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Acute inflammatory demyelinating polyradiculoneuropathy in a patient receiving oxaliplatin-based chemotherapy
Abstract
We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin.
... Nitrous oxide [45] Vitamin B12 [45] Immune-based demyelination Etanercept, infliximab, adalimumab [46] IVIG [47] Oxaliplatin [47] IVIG [47] Reduction of VEGF neuroprotective effect ( inhibitor of anandamide hydrolysis implicated in the endocannabinoid system. Although the mechanisms by which anandamide reduces neurotoxicity and prevents development of neuropathy remain to be resolved, this study underscores the potential utility of stimulating the endocannabinoid system for the management of neuropathic pain produced by chemotherapy [73]. ...
... Nitrous oxide [45] Vitamin B12 [45] Immune-based demyelination Etanercept, infliximab, adalimumab [46] IVIG [47] Oxaliplatin [47] IVIG [47] Reduction of VEGF neuroprotective effect ( inhibitor of anandamide hydrolysis implicated in the endocannabinoid system. Although the mechanisms by which anandamide reduces neurotoxicity and prevents development of neuropathy remain to be resolved, this study underscores the potential utility of stimulating the endocannabinoid system for the management of neuropathic pain produced by chemotherapy [73]. ...
... Nitrous oxide [45] Vitamin B12 [45] Immune-based demyelination Etanercept, infliximab, adalimumab [46] IVIG [47] Oxaliplatin [47] IVIG [47] Reduction of VEGF neuroprotective effect ( inhibitor of anandamide hydrolysis implicated in the endocannabinoid system. Although the mechanisms by which anandamide reduces neurotoxicity and prevents development of neuropathy remain to be resolved, this study underscores the potential utility of stimulating the endocannabinoid system for the management of neuropathic pain produced by chemotherapy [73]. ...
Drug-induced peripheral neuropathies are common, secondary to multiple drug classes, in particular chemotherapeutic agents. They have an important impact on patients' quality of life. In recent years, significant progress has been made in the understanding of some pathophysiological mechanisms. The use of more objective assessment tools should allow the development of individualized and more effective therapeutic strategies.
... Clinically it is manifested by acute distal muscular weakness up to flaccid paralysis, with symmetrical and ascending course, a lack of reflexes and mild to moderate sensory disturbances. Few cases of GBS are associated with platinum compounds in the literature [147,148]. It is an immune-mediated, non-dose-related side effect. ...
... Anecdotal cases of Guillain-Barrè syndromes [147,148]. Table 4. Major form of autoimmune neuropathy and related antibodies. ...
Peripheral neuropathy is a well described complication in children with cancer. Oncologists are generally well aware of the toxicity of the main agents, but fear the side effects of new drugs. As chemotherapeutic agents have been correlated with the activation of the immune system such as in Chemotherapy Induced Peripheral Neuropathy (CIPN), an abnormal response can lead to Autoimmune Peripheral Neuropathy (APN). Although less frequent but more severe, Radiation Induced Peripheral Neuropathy may be related to irreversible peripheral nervous system (PNS). Pediatric cancer patients also have a higher risk of entering a Pediatric Intensive Care Unit for complications related to therapy and disease. Injury to peripheral nerves is cumulative, and frequently, the additional stress of a malignancy and its therapy can unmask a subclinical neuropathy. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication along with patient factors, namely age and inherited susceptibilities. The recent identification of individual genetic variations has advanced the understanding of physiopathological mechanisms and may direct future treatment approaches. More research is needed on pharmacological agents for the prevention or treatment of the condition as well as rehabilitation interventions, in order to allow for the simultaneous delivery of optimal cancer therapy and the mitigation of toxicity associated with pain and functional impairment. The aim of this paper is to review literature data regarding PNS complications in non-primary pediatric cancer.
