Iatrogenic neuropathies

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Toxic neuropathies:

Toxic neuropathies Dr ravi uniyal

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Idiopathic polyneuropathy constitutes a significant proportion of peripheral neuropathy cases. A number of identifiable causes of neuropathy have no preventative or curative interventions available, only symptomatic treatment. Thus , detection of toxic or medication induced neuropathy can be an important diagnosis that impacts quality of life. Medication-induced neuropathies are uncommon (2-4% of cases in one outpatient neurology setting) 1 , but crucial to recognize because intervention can lead to significant improvement or symptom resolution.

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Identification of a toxic effect is simplest when acute or subacute onset of symptoms occurs soon after the initial drug exposure or a change of medication dosage . Most patients fall into this category . In contrast, it is much more problematic to diagnose a slowly progressive neuropathy starting many months or years after starting a chronic agent. Statin drugs provides a recent case in point and is discussed below.

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The majority of patients with cancer are treated with chemotherapy. Most drugs are pharmacological agents that act on all cells. They preferentially kill cancer cells by exploiting their unique characteristics. Rapid proliferation of malignant cells is a target characteristic and many agents damage rapidly proliferating normal tissues. Gut lining, hematopoietic, and lymphoid tissue often suffer bystander injury with prominent gastrointestinal side effects, anemia, leukopenia , thrombocytopenia, and immune suppression. Drugs have become more selective and newer

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It is paradoxical that nondividing neurons and supporting cells of the peripheral nervous system are susceptible. For many classes of agents, peripheral neurotoxicity is dose limiting. Patients are unable to complete full or optimal treatment schedules because of the development of chemotherapy-induced neuropathy (CIN)

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Cells of the peripheral nervous system are vulnerable because of several unique characteristics. Primary sensory and autonomic neurons are contained in ganglia that lie outside the blood-brain barrier and are supplied by capillaries with fenestrated walls that allow free passage of molecules between the circulation and the extracellular fluid in the ganglia. Long peripheral nerve axons are susceptible to any agents that interfere with the energy metabolism or the structural basis of axonal transport. Drugs that act by disrupting microtubules of the mitotic spindle also disrupt microtubule-based axonal transport. Agents targeting the increased mitochondrial activity of cancer cells may impair axonal transport. Finally, neurons have programmed cell death pathways that are particularly sensitive to DNA damage induced by many chemotherapeutic agents.

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Susceptibility of peripheral nerve Protected by a blood-nerve barrier and would seem to be at lesser risk than other organs for toxicity. However , a number of factors enhance peripheral nerve vulnerable, especially compared to the central nervous system. 1 Some examples include:

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Blood flow to peripheral nerve not autoregulated and vulnerable to sudden microenvironment changes. Dorsal root ganglia (DRG) lack an efficient vascular barrier making t cell body a target . Endothelial cells in the epineurium are fenestrated and allow escape of some blood proteins in the extracellular space. Blood-nerve barrier is less efficient than BBB, allowing easier access for potential neurotoxins into periphery. Endoneural nerves have no lymphatic system to remove toxins. Peripheral nerve has nothing analogous to the sink action of CSF

Assessment of CIN :

Assessment of CIN CIN is assessed in two different clinical contexts- clinical trials of new agents and evaluation of individual patients who have developed neuropathy while undergoing treatment for cancer

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The number of patients enrolled in controlled trials is relatively small, the instruments used to detect neuropathy are relatively insensitive, and patients are often ill with multisystem symptoms. For these reasons, neuropathy may only been detected as a side effect after drugs have been introduced into general clinical practice.

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Patients on new or complex chemotherapy regimes may develop neuropathy as a result of therapy that has not previously been reported. This has been the case for most of the drugs now known to consistently cause neuropathy.

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Are the symptoms and signs due to neuropathy? If so, are they caused by chemotherapy or by the underlying cancer or unrelated to either? Should the chemotherapy be stopped or modified because of the neuropathy? The temporal profile of the development of symptoms, the type of symptoms, and specific laboratory studies are helpful for answering these questions. Finally, the neurologist should recommend the best treatment for relief of symptoms.

Clinical Assessment :

Clinical Assessment Temporal Profile- Detailed clinical assessment defines the temporal relationship between chemotherapy treatment and development of neuropathy. Usually, the development of CIN is related to time of administration and dose. For many compounds, toxicity progressively develops once the cumulative dose has been exceeded. Symptoms typically begin several weeks to months after initiation of therapy and progress while treatment continues. Careful prospective studies demonstrate that maximum symptoms and deficit may occur up to a month after discontinuation of treatment for some patients ( Verstappen et al., 2005).

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Symptoms and signs reach a plateau at or soon after the end of treatment and improve after treatment is discontinued. The notable exceptions are the platinum Compounds which produce ‘‘coasting’’ where neuropathy progresses for weeks to several months after drug treatment ends. There are no examples of compounds where CIN begins months after drug cessation.

Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. :

Ethosuximide reverses paclitaxel - and vincristine -induced painful peripheral neuropathy. Pain [2004, 109(1-2):150-161] Thus these studies aim to test potential analgesics on established paclitaxel -induced pain. Paclitaxel -induced pain appears to be relatively resistant to opioid therapy i.p . 4 mg/kg morphine was ineffective and i.p . 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia / hyperalgesia . Interestingly, a maximally tolerated dose ( i.p . 0.2 mg/kg) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia / hyperalgesia suggesting that NMDA receptors have little role in paclitaxel -induced pain. Ethosuximide ( i.p . 450 mg/kg) an anti- epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia / hyperalgesia . Repetitive dosing with ethosuximide ( i.p . 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia / hyperalgesia with no evidence of tolerance. Ethosuximide ( i.p . 300 mg/kg) also reversed paclitaxel -induced cold allodynia and vincristine -induced mechanical allodynia / hyperalgesia . These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain

  Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy :

Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy Ann Oncol (1998) 9 (7): 739-744. T. J. Postma 1 , J. J. Heimans 1 , M. J. Muller 2 , G. J. Ossenkoppele 3 , J. B. Vermorken 4 , 6 and N. K. Aaronson 2 , 5

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Patients and methods Two neurologists independently rated the severity of chemotherapy-induced peripheral neuropathy, according to WHO, ECOG, Ajani, and NCIC-CTC criteria in 37 patients. Results The highest percentage grade 1, grade 2 and grade 3 peripheral neurotoxicity was noted when employing the WHO, Ajani and NCIC-CTC scales, respectively. Percentage inter-observer agreement across all grades of severity ranged from 45.9 (NCIC-CTC) to 83.8 (WHO). The degree of agreement varied from ‘poor to fair’ to ‘substantial’. Percentage interobserver agreement for the dichotomy grade ≤ 2 and grade 3 ranged from 81.1 (NCIC-CTC) to 94.6 (Ajani and WHO), however, exact agreement on grade 3 peripheral neurotoxicity ranged from 0 (Ajani and WHO) to 42% (NCIC-CTC). Percentage interscale agreement for the dichotomy grade ≤ 2 and grade 3 varied from 67.6 (WHO and NCIC-CTC) to 100 (WHO and ECOG). Interobserver disagreement of severity grading was partly due to different interpretation of scale parameters.

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Conclusions Our results suggest that caution should be used in interpreting results across studies using different scales for neurotoxicity grading in chemotherapy-related peripheral neuropathy. When (multicentre) trials are to be undertaken with potential neurotoxic or neuroprotective agents, consensus should be sought regarding the toxicity rating scale used, and its interpretation by participating physicians.

Healthcare Costs and Workloss Burden of Patients with Chemotherapy-Associated Peripheral Neuropathy in Breast, Ovarian, Head and Neck, and Nonsmall Cell Lung Cancer:

Healthcare Costs and Workloss Burden of Patients with Chemotherapy-Associated Peripheral Neuropathy in Breast, Ovarian, Head and Neck, and Nonsmall Cell Lung Cancer Chemother Res Pract . 2012; 2012: 913848 Crystal T. Pike , 1 ,* Howard G. Birnbaum , 1 Catherine E. Muehlenbein , 2 Gerhardt M. Pohl , 2 and Ronald B. Natale 3

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Objective . Chemotherapy-associated peripheral neuropathy (CAPN) is a painful side-effect of chemotherapy. This study assesses healthcare and workloss costs of CAPN patients with breast, ovarian, head/neck, or non-small cell lung cancer (NSCLC) from a third-party payor /employer perspective. Research Design and Methods . Patients with qualifying tumors, and claims for chemotherapy and services indicative of peripheral neuropathy (PN) within 9-months of chemotherapy (cases) were identified in a administrative claims database. Cases were matched 1:1 to controls with no PN-related claims based on demographics, diabetes history and propensity for having a diagnosis of PN during the study period (based on resource use and comorbidities in a 3-month baseline period). Average all-cause healthcare costs, resource use and workloss burden were determined. Results . Average healthcare costs were $17,344 higher for CAPN cases than their non-CAPN controls, with outpatient costs being the highest component (with cases having excess costs of $8,092). On average, each CAPN case had 12 more outpatient visits than controls, and spent more days in the hospital. Workloss burden was higher for cases but not statistically different from controls. Conclusion . This study establishes that breast, ovarian, head/neck, or NSCLC patients with CAPN have significant excess healthcare costs and resource use

Persistent Mobility Disability After Neurotoxic Chemotherapy:

Persistent Mobility Disability After Neurotoxic Chemotherapy Elizabeth S. Hile , G. Kelley Fitzgerald , Stephanie A. Studenski Background and Purpose The impact of cancer and its treatments on balance and functional mobility in older adults remains unknown but is increasingly important, given the evolution of cancer treatments. Subacute and more persistent side effects such as chemotherapy-induced peripheral neuropathy are on the rise, and the effects on mobility and balance, as well as the prognosis for resolution of any functional deficits, must be established before interventions can be trialed. The purpose of this case report is to describe the severity and long-term persistence of mobility decline in an older adult who received neurotoxic chemotherapy. To our knowledge, this is the first case report to describe an older adult with chemotherapy-induced peripheral neuropathy using results of standardized balance and mobility tests and to focus on prognosis by repeating these measures more than 2 years after chemotherapy. Case Description An 81-year-old woman received a neurotoxic agent ( paclitaxel ) after curative mastectomy for breast cancer. Baseline testing prior to taxane therapy revealed a socially active woman with no reported functional deficits or neuropathic symptoms, 1.2-m/s gait speed, and performance at the ceiling on balance and gait portions of a standardized mobility measure. Outcomes After 3 cycles, paclitaxel therapy was stopped by the oncologist because of neurotoxicity. Declines as large