Impact of oxaliplatin-induced neuropathy in patients with colorectal cancer: a prospective evaluation at a single institution

Oxaliplatin plays a major role in the treatment of colorectal cancer (crc), but is associated with the development of neuropathies. The main objective of the present prospective study was to estimate the proportion of participants with grade 1, 2, 3, or 4 peripheral sensory neuropathies according to the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4) among crc patients treated with oxaliplatin (adjuvant or metastatic, folfox or xelox regimens) at the Centre hospitalier universitaire de Sherbrooke. Among the 57 patients so treated between May 2012 and April 2013, about 60% reported grade 2 neuropathy, at maximum, during treatment. About 25% of patients had to stop treatment because of neuropathies. In a subset of patients contacted approximately 22 months after treatment cessation, neuropathies persisted in 70%. Oxaliplatin-induced neuropathy affects a significant number of crc patients and can influence the course of treatment and outcomes.     

Risk-reduction and treatment of chemotherapy-induced peripheral neuropathy

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN), a common adverse effect of several chemotherapeutic agents, has a significant impact on quality of life and may even compromise treatment efficacy, requiring chemotherapy dose reduction or discontinuation. CIPN is predominantly related with sensory rather than motor symptoms and the most common related cytotoxic agents are platinum compounds, taxanes and vinca alkaloids. CIPN symptoms may resolve after treatment cessation, but they can also be permanent and continue for years.

Areas covered: We present an overview of CIPN pathophysiology, clinical assessment, prevention and treatment identified through a Pubmed search.

Expert commentary: No substantial progress has been made in the last few years within the field of prevention and/or treatment of CIPN, in spite of remarkable efforts. Continuous research could expand our knowledge about chemotherapeutic-specific neuropathic pathways and eventually lead to the conception of innovative and targeted agents for the prevention and/or treatment of this debilitating chemotherapy adverse effect.     

Long term effects of vincristine on the peripheral nervous system

Summary Forty patients with Non-Hodgkin's Lymphoma treated with vincristine between 1984 and 1990 (cumulative dose 12 mg in 18–24 weeks) were investigated in order to evaluate the long term effects of vincristine on the peripheral nervous system. The patients were interviewed with emphasis on neuropathic symptoms. Physical and quantitative sensory examination with determination of vibratory perception and thermal discrimination thresholds were performed, four to 77 months (median 34 months) after vincristine treatment. Twenty-seven patients reported neuropathic symptoms. In 13 of these 27 patients symptoms were still present at the time of examination. In these patients sensory signs and symptoms predominated. In the other 14 patients symptoms had been present in the past. Symptoms persisted maximally 40 months since cessation of therapy. There was no age difference between patients with and without complaints at the time of examination. Normal reflexes were found in two third of patients. Neuropathic complaints were not very troublesome on the long term. It is concluded that with the above mentioned vincristine dose schedule signs and symptoms of vincristine neuropathy are reversible for a great deal and prognosis is fairly good.     

Chemotherapy-induced neurotoxicity in the treatment of gynecological cancers: State of art and an innovative approach for prevention

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that occurs in 20% of ovarian cancer patients treated with the combination of carboplatin/paclitaxel (CP). This toxicity is directly correlated with the dose of paclitaxel administered. Several studies have investigated whether different formulations of taxane can induce this side effect at a lower rate, but, unfortunately, no significant improvement was obtained. CIPN can be disabling in the daily lives of patients and can cause dose reduction or early termination of the treatment. Neuropathy can last for months and even years after its onset. Moreover, patients responsive to CP treatment are candidates for a reintroduction of the same drugs when disease relapse occurs, and residual neuropathy can affect the continuation of treatment. There are no approved drugs that mitigate or prevent the onset of CIPN. In this review, we summarize the evidence regarding the incidence of CIPN with different taxane formulations, regimen schedules and prevention systems. In particular, the Hilotherm^® Chemo care device is a regional cooling system that lowers the temperature of the hands and feet to reduce the flow of chemotherapy into the capillaries. We used hilotherapy during chemotherapy infusion to prevent the onset of CIPN. Updated data from 44 ovarian cancer patients treated with 6 cycle of CP show that hilotherapy was well tolerated; only two patients (4.5%) stopped hilotherapy because of cold intolerance, and only one patient (2.2%) experienced grade ≥ 2 CIPN.     

