Case Report
A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity Marian Vandamme1,2, Walter Pauwels2, Jan De Bleecker3 1
Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium, 2Department of Gastroenterology, St. Lucas General Hospital, Ghent, Belgium, 3Department of Neurology, Ghent University Hospital and St. Lucas General Hospital, Ghent, Belgium Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a thirdgeneration platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudoobstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up.
Keywords: Autonomic neuropathy, Metastatic colorectal cancer, Neurotoxicity, Oxaliplatin, Pseudo-obstruction
Introduction Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. The platinum-DNA adducts formed are believed to inhibit DNA replication and transcription. As such they induce apoptosis or necrosis in cancer cells and rapidly dividing cell lines.1 Among the widely used anticancer drugs, the platinum compounds cisplatinum and oxaliplatin are most commonly associated with various forms of peripheral neurotoxicity. Two patterns are displayed: the acute form, a sensory neuropathy characterised by cold triggered symptoms, and the late cumulative neurotoxicity most often manifesting as distal painful paresthesias and numbness in the extremities and sensory ataxia resulting in functional impairment. The acute neuropathy is due to an effect of the oxalate salt on axonal sodium channels. The underlying pathologic mechanism of the late side effects is incompletely understood.2 The platinum compounds have a high affinity for the peripheral nervous system. They may affect the enteric nervous system, part of the peripheral
Correspondence to: Marian Vandamme, Department of Internal Medicine, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000110
nervous system. These interactions can result in changes in secretion, blood flow and motility.1,3 We describe a case of platinum drug-induced intestinal pseudo-obstruction in a patient treated with oxaliplatin for metastatic colorectal cancer.
Case Report A 75-year-old male was diagnosed with an invading adenocarcinoma of the colon ascendens by coloscopy with biopsy. Further staging by computed tomography (CT) scan and positron emission tomography (PET)– CT showed four metastatic lesions in the liver (segments 6 and 7) and no evidence of disease progression at other locations. The only gastro-intestinal antecedent of this patient was coeliac disease, diagnosed histologically and by the presence of anti-gliadin antibodies at the age of 55, currently controlled by a gluten-free diet. Other antecedents consist of prostatic carcinoma treated curatively with prostatectomy, and surgical correction of an inguinal hernia. There was no nicotine, alcohol or drug use. The carcinoembryonic antigen (CEA) level at presentation was 59.8 mg/l. The multidisciplinary board decided to start with neo-adjuvant chemotherapy, type Folfox (Folinic acid, 5-Fluorouracil and Oxaliplatin). Six cycles were administered. The CEA level fell back at 3.6 mg/l and there was a volume decrease in the metastatic liver lesions. The neo-adjuvant chemotherapy
Acta Clinica Belgica
2014
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NO.
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1
Vandamme et al.
A case of delayed oxaliplatin-induced pseudo-obstruction
was followed by a right hemi-colectomy with combined right hepatectomy and cholecystectomy. Pathologic analysis showed a moderately differentiated adenocarcinoma with infiltration of the paracolic tissue. There was no invasion of 32 lymph nodes and no perineural invasion. The tumor was finely staged as YT3pN0M1. The post-operative period was uneventful and transit resumed spontaneously. Further treatment consisted of another 6 cycles of Folfox after surgery. The patient finished the full schedule of 12 cycles of Folfox. Folfox was given at a dose of 85 mg/m2 and the cumulative dose pre-operatively given was 833 and 864 mg postoperatively. Total weight loss was 16 kg and at the last cycle he complained of anorexia and paresthesia in both hands. These side effects diminished slowly after treatment. During the follow-up he developed a small amount of ascites without elevation of the CEA level. Further analysis showed no presence of malignancy in the fluid. Based on the albumin gradient (.11 g/l) the result was suggestive for portal hypertension probably due to hepatic resection in combination with hepatic toxicity of the oxaliplatin therapy (a sinusoidal obstruction syndrome). A treatment with a salt free diet and diuretics was administered. Two months after cessation of the chemotherapy the patient presented to the emergency department with a painful acute abdomen. Computed tomography scan showed a dilated small intestine and distal colon with ascites. Tumor progression was suspected but there was no evidence of an obstructing tumoral mass or adherences on imaging studies and no elevation of CEA level. The patient was put on a nil by mouth diet and a nasogastric tube was inserted. Two days later there was still no improvement. On clinical exam there was no peristalsis and the patient had not had any stools yet. A surgical intervention was performed by open laparoscopy with small laparotomy. Against all expectations there was no evidence of obstruction or peritoneal infiltration. There was evidence of elevated pressure at the omentum and dilated veins in the liver. An intra-abdominal drain was placed to evacuate the ascites. Cytologic analysis showed no malignant cells in the fluid. A coloscopy was performed and showed a dilated colon. Because the colon dilatation was so distal, an organic stenosis at the site of anastomosis was very unlikely. This was confirmed by re-evaluation of the previous CT abdomen. A PET–CT scan showed no evidence of malignancy. Treatment consisted of supportive interventions including total parenteral nutrition (TPN) and gastroprokinetic agents. During the following months there was slow improvement, normal transit was recovering and he gained weight again. There was no increase in CEA levels and after 3 months the TPN could be stopped.