... jejuni)-reactive and various anti-ganglioside antibodies, suggesting a strong link between microbial pathogens and the disease initiation [8]. So far, it has rarely been observed that GBS or any of its variants can complicate chemotherapy [9][10][11][12][13][14][15]. To the best of our knowledge, this is the first report of AMAN in a patient receiving chemotherapy with CAPTEM. ...
... GBS as a complication of chemotherapy has rarely been observed. There exist few reports of GBS manifestation in cancer patients treated with platinum compounds, nab-paclitaxel, vincristine, cytarabine or cladribine and only one case of a pure AMAN was reported [9][10][11][12][13][14][15]. However, in all of these cases it was not possible to verify a clear correlation between AMAN and the administration of chemotherapy and the underlying mechanisms remain unclear. ...
... Motor and autonomic symptoms and signs are infrequent but may occur in severe cases. Treatment with platinum analogs has been rarely associated with acute inflammatory demyelinating polyradiculoneuritis in patients with solid tumors [92]. ...
Neurotoxicity may develop with exposure to various substances such as antibiotics, chemotherapeutics, heavy metals, and solvents. Some plants and fungi are also known to be neurotoxic. Neurotoxicity can develop acutely within hours, or it can develop as a result of exposure for years. Neurotoxicity can be presented with central or peripheral nervous system findings such as neurobehavioral symptoms, extrapyramidal signs, peripheral neuropathy. Peripheral nerve fibers are affected in different ways by neurotoxicant injury. The pattern of injury depends on the target structure involved. The focus of this chapter includes signs, symptoms, pathophysiology, and treatment options of neurotoxicity.
... Some reports have shown that cytotoxic drugs, especially vinca alkaloids or oxaliplatin, or the tumor itself can induce neurological syndromes such as GBS over a period of weeks or longer [8][9][10][11]. Severe neurological disturbance in our patient appeared shortly after tumor lysis induced by chemoradiotherapy initiation; this disturbance was inconsistent with GBS induced by drug or tumor. Rather, the massive tumor lysis may have stimulated autoimmune reactions resulting in rapid destruction of neurons having similar antigens to the tumor. ...
We present the case of a 68-year-old woman who presented with a swelling on the left side of her lower jaw. Biopsy revealed neuroendocrine carcinoma of the mandible. Chemoradiotherapy with carboplatin and etoposide with local irradiation induced very rapid remission of the tumor. The massive tumor remission caused severe exacerbation of symptoms, including fatigue and muscle weakness. Her condition was diagnosed as paraneoplastic neurological syndrome with generalized peripheral nerve paralysis and respiratory failure. The syndrome was thought to be triggered by an accelerated immune reaction against the tumor, which attacked neurons with similar antigens to the tumor. The immune attack resulted in overt neurological disturbance that was not well recognized at the time of tumor diagnosis.
... In this issue of the Asia-Pacific Journal of Clinical Oncology, Yoon et al. report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in a patient with advanced cholangiocarcinoma after receiving the biweekly infusional 5-FU plus oxaliplatin FOLFOX6 chemotherapy regimen. 10 The clinical presentation of this case was consistent with AIDP and its diagnosis was supported by the results of nerve conduction studies and cerebrospinal fluid analysis. To our knowledge, this is the second case of AIDP reported in a cancer patient after oxaliplatin-based chemotherapy. ...
Platinum‐induced peripheral neurotoxicity (PIPN) is a common side effect of platinum‐based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non‐length‐dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking‐and‐glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum‐based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.