Effects of intraoperative hyperthermia on canine sciatic nerve: histopathologic and morphometric studies

Failure to achieve local control in the treatment of pelvic and retroperitoneal tumours results in a high rate of recurrences. The objective of intraoperative hyperthermia (IOHT) is to enhance the effect of intraoperative radiation therapy and to increase local tumour control. The tolerance of peripheral nerves to heat may limit the heat dose that can be applied to tumours. Histopathologic and histomorphometric changes of canine sciatic nerve after 60-min IOHT were studied in three groups of five dogs each for temperatures of 43, 44 and 45°C. IOHT was performed using a water-circulating hyperthermia device with a multichannel thermometry system on surgically exposed sciatic nerve. Histopathologic and histomorphometric studies were done immediately, 3 weeks and 12 months after IOHT. Histologic changes observed immediately after treatment were minimal but at 3 weeks following 60-min 45°C IOHT both axon and myelin loss and an increase in endoneurial fibrous tissue were observed. Twelve months after treatment a statistically significant decrease in axon, myelin and small vessel percentages as well as an increase in endoneurial and epineural connective tissue were observed for dog treated to 45°C. Dog treated to 44°C for 60 min had similar statistically significant but less severe changes. Twelve months after 43°C IOHT for 60 min, nerve fibres appeared normal and endoneurial connective tissue was only increased mildly around small and medium-sized vessels. These results suggest that temperatures to the peripheral nerve >44°C for 60 min are likely to cause significant histopathologic changes that can be found 12 months after treatment. A hypothesis of the mechanism of heat injury to peripheral nerves was developed.     

Visual evoked potentials findings in course of paclitaxel doxorubicin combination chemotherapy

The case of a 63 year-old woman affected by advanced breast cancer is reported. Chemotherapy with paclitaxel (200 mg/m2) and doxorubicin (60 mg/m²) every three weeks was given for 8 cycles. The patient progressively developed a sensory-motor neuropathy of axonal type. After the 6th chemotherapy cycle the patient complained of subjective visual symptoms without a relevant reduction of visual acuity. Visual evoked potentials (VEPs) showed an important reduction of the amplitude of the P100 component with a less pronounced delay in latency. Electroretinic responses were normal. These findings suggest an optic neuropathy, confirming previous reports of the occurrence of optic nerve involvement in course of paclitaxel chemotherapy. The role of VEP assessment in course of paclitaxel chemotherapy is discussed comparing clinical and neurophysiological findings in this case with three previously reported cases.     

Pediatric chemotherapy induced peripheral neuropathy: A systematic review of current knowledge

BackgroundThe dramatic increase in the number of childhood cancer survivors over the last 60 years has made monitoring and minimising long term side effects of cancer treatment increasingly important. Chemotherapy induced peripheral neuropathy (CIPN) has been described with many commonly used chemotherapy agents. This article provides a critical overview of pediatric CIPN, its incidence, clinical manifestations, late effects, and recent advances in understanding of risk factors and pharmacogenomics as well as evaluating current assessment strategies and treatment approaches.MethodsNeurotoxicity data was systematically collated from Medline, Embase and Pubmed and analysed for quality, relevance and originality in three stages prior to inclusion. Quality scoring was done using the QUALSYST assessment tool.ResultsA total of 61 studies met inclusion criteria. Peripheral neuropathy is common and may be long lasting with characteristics specific to each chemotherapy agent. There is significant variability in reported incidence and natural history, related to challenges in clinical assessment and diagnosis. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication and patient factors such as age and inherited susceptibilities. Recent identification of individual genetic variations has advanced understanding of pathomechanisms and may direct future treatment approaches.ConclusionWhile these studies guide suggestions for current clinical practice, further systematic research with development of strategies for amelioration and prevention of CIPN is necessary. Standardised assessment protocols and objective outcomes measures of CIPN applicable to patients of different ages are critical to enabling the development of novel treatments and facilitation of future clinical trials and treatment individualisation.     

Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin

Mc HUGH J.C., TRYFONOPOULOS D., FENNELLY D., CROWN J. & CONNOLLY S. (2012) European Journal of Cancer Care Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin Peripheral neuropathy is the principal dose‐limiting side effect of chemotherapy with oxaliplatin. Early biomarkers of oxaliplatin‐related neuropathy (ON) are important for guiding management and as outcomes for neuroprotective trials. We compared a number of clinical and neurophysiological techniques to identify early features of ON. Median nerve motor excitability testing, nerve conduction studies, vibration perception threshold (VPT) and clinical assessments were carried out on 17 patients and 105 controls. Neuropathy was graded using the total neuropathy score and National Cancer Institute Common Toxicity Criteria scales. Oxaliplatin causes a length‐dependent sensory neuropathy. The most sensitive early marker of neuropathy was abnormal VPT in the foot followed by diminished sensory nerve action potential amplitudes. Median nerve excitability studies revealed no biologically significant effects of treatment on motor axons. VPT is an easily applicable and effective marker of neuropathy at low cumulative doses of oxaliplatin. Nerve excitability measures may be useful in predicting ON but motor studies do not reveal early cumulative changes following treatment with the drug.     

Chemotherapy-induced peripheral neuropathy

While cancer remains an important public health concern, novel and enhanced treatment modalities have increased the length of survival of individuals diagnosed with the disease. The treatment of most cancers requires the use of chemotherapeutic agents to affect cure, maintain control of the disease, or provide palliation of symptoms. Although the use of chemotherapeutic agents can serve to prolong life, such agents are associated with significant side effects.

Increasing clinical evidence suggests treatment of cancer with neurotoxic agents results in some degree of peripheral neuropathy. Specific drug categories implicated in the development of peripheral neuropathy are the plant alkaloids, interferons, antimitotics, taxanes, and platinum-based compounds. Drug-induced peripheral neuropathy is sensory, dose-related and cumulative and is usually delayed, appearing weeks after initiation of therapy. The number of individuals at risk for the development of chemotherapy-induced neuropathy is expected to increase proportionately with clinical protocols utilizing higher or more frequent dosing. As advanced cancer treatments and clinical trials can result in extending the lives of individuals affected by cancer, long-term functional deficits resulting from life-saving treatments must now be addressed. As such, peripheral neuropathy has emerged as an important consequence of cancer therapy.     

Rituximab therapy in monoclonal IgM-related neuropathies

Monoclonal IgM-related neuropathies constitute a heterogeneous group of disorders, which are generally poorly responsive to treatment. Rituximab, a chimeric monoclonal antibody against the CD20 molecule, has been used with success in patients with neuropathy and monoclonal IgM with anti-MAG or anti-GM1 ganglioside activity. Based on this observation, four patients were treated with IgM-related neuropathy with rituximab. Between January 1999 - December 2000, four patients with IgM-related neuropathy (one with chronic inflammatory demyelinating polyneuropathy (CIDP) and three with sensorimotor demyelinating neuropathy) were treated with rituximab. Rituximab was administered at a standard dose of 375 mg m^-2 iv weekly for a consecutive 4 weeks; 3 months later, four additional weekly courses were administered to patients who did not experience deterioration of their neuropathy symptoms. Neurological evaluation was performed before each rituximab infusion and at 1 week and 2 months after last infusion and every 6 months the following years; including motor (MRC in six muscle groups, 9-hole peg test, 10 m walk, hand grip strength), sensory neuropathy (vibration threshold and sensory subjective score) assessment. Neurophysiological parameters were also assessed (MNCV, SNCV, CMAP, SNAP). Strength improved in three of four patients; including the patient with CIDP. This patient developed a significant worsening of her weakness 3 weeks after the initiation of rituximab. This phenomenon coincided with a serum monoclonal IgM flare and resolved spontaneously 1 week later. Her improvement is ongoing for more than 5 years. Considering neurophysiological parameters, two patients showed a slight improved regarding conduction velocities and CMAP (10%) and the patient with IgM flare had a transient worsening of conduction velocities followed by improvement. In conclusion, rituximab is a safe and well-tolerated treatment which may be effective in some patients with IgM-related neuropathy.     

Misonidazole with dexamethasone rescue: An escalating dose toxicity study

Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. Furthermore, in that study we have observed that DEXA did not alter the plasma pharmacokinetics of misonidazole. We are presently investigating the use of DEXA (2 mg t.i.d. during treatment), with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO ranging from 13.5 to 17.5 gm/M² given in 9 equally divided doses over 3 weeks. DEXA, 2 mg t.i.d. is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M². One grade I PN occurred in the first four patients receiving 15.5 gm/M². Six additional patients were entered at this dose level and no further incidence of PN was observed. Patients are being entered at the next step of 17.5 gm/M².     