2
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We excluded relapsing malignancy based on consistently negative test results during 1 year of follow up. The celiac disease has been completely controlled by dietary measures for 20 years and no signs of recurrence were noticed on biopsy during follow up. We could only incriminate a delayed expression of neurotoxicity due to the chemotherapy, most likely oxaliplatin. Electromyography at the time of the pseudo-obstruction showed a mild to moderate sensory axonal neuropathy, compatible with oxaliplatin-induced polyneuropathy. The distinct autonomic neuropathy with gastro-intestinal symptoms is a very rare late presentation of oxaliplatin neuropathy. It was unexpected because the paresthesia at the end of the treatment had already largely recovered when the first symptoms of gastro-intestinal pseudo-obstruction arose 2 months after cessation of the therapy.
Discussion Peripheral neuropathy is a common complication of platinum-based chemotherapy. Our patient presented with a pseudo-obstruction. Relapsing malignancy was carefully excluded by means of CEA monitoring, histologic and cytologic analysis of the ascites fluid, abdominal CT scan, PET–CT and open laparoscopy with small laparotomy. During the months of follow-up all these studies remained consistently negative for relapsing malignancy and no evidence emerged for a paraneoplastic process. Surgical exploration and radiological studies showed no evidence of adhesions as etiology for the pseudo-obstruction. Coloscopy showed distal dilatation of the colon, which makes a stenosis of the anastomosis very unlikely. By exclusion the only explanation remained a toxic autonomic neuropathy, probably due to the previous oxaliplatin use. The gastro-intestinal motility depends on the interaction of local networks of neurons in the wall of the gut, called the enteric nervous system. The activity of the enteric nervous system is independent of extrinsic innervations but is modulated by vagal and sympathetic input. Neurons in the dorsal vagal nucleus participate in the vaso-vagal reflexes triggered by input from the gastro-intestinal tract by afferent sensory neurons. The main manifestations of generalized autonomic failure are orthostatic hypotension, anhidrosis, constipation, urinary retention and erectile dysfunction. Our patient only experienced mild orthostatism and gastrointestinal dysfunction revealed by signs of pseudo-obstruction. Erectile dysfunction was pre-existing after a prostatectomy. The most common causes of generalised autonomic failure are multiple systems atrophy or peripheral neuropathies affecting sympathetic and parasympathic output as seen in diabetes mellitus and drug
Vandamme et al.