Platinum-based chemotherapy is commonly associated with toxic sensory neuropathies, but also, although rarely, with Guillain-Barré syndrome (GBS). We describe five patients who developed GBS while receiving platinum-based chemotherapy for a solid tumor and report the five cases published so far. Most patients had received cumulative platinum doses below known neurotoxic levels, and all of them had an optimal outcome after platinum discontinuation, associated in most cases with administration of intravenous immunoglobulin. Clinical presentation, electroneuromyography, and cerebrospinal fluid analysis help clinicians to differentiate GBS from toxic neuropathy. Platinum compounds are the only chemotherapeutic agents used for solid tumors that have been associated to GBS. Thus, we propose that GBS may constitute a non-dose-dependent side effect of platinum drugs and that awareness needs to be raised among oncologists on this rare but potentially life-threatening complication of platinum chemotherapy. IMPLICATIONS FOR PRACTICE: Many patients on platinum-based chemotherapy for solid tumors develop sensory neuropathy, a common dose-dependent side effect. The authors propose that Guillain-Barré syndrome may constitute an immune-mediated, non-dose-related side effect of platinum-based chemotherapy. Prompt diagnosis of Guillain-Barré syndrome and distinction from classical toxic neuropathy are crucial for optimal treatment. Platinum discontinuation, associated if needed to intravenous immunoglobulin administration, radically changes the course of the disease and minimizes neurological sequelae.
So far, very few cases describing an interrelation between chemotherapy and Guillain-Barré syndrome have been published. We describe the first case of a paraparetic, pure acute motor axonal neuropathy variant of Guillain-Barré syndrome, early complicating protein-bound paclitaxel (nab-paclitaxel/abraxane) chemotherapy (first and sole session at a 350 mg dose) in a female patient with metastatic breast cancer. Although our patient was treated with the standard regimen of intravenous immunoglobulin for 5 days, she showed no evidence of motor improvement and died 1 month after the onset of the neurological deficit.
This review discusses publications highlighting current research on toxic, chemotherapy-induced peripheral neuropathies (CIPNs), and drug-induced peripheral neuropathies (DIPNs).
The emphasis in clinical studies is on the early detection and grading of peripheral neuropathies, whereas recent studies in animal models have given insights into molecular mechanisms, with the discovery of novel neuronal, axonal, and Schwann cell targets. Some substances trigger inflammatory changes in the peripheral nerves. Pharmacogenetic techniques are underway to identify genes that may help to predict individuals at higher risk of developing DIPNs. Several papers have been published on chemoprotectants; however, to date, this approach has not been shown effective in clinical trials.
Both length and nonlength-dependent neuropathies are encountered, including small-fiber involvement. The introduction of new diagnostic techniques, such as excitability studies, skin laser Doppler flowmetry, and pharmacogenetics, holds promise for early detection and to elucidate underlying mechanisms. New approaches to improve functions and quality of life in CIPN patients are discussed. Apart from developing less neurotoxic anticancer therapies, there is still hope to identify chemoprotective agents (erythropoietin and substances involved in the endocannabinoid system are promising) able to prevent or correct painful CIPNs.
Background: studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6). Patients and methods: Data on 126/161 patients were ana-lyzed. FOLFOX2 included oxaliplatin 100 mg/m 2 ; FOLFOX3, 85 mg/m 2 ; and FOLFOX6, 100 mg/m 2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: J£ 85 mg/m 12 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m 2 /2 weeks). Results: Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients {P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regi-mens for treating LV-5-FU-resistant metastatic colorectal cancer. Conclusions: This study shows that oxaliplatin dose intensifi-cation significantly improves response rate and PFS in pre-treated metastatic disease without increasing severe toxicity.
Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron or the distal axon was primarily affected, we have carried out serial clinical and electrophysiological studies in 16 males with testicular cancer before or early and late during and after treatment with cisplatin, etoposide and bleomycin at limited (<400 mg/m2 cisplatin), conventional (approximately 400 mg/m2 cisplatin) or high (>400 mg/m2 cisplatin) doses. At cumulative doses of cisplatin higher than 300 mg/m2 the patients lost distal tendon and H-reflexes and displayed reduced vibration sense in the feet and the fingers. The amplitudes of sensory nerve action potentials (SNAP) from the fingers innervated by the median nerve and the dorsolateral side of the foot innervated by the sural nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side of the foot evoked by a tactile probe showed similar changes to those observed in SNAPs evoked by electrical stimulation. At these doses, somatosensory evoked potentials (SEPs) from the tibial nerve had increased latencies of peripheral, spinal and central responses suggesting loss of central processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal axonal degeneration even at the lowest toxic doses of cisplatin.
PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point.
PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m²/d) followed by a 5FU bolus (400 mg/m²/d) and 22-hour infusion (600 mg/m²/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m² as a 2-hour infusion on day 1.
RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004).
CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
WITH the virtual elimination of poliomyelitis, Guillain—Barre syndrome has become the most common cause of acute generalized paralysis, with an annual incidence of 0.75 to 2 cases per 100,000 population. Several clinical variants of this demyelinating polyneuropathy have been described, the electrophysiologic aspects better understood, and the immunologic basis clarified, but the diagnosis is still made by clinical acumen and experience. The eponym derives from the description in 1916 by G. Guillain and J.A. Barre, then French army neurologists, and A. Strohl, who performed the electrophysiologic recordings1; it remains useful because of uncertainty about the cause and pathogenesis of . . .
Guillain-Barré syndrome (GBS) is viewed as a reactive, self-limited, autoimmune disease triggered by a preceding bacterial or viral infection. Campylobacter jejuni, a major cause of bacterial gastroenteritis worldwide, is the most frequent antecedent pathogen. It is likely that immune responses directed towards the infecting organisms are involved in the pathogenesis of GBS by cross-reaction with neural tissues. The infecting organism induces humoral and cellular immune responses that, because of the sharing of homologous epitopes (molecular mimicry), cross-react with ganglioside surface components of peripheral nerves. Immune reactions against target epitopes in Schwann-cell surface membrane or myelin result in acute inflammatory demyelinating neuropathy (85% of cases); reactions against epitopes contained in the axonal membrane cause the acute axonal forms of GBS (15% of cases). Care for such patients may be challenging, yet the prognosis overall is favourable. Optimal supportive care and anticipation and prevention of complications are the mainstay of therapy. Admission to the intensive-care unit is necessary in 33% of patients who require intubation and assisted ventilation. Immunomodulation with infusions of IgG or plasma exchange treatments foreshorten the disease course.
To determine which antecedent infections are specifically associated with the Guillain-Barré syndrome (GBS).
Infections with many agents have been reported preceding GBS. Some infections are related to specific clinical and immunologic subgroups in GBS. Most agents were reported in case reports and uncontrolled small series of GBS patients only, and their relation to GBS and its subgroups remains unclear.
A serologic study for 16 infectious agents in 154 GBS patients and 154 sex- and age-matched controls with other neurologic diseases. Acute phase, pretreatment samples were used from clinically well-defined GBS patients. The seasonal distribution of serum sampling in the GBS and control group was the same.
Multivariate analysis showed that in GBS patients, infections with Campylobacter jejuni (32%), cytomegalovirus (13%), and Epstein-Barr virus (10%) were significantly more frequent than in controls. Mycoplasma pneumoniae infections occurred more often in GBS patients (5%) than in controls in univariate analysis. Infections with Haemophilus influenzae (1%), parainfluenza 1 virus (1%), influenza A virus (1%), influenza B virus (1%), adenovirus (1%), herpes simplex virus (1%), and varicella zoster virus (1%) were also demonstrated in GBS patients, but not more frequently than in controls. C. jejuni infections were associated with antibodies to the gangliosides GM1 and GD1b and with a severe pure motor form of GBS. Cytomegalovirus infections were associated with antibodies to the ganglioside GM2 and with severe motor sensory deficits. Other infections were not related to specific antiganglioside antibodies and neurologic patterns.
Recent infections with C. jejuni, cytomegalovirus, Epstein-Barr virus, and M. pneumoniae are specifically related to GBS. The variety of infections may contribute to the clinical and immunologic heterogeneity of GBS.
