle of the cancer cells, disrupting the process of mitosis and therefore blocking the propagation of cancer cells (3). In the neuron, vincristine damages the axon by disrupting the neurotubules, a mechanism that impedes axoplasmic flow (4,13). However, because breakdown of the myelin sheath of the neuron by vincristine is minimal, the nerve conduction velocity is preserved and there are only minimal atrophic changes in the innervated muscles (4). The pathological evaluation of the spinal cords and brains of patients receiving vincristine revealed no apparent changes that could be identified in these areas (4,14).
Some authors have proposed that malignancy itself may cause neuropathy (4). That neuropathy is caused by malignancy itself rather than by vincristine has been suggested by Bradley et al. (3). However, after pathological examination, only the patients who received vincristine had axonal neuropathy. In another series of cancer patients taking vincristine, there was increased neurotoxicity in those with lymphoma in comparison with other malignancies (15). In this series, the increased neurotoxicity also could have been potentiated by the combination of other chemotherapeutic agents with vincristine and poor drug metabolism secondary to liver metastasis or age variables (15).
Although vincristine-induced neurotoxicity usually manifests as a dose-related, peripheral, sensori-motor neuropathy, the autonomic nervous system is often involved. Autonomic neuropathy involving the cardiovascular system inducing postural hypotension (16) and detrusor areflexia causing atonic bladder have been reported (17). Autonomic nervous system innervating the gastrointestinal tract is also often affected and the earliest symptoms may include adynamic ileus, colicky abdominal pain and constipation (4,5). Gastrointestinal tract toxicity can occur in up to 30–40% of patients receiving vincristine (4). Constipation may be severe and may lead to fecal impaction. Very severe cases may present as an acute abdomen with diminished bowel sounds with a radiographic finding of adynamic ileus (18). However, severely impaired motility of the esophagus with dysphagia induced by vincristine is uncommon (9–12). In 1978, Chisholm and Curry first reported two patients who developed transient dysphagia after receiving vincristine-containing chemotherapy for metastatic breast cancer (9). The results of esophagogram and esophagoscopy were normal in both of them. The authors found that cessation of vincristine therapy resulted in definite improvement and that re-administration of vincristine would cause prompt recurrence of dysphagia, which again disappeared upon discontinuation of the drug. Vincristine was therefore considered as the causative agent. In 1984, Elomaa et al. reported another case in which severe dysphagia developed after vincristine-containing chemotherapy for malignant lymphoma (11). Besides dysphagia, severe vertigo, nystagmus and Raynaud’s phenomenon with cyanotic fingers also occurred in the patient. Severe dysphagia and other cerebral symptoms disappeared spontaneously, but two of the patient’s fingers had to be partially amputated because of severe gangrene. In a larger study conducted by Bleehen et al., moderate to severe dysphagia was observed in 10 out of 309 patients (3.2%) receiving vincristine-containing regimens for the treatment of small cell lung cancer (12). According to their data, vincristine-induced dysphagia is really uncommon, but not extremely rare. In our patient, because esophageal manometry was not performed, the diagnosis of esophageal motor dysfunction is not definitive. However, the clinical symptoms and signs suggest the diagnosis.
Empirical vitamin therapy was reported to afford no protection from the neurotoxic side effects of vincristine (7). The administration of glutamic acid at a dosage of 500 mg orally three times a day concurrently with vincristine has been reported to be capable of reducing vincristine-induced neurotoxicity without any attendant side effects (19). Another useful drug for reducing the symptoms of vincristine-induced gastrointestinal toxicity is metoclopramide. Metoclopramide is known to be capable of increasing gastrointestinal tract motility with activity on the esophagus, stomach and small intestine (20). In 1985, Garewal and Dalton reported three patients who developed adynamic ileus after receiving vincristine-containing chemotherapy for malignant disease (18). Rapid resolution of symptoms occurred in all three patients within 24 h of initiating metoclopramide and the authors concluded that metoclopramide is useful in the management of vincristine-induced adynamic ileus (18). However, in our patient, metoclopramide was given but the clinical symptoms of dysphagia did not improve promptly. The patient suffered from severe dysphagia for at least 2 weeks. The effectiveness of metoclopramide in the treatment of vincristine-induced esophageal imotility with severe dysphagia remains doubtful.
In conclusion, vincristine-induced esophageal motor dysfunction with dysphagia is uncommon but generally reversible. The oncologist and chemotherapist should be aware of this complication.
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FOOTNOTES |
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+ For reprints and all correspondence: Po-Min Chen, Division of Medical Oncology, Department of Medicine, Veterans General Hospital–Taipei, Taipei 11217, Taiwan
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REFERENCES |
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Received May 8, 2000; accepted September 11, 2000.
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