or toxin-induced block of adrenergic or muscarin receptors.4 Most studies focus on the two most frequent oxaliplatin-induced polyneuropathies (OXAIPN).5 The acute form, frequently manifesting by cold-triggered symptoms, occurs immediately after infusion and is usually entirely reversible by prolonged infusion time or cessation of the therapy. The second form is the cumulative neurotoxicity with distal paresthesias and numbness in extremities. This form is dose dependent (threshold dose of 600–700 mg) and occurs later in the treatment process. It is the most frequent reason to stop or adjust treatment and has long-term neurological sequelae which influence quality of life during and after treatment. Consequently this is the clinically most important complication. Presentation of neurotoxic side effects occurring after cessation of the therapy has only rarely been described in case reports.5 The underlying mechanism of late oxaliplatininduced polyneuropathy is still unclear. The chemotherapeutic efficacy is believed to be based on the platinum-DNA adducts formed that inhibit DNA replication and transcription. As such they induce apoptosis or necrosis in cancer cells and rapidly dividing cell lines.2 Since sensory neurons and dorsal root ganglia are differentiated and thus amitotic, the mechanism of platinum-induced neuronal damage has to be different. The predominant sensory neurotoxicity probably relates to drug access rather than selective neuronal vulnerability. Platinum cannot pass the blood-brain barrier. The main site of affection is suspected to be the dorsal root ganglia. Both dorsal root ganglia and post-ganglionic autonomic neurons are not protected by the blood-brain barrier.6 Development of animal models for extended study of platinum neurotoxicity has been difficult. Most animals tend to develop severe nephrotoxicity before neurotoxicity appears.7 Autonomic neuropathy due to oxaliplatin use has been reported in case reports. Taieb et al.6 reported on four patients with atypical neurologic signs and symptoms after oxaliplatin-containing chemotherapy. Some of the patients experienced severe micturition difficulties. It is unclear if this is a result of a sensory neuropathy or an autonomic neuropathy. The atonic bladder can stem from damage to the sensory portion of the sacral reflex arc, either in the dorsal root or posterior columns, or alternatively it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. Only limited research has been done to evaluate possible enteric neuropathy as a side effect of platinumbased chemotherapy. There have been some studies on the effect of oxaliplatin on myenteric neurons and colon motility in mouse models. A significant reduction in the total number of myenteric neurons
A case of delayed oxaliplatin-induced pseudo-obstruction
and an increase in the proportion of nitric oxide synthase-immunoreactive neurons was associated with both short- and long-term oxaliplatin administration. Moreover, long-term administration induced a substantial neuronal loss that correlates with a reduction in both frequency and propagation speed of colonic migrating motor complexes.1 Similar results were obtained by Vera et al. studying the effects of cisplatin on the enteric nervous system of rats. These researchers assumed that the underlying mechanism consists of a platinum-induced apoptosis of dorsal root ganglia which also involves the death of afferent neurons innervating the gastrointestinal tract.3 The most recent mouse model suggests that oxaliplatin might also induce apoptosis of myenteric neurons themselves, but the precise mechanisms have not yet been studied. Our patient experienced the first signs of pseudo-obstruction 2 months after cessation of the oxaliplatin therapy. At that time the signs of paresthesia that he experienced at the end of the treatment had already largely disappeared. We assume that a separate pathophysiologic mechanism is causing this autonomic neuropathy, different from the mechanisms in the acute and cumulative OXAIPN. A full-thickness biopsy would be required to prove the absolute reduction in amount of enteric neurons and proportional increase of nitric oxide synthase-immunoreactive neurons in patients. Given the limited therapeutic consequences for our patient, possible procedural complications and ethical reasons, we decided not to biopsy. In summary this case shows an extremely uncommon and late presentation of the possible neurotoxic side-effects of oxaliplatin. The literature contains little data on the underlying pathophysiologic mechanisms and no etiologic treatment options are available. Only few cases of autonomic dysfunction and delayed onset of complications, months after cessation of therapy, have been described. Further clinical observations, increased awareness of this possible complication and basic research in animal models may yield further insights on prevention, early diagnosis and treatment of this serious complication
References 1 Wafai L, Taher M, Jovanovska V, Bornstein JC, Dass CR, Nurgali K. Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci. 2013;7:30. 2 Xiao WH, Zheng H, Bennett GJ. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison to the neuropathy induced by paclitaxel. Neuroscience. 2012;203:194–206. 3 Vera G, Castillo M, Cabezos PA, Chiarlone A, Martin MI, Gori A, et al. Enteric neuropathy evoked by repeated cisplatin in the rat. Neurogastroenterol Motil. 2011;23:370–8. 4 Benarroch EE, Daube JR, Flemming KD, Westmoreland BF. Chapter 9: The internal regulation system. In: Benarroch EE, Daube JR, Flemming KD, Westmoreland BF, editors. Mayo clinic medical neurosciences: organized by neurologic systems and levels. 5th ed. Mayo Clinic Scientific Press; 2008. p. 379–80.
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Vandamme et al.
A case of delayed oxaliplatin-induced pseudo-obstruction
5 Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, Kalofonos HP. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev. 2008;34(4):368– 77. 6 Taieb S, Trillet-Lenoir V, Rambaud L, Descos L, Freyer G. Lhermitte sign and urinary retention, atypical presentation of
4
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oxaliplatin neurotoxicity in four patients. Cancer. 2002;94: 2434–40. 7 Windebank AJ. Diseases of the peripheral nervous system: metal neuropathy. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. 4th ed. Vol. 2. Philadelphia, PA: Elsevier; 2005. p. 2544–5.