Fourteen of 320 patients (4%) admitted with Guillain-Barré syndrome (GBS) died as a direct result of the illness. Deaths most commonly resulted from ventilator-associated pneumonia. In comparison with 101 other patients with severe GBS admitted to the intensive care unit, the patients who died were older (p = 0.006) and more likely to have underlying pulmonary disease (p = 0.004). In a specialized center, the primary event leading to death in GBS was ventilator-associated pulmonary infection, predominantly in elderly patients with significant comorbidity.
In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point.
Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1.
Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004).
The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.
Studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6).
Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m2; FOLFOX3, 85 mg/m2; and FOLFOX6, 100 mg/m2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: < or = 85 mg/m2/2 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m2/2 weeks).
Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients (P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer.
This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.
To test the hypothesis that different preceding infections influence the neurophysiologic classification and clinical features of Guillain-Barré syndrome (GBS).
We tested pretreatment sera, 7 +/- 3 (mean +/- SD) days from onset, from 229 patients with GBS in a multicenter trial of plasma exchange and immunoglobulin, for serological markers of infection, adhesion molecules, and cytokine receptors, and compared these with neurophysiologic and clinical features.
Recent infection by Campylobacter jejuni was found in 53 patients (23%), cytomegalovirus in 19 (8%), and Epstein-Barr virus in four (2%). Patients with C. jejuni infection were more likely than others to have neurophysiologic criteria of axonal neuropathy or inexcitable nerves, antiganglioside GM(1) antibodies, pure motor GBS, lower CSF protein, and worse outcome. Patients with cytomegalovirus infection were younger and more likely than others to have raised serum concentrations of molecules important in T lymphocyte activation and migration, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble leukocyte selectin, and soluble interleukin-2 receptor (sIL-2R). Concentrations of sICAM-1 and soluble tumor necrosis factor receptor were higher in patients with inexcitable nerves than those with demyelinating neurophysiology. Logistic regression analysis showed death or inability to walk unaided at 48 weeks were associated with diarrhea, inexcitable nerves, severe arm weakness, age over 50, raised sIL-2R concentration and absence of immunoglobulin (Ig) M antiganglioside GM(1) antibodies.
Subtypes of GBS defined by preceding infections were only approximately associated with different patterns of clinical, neurophysiologic, and immunologic features. A single infectious agent caused more than one type of pathology in GBS, implying interaction with additional host factors. Most patients had no identified infection.
Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute neurotoxicity is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration, suggesting a specific effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells that is not observed with other platinum agents. The similarity of the acute symptoms induced by oxaliplatin with those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with ion channels located in the cellular membrane. Recent data indicate that oxaliplatin may act on specific isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability of sensory neurons, an action inhibited by the Na(+) channel blocker carbamazepine. This contention is supported by recent clinical findings indicating that pharmacologic blockade of Na(+) channels may prevent and/or repress the acute neurotoxicity of oxaliplatin. Although there is no indication at the moment that a common cellular mechanism induces both the acute and the cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently underway to establish the value of Na(+) channel blockade against both acute and cumulative oxaliplatin neurotoxicities.
To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer.
Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed.
All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths.
Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.
We report Guillain-Barre syndrome (GBS), developed in a patient with metastatic colon cancer, receiving oxaliplatin-based chemotherapy. The 53-year-old patient was treated with first-line chemotherapy consisting of oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day in a weekly schedule. After 13 weeks of treatment and a cumulative oxaliplatin dose of 585 mg/m2, the patient developed unsteadiness of gait, dysphagia, and weakness of both the upper and lower limbs, as well as impairment of all sensory modalities. Clinical examination, computed tomography and magnetic resonance imaging scans of the brain, blood tests, nerve conduction studies, and cerebrospinal fluid analysis confirmed the diagnosis of GBS. Intravenous immunoglobulin G was administered for 5 days and the patient recovered fully. Oxaliplatin can cause acute and delayed neurotoxicity, but this is the first report of GBS in a patient receiving oxaliplatin-based chemotherapy. Elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin, may represent the relevant causal links involved in the cascade of events which have led to the immune-mediated demyelination in the peripheral nervous system in this patient.
Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens.
In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca2+ concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected.
In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na+ channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, β-pompilidotoxin (100 μM), which slows Na+ channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K+ channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm.
The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between β-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na+ channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.
British Journal of Pharmacology (2005) 146, 1027–1039. doi:10.1038/sj.bjp.0706407
Oxaliplatin, a platinum-based chemotherapeutic agent, is effective in the treatment of solid tumors, particularly colorectal cancer. During and immediately following oxaliplatin infusion, patients may experience cold-induced paresthesias, throat and jaw tightness, and occasionally focal weakness. We assessed nerve conduction studies and findings on needle electromyography of patients with metastatic colorectal cancer before and during treatment with oxaliplatin. Twenty-two patients had follow-up studies within 48 h following oxaliplatin infusions, and 14 patients had follow-up studies after 3-9 treatment cycles. Repetitive compound muscle action potentials and neuromyotonic discharges were observed in the first 24-48 h following oxaliplatin infusion, but resolved by 3 weeks. After 8-9 treatment cycles, sensory nerve action potential amplitudes declined, without conduction velocity changes or neuromyotonic discharges. The acute neurological symptoms reflect a state of peripheral nerve hyperexcitability that likely represents a transient oxaliplatin-induced channelopathy. Chronic treatment causes an axonal neuropathy similar to other platinum-based chemotherapeutic agents.
Guillain-Barré syndrome (GBS) is an acute post-infectious immune-mediated peripheral neuropathy with a highly variable clinical course and outcome. We aimed to develop and validate a scoring system based on clinical characteristics in the acute phase of GBS to predict outcome at 6 months.
We studied patients with GBS who were unable to walk independently. A derivation set included 388 patients from two randomised controlled trials and one pilot study. Potential predictors were assessed for their association with the inability to walk independently at 6 months. A simple clinical scoring system was developed on the basis of regression coefficients of predictors in a multivariable logistic regression model. Model performance was quantified with respect to discrimination (area under receiver operating characteristics curve, AUC) and calibration (graphically). We validated our scoring system in a set of 374 patients from another randomised trial.
We included three variables that were predictive of poor outcome at 6 months in our model: age, preceding diarrhoea, and GBS disability score at 2 weeks after entry. Scores ranged from 1 to 7, with three categories for age, two for diarrhoea, and five for GBS disability score at 2 weeks. Predictions corresponding to these prognostic scores ranged from 1% to 83% for the inability to walk independently at 6 months. Predictions agreed well with observed outcome frequencies (adequate calibration) and showed a very good discriminative ability (AUC 0.85) in both data sets.
A simple scoring system for patients with GBS, based on three clinical characteristics, accurately predicts outcome at 6 months. The system could be used to counsel individual patients and identify high-risk groups to guide future trials.
Bolded numbers indicate abnormal values. A, ankle; AX, axilla; E, elbow; F, finger; FA, forearm; MC, middle calf; ND, not done; NP; NP, no potential
- W – Fa Np / Nd Np / Nd Np / Nd Np / Nd Sural Mc – A Np / Nd Np / Nd Np / Np
- Nd
/ND 75.0/ND 10.2/ND 58.5/ND Radial W–FA NP/ND NP/ND NP/ND NP/ND Sural MC–A NP/ND NP/ND NP/ND NP/ND Bolded numbers indicate abnormal values. A, ankle; AX, axilla; E, elbow; F, finger; FA, forearm; MC, middle calf; ND, not done; NP; NP, no potential; P, palm. W, wrist.
Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer
- S E Al-Batran
- A Atmaca
- S Hegewisch-Becker
Al-Batran SE, Atmaca A, Hegewisch-Becker S et al. Phase
II trial of biweekly infusional fluorouracil, folinic acid, and
oxaliplatin in patients with advanced gastric cancer. J Clin
Oncol 2004; 22: 658-63.
Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer
- Al-Batran