Cervical neuropathy following mantle radiotherapy

ABSTRACT:The majority of newly diagnosed patients with Hodgkin's lymphoma are expected to survive because of effective therapies established during the last 40 years. Long-term observations from large populations of treated patients have disclosed a variety of late effects of the disease and its therapy that have contributed morbidity and excess mortality to Hodgkin's lymphoma survivors. As such complications have been recognized treatment approaches have been modified. Here we report a case of cervical neuropathy secondary to mantle radiotherapy, a complication not previously reported in the literature. Copyright 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.     

Impact of Body Mass Index on the Incidence of Bortezomib-induced Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma

BackgroundPeripheral neuropathy is one of the most common dose-limiting toxicities associated with bortezomib; it can lead to dose reductions or therapy discontinuation. Obesity has been identified as being a risk factor for the development of peripheral neuropathy with other neurotoxic anticancer agents. We aimed to evaluate the impact of obesity on the incidence and severity of bortezomib-induced peripheral neuropathy.Patients and MethodsThis is a retrospective, single-center study of patients treated with subcutaneous bortezomib between January 1, 2012 and June 1, 2017. Eligible patients received at least 1 full cycle of subcutaneous bortezomib and had previously untreated, newly diagnosed multiple myeloma. Patients who received intravenous bortezomib or concomitant thalidomide were excluded. Patients were divided into 3 groups based on their body mass index (BMI): normal/underweight (BMI < 25), overweight (BMI = 25-29.9), and obese (BMI ≥ 30).ResultsA total of 143 patients fitting the inclusion criteria were identified. Patients across the 3 groups received bortezomib at similar doses and schedules (weekly vs. biweekly). Obese patients had an increased incidence in developing bortezomib-induced peripheral neuropathy (56.4%) compared with normal/underweight (17.3%) and overweight patients (26.9%). Further analysis showed that, compared with normal/underweight and overweight patients, obesity was not found to be associated with an increased risk of grade 3 to 4 bortezomib-induced peripheral neuropathy (P = .451).ConclusionObese patients were found to be at higher risk for the development of bortezomib-induced peripheral neuropathy compared with non-obese patients.     

Complications of hypogastric artery cisplatin infusions

In an attempt to increase the therapeutic index of Cisplatin (CDDP), 29 continuous 48 hour intra-arterial (IA) infusions of 100-150 mg/m2 CDDP were given to 26 patients with bulky stage T3-T4 bladder cancer. Hypogastric artery catheters were placed distal (n = 42) or proximal (n = 7) to the origin of the superior gluteal artery. Atherosclerosis (n = 5) or aneurysm (n = 2) prevented successful IA catheter placement. Catheter maintenance resulted in no bleeding or thromboembolic episodes. Urethral catheters caused two urinary tract infections. Systemic toxicity was mild with on 4/29 infusions resulting in WBC less than 3,000, 3/29 infusions resulting in creatinine elevation, and 1/29 in peripheral neuropathy. Local effects of the IA CDDP included gluteal pain and ecchymosis (n = 1) and moderately disabling lower extremity neuropathies (n = 3). Systemic side effects of CDDP can be diminished by use of IA route of administration and slow continuous infusion.     

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone.

BACKGROUND: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. RESULTS: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050). CONCLUSIONS: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.     

Metastatic epidural osteosarcoma initially diagnosed as cisplatin neuropathy

Unexpected early epidural spinal metastatis in a case of osteosarcoma occurred in a patient receiving treatment with cis-diamminedichloroplatinum-II (cisplatin). The initial neurologic symptomatology manifested as paresthesias in the feet which developed 2 months after initiation of treatment (cumulative dose of cisplatin 450 mg/M²) at which stage the primary tumor demonstrated a marked response. Concurrently two small pulmonary metastases appeared. Epidural metastasis in osteosarcoma is generally considered a late complication and is usually associated with disseminated disease. This communication draws attention to changes in the metastatic pattern which may occur with the administration of seemingly effective treatment and the potential for confusing the symptomatology of epidural spinal metastasis with cisplatin neuropathy.