A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity Marian Vandamme1,2, Walter Pauwels2, Jan De Bleecker3 1
Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium, 2Department of Gastroenterology, St. Lucas General Hospital, Ghent, Belgium, 3Department of Neurology, Ghent University Hospital and St. Lucas General Hospital, Ghent, Belgium Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a thirdgeneration platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudoobstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up.
Keywords: Autonomic neuropathy, Metastatic colorectal cancer, Neurotoxicity, Oxaliplatin, Pseudo-obstruction
Introduction Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. The platinum-DNA adducts formed are believed to inhibit DNA replication and transcription. As such they induce apoptosis or necrosis in cancer cells and rapidly dividing cell lines.1 Among the widely used anticancer drugs, the platinum compounds cisplatinum and oxaliplatin are most commonly associated with various forms of peripheral neurotoxicity. Two patterns are displayed: the acute form, a sensory neuropathy characterised by cold triggered symptoms, and the late cumulative neurotoxicity most often manifesting as distal painful paresthesias and numbness in the extremities and sensory ataxia resulting in functional impairment. The acute neuropathy is due to an effect of the oxalate salt on axonal sodium channels. The underlying pathologic mechanism of the late side effects is incompletely understood.2 The platinum compounds have a high affinity for the peripheral nervous system. They may affect the enteric nervous system, part of the peripheral
Correspondence to: Marian Vandamme, Department of Internal Medicine, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000110
nervous system. These interactions can result in changes in secretion, blood flow and motility.1,3 We describe a case of platinum drug-induced intestinal pseudo-obstruction in a patient treated with oxaliplatin for metastatic colorectal cancer.
Case Report A 75-year-old male was diagnosed with an invading adenocarcinoma of the colon ascendens by coloscopy with biopsy. Further staging by computed tomography (CT) scan and positron emission tomography (PET)– CT showed four metastatic lesions in the liver (segments 6 and 7) and no evidence of disease progression at other locations. The only gastro-intestinal antecedent of this patient was coeliac disease, diagnosed histologically and by the presence of anti-gliadin antibodies at the age of 55, currently controlled by a gluten-free diet. Other antecedents consist of prostatic carcinoma treated curatively with prostatectomy, and surgical correction of an inguinal hernia. There was no nicotine, alcohol or drug use. The carcinoembryonic antigen (CEA) level at presentation was 59.8 mg/l. The multidisciplinary board decided to start with neo-adjuvant chemotherapy, type Folfox (Folinic acid, 5-Fluorouracil and Oxaliplatin). Six cycles were administered. The CEA level fell back at 3.6 mg/l and there was a volume decrease in the metastatic liver lesions. The neo-adjuvant chemotherapy
Acta Clinica Belgica
2014
VOL.
000
NO.
000
1
Vandamme et al.
A case of delayed oxaliplatin-induced pseudo-obstruction
was followed by a right hemi-colectomy with combined right hepatectomy and cholecystectomy. Pathologic analysis showed a moderately differentiated adenocarcinoma with infiltration of the paracolic tissue. There was no invasion of 32 lymph nodes and no perineural invasion. The tumor was finely staged as YT3pN0M1. The post-operative period was uneventful and transit resumed spontaneously. Further treatment consisted of another 6 cycles of Folfox after surgery. The patient finished the full schedule of 12 cycles of Folfox. Folfox was given at a dose of 85 mg/m2 and the cumulative dose pre-operatively given was 833 and 864 mg postoperatively. Total weight loss was 16 kg and at the last cycle he complained of anorexia and paresthesia in both hands. These side effects diminished slowly after treatment. During the follow-up he developed a small amount of ascites without elevation of the CEA level. Further analysis showed no presence of malignancy in the fluid. Based on the albumin gradient (.11 g/l) the result was suggestive for portal hypertension probably due to hepatic resection in combination with hepatic toxicity of the oxaliplatin therapy (a sinusoidal obstruction syndrome). A treatment with a salt free diet and diuretics was administered. Two months after cessation of the chemotherapy the patient presented to the emergency department with a painful acute abdomen. Computed tomography scan showed a dilated small intestine and distal colon with ascites. Tumor progression was suspected but there was no evidence of an obstructing tumoral mass or adherences on imaging studies and no elevation of CEA level. The patient was put on a nil by mouth diet and a nasogastric tube was inserted. Two days later there was still no improvement. On clinical exam there was no peristalsis and the patient had not had any stools yet. A surgical intervention was performed by open laparoscopy with small laparotomy. Against all expectations there was no evidence of obstruction or peritoneal infiltration. There was evidence of elevated pressure at the omentum and dilated veins in the liver. An intra-abdominal drain was placed to evacuate the ascites. Cytologic analysis showed no malignant cells in the fluid. A coloscopy was performed and showed a dilated colon. Because the colon dilatation was so distal, an organic stenosis at the site of anastomosis was very unlikely. This was confirmed by re-evaluation of the previous CT abdomen. A PET–CT scan showed no evidence of malignancy. Treatment consisted of supportive interventions including total parenteral nutrition (TPN) and gastroprokinetic agents. During the following months there was slow improvement, normal transit was recovering and he gained weight again. There was no increase in CEA levels and after 3 months the TPN could be stopped.
2
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We excluded relapsing malignancy based on consistently negative test results during 1 year of follow up. The celiac disease has been completely controlled by dietary measures for 20 years and no signs of recurrence were noticed on biopsy during follow up. We could only incriminate a delayed expression of neurotoxicity due to the chemotherapy, most likely oxaliplatin. Electromyography at the time of the pseudo-obstruction showed a mild to moderate sensory axonal neuropathy, compatible with oxaliplatin-induced polyneuropathy. The distinct autonomic neuropathy with gastro-intestinal symptoms is a very rare late presentation of oxaliplatin neuropathy. It was unexpected because the paresthesia at the end of the treatment had already largely recovered when the first symptoms of gastro-intestinal pseudo-obstruction arose 2 months after cessation of the therapy.
Discussion Peripheral neuropathy is a common complication of platinum-based chemotherapy. Our patient presented with a pseudo-obstruction. Relapsing malignancy was carefully excluded by means of CEA monitoring, histologic and cytologic analysis of the ascites fluid, abdominal CT scan, PET–CT and open laparoscopy with small laparotomy. During the months of follow-up all these studies remained consistently negative for relapsing malignancy and no evidence emerged for a paraneoplastic process. Surgical exploration and radiological studies showed no evidence of adhesions as etiology for the pseudo-obstruction. Coloscopy showed distal dilatation of the colon, which makes a stenosis of the anastomosis very unlikely. By exclusion the only explanation remained a toxic autonomic neuropathy, probably due to the previous oxaliplatin use. The gastro-intestinal motility depends on the interaction of local networks of neurons in the wall of the gut, called the enteric nervous system. The activity of the enteric nervous system is independent of extrinsic innervations but is modulated by vagal and sympathetic input. Neurons in the dorsal vagal nucleus participate in the vaso-vagal reflexes triggered by input from the gastro-intestinal tract by afferent sensory neurons. The main manifestations of generalized autonomic failure are orthostatic hypotension, anhidrosis, constipation, urinary retention and erectile dysfunction. Our patient only experienced mild orthostatism and gastrointestinal dysfunction revealed by signs of pseudo-obstruction. Erectile dysfunction was pre-existing after a prostatectomy. The most common causes of generalised autonomic failure are multiple systems atrophy or peripheral neuropathies affecting sympathetic and parasympathic output as seen in diabetes mellitus and drug
Vandamme et al.
or toxin-induced block of adrenergic or muscarin receptors.4 Most studies focus on the two most frequent oxaliplatin-induced polyneuropathies (OXAIPN).5 The acute form, frequently manifesting by cold-triggered symptoms, occurs immediately after infusion and is usually entirely reversible by prolonged infusion time or cessation of the therapy. The second form is the cumulative neurotoxicity with distal paresthesias and numbness in extremities. This form is dose dependent (threshold dose of 600–700 mg) and occurs later in the treatment process. It is the most frequent reason to stop or adjust treatment and has long-term neurological sequelae which influence quality of life during and after treatment. Consequently this is the clinically most important complication. Presentation of neurotoxic side effects occurring after cessation of the therapy has only rarely been described in case reports.5 The underlying mechanism of late oxaliplatininduced polyneuropathy is still unclear. The chemotherapeutic efficacy is believed to be based on the platinum-DNA adducts formed that inhibit DNA replication and transcription. As such they induce apoptosis or necrosis in cancer cells and rapidly dividing cell lines.2 Since sensory neurons and dorsal root ganglia are differentiated and thus amitotic, the mechanism of platinum-induced neuronal damage has to be different. The predominant sensory neurotoxicity probably relates to drug access rather than selective neuronal vulnerability. Platinum cannot pass the blood-brain barrier. The main site of affection is suspected to be the dorsal root ganglia. Both dorsal root ganglia and post-ganglionic autonomic neurons are not protected by the blood-brain barrier.6 Development of animal models for extended study of platinum neurotoxicity has been difficult. Most animals tend to develop severe nephrotoxicity before neurotoxicity appears.7 Autonomic neuropathy due to oxaliplatin use has been reported in case reports. Taieb et al.6 reported on four patients with atypical neurologic signs and symptoms after oxaliplatin-containing chemotherapy. Some of the patients experienced severe micturition difficulties. It is unclear if this is a result of a sensory neuropathy or an autonomic neuropathy. The atonic bladder can stem from damage to the sensory portion of the sacral reflex arc, either in the dorsal root or posterior columns, or alternatively it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. Only limited research has been done to evaluate possible enteric neuropathy as a side effect of platinumbased chemotherapy. There have been some studies on the effect of oxaliplatin on myenteric neurons and colon motility in mouse models. A significant reduction in the total number of myenteric neurons
A case of delayed oxaliplatin-induced pseudo-obstruction
and an increase in the proportion of nitric oxide synthase-immunoreactive neurons was associated with both short- and long-term oxaliplatin administration. Moreover, long-term administration induced a substantial neuronal loss that correlates with a reduction in both frequency and propagation speed of colonic migrating motor complexes.1 Similar results were obtained by Vera et al. studying the effects of cisplatin on the enteric nervous system of rats. These researchers assumed that the underlying mechanism consists of a platinum-induced apoptosis of dorsal root ganglia which also involves the death of afferent neurons innervating the gastrointestinal tract.3 The most recent mouse model suggests that oxaliplatin might also induce apoptosis of myenteric neurons themselves, but the precise mechanisms have not yet been studied. Our patient experienced the first signs of pseudo-obstruction 2 months after cessation of the oxaliplatin therapy. At that time the signs of paresthesia that he experienced at the end of the treatment had already largely disappeared. We assume that a separate pathophysiologic mechanism is causing this autonomic neuropathy, different from the mechanisms in the acute and cumulative OXAIPN. A full-thickness biopsy would be required to prove the absolute reduction in amount of enteric neurons and proportional increase of nitric oxide synthase-immunoreactive neurons in patients. Given the limited therapeutic consequences for our patient, possible procedural complications and ethical reasons, we decided not to biopsy. In summary this case shows an extremely uncommon and late presentation of the possible neurotoxic side-effects of oxaliplatin. The literature contains little data on the underlying pathophysiologic mechanisms and no etiologic treatment options are available. Only few cases of autonomic dysfunction and delayed onset of complications, months after cessation of therapy, have been described. Further clinical observations, increased awareness of this possible complication and basic research in animal models may yield further insights on prevention, early diagnosis and treatment of this serious complication
References 1 Wafai L, Taher M, Jovanovska V, Bornstein JC, Dass CR, Nurgali K. Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci. 2013;7:30. 2 Xiao WH, Zheng H, Bennett GJ. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison to the neuropathy induced by paclitaxel. Neuroscience. 2012;203:194–206. 3 Vera G, Castillo M, Cabezos PA, Chiarlone A, Martin MI, Gori A, et al. Enteric neuropathy evoked by repeated cisplatin in the rat. Neurogastroenterol Motil. 2011;23:370–8. 4 Benarroch EE, Daube JR, Flemming KD, Westmoreland BF. Chapter 9: The internal regulation system. In: Benarroch EE, Daube JR, Flemming KD, Westmoreland BF, editors. Mayo clinic medical neurosciences: organized by neurologic systems and levels. 5th ed. Mayo Clinic Scientific Press; 2008. p. 379–80.
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NO .
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Vandamme et al.
A case of delayed oxaliplatin-induced pseudo-obstruction
5 Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, Kalofonos HP. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev. 2008;34(4):368– 77. 6 Taieb S, Trillet-Lenoir V, Rambaud L, Descos L, Freyer G. Lhermitte sign and urinary retention, atypical presentation of
4
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oxaliplatin neurotoxicity in four patients. Cancer. 2002;94: 2434–40. 7 Windebank AJ. Diseases of the peripheral nervous system: metal neuropathy. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. 4th ed. Vol. 2. Philadelphia, PA: Elsevier; 2005. p. 2544–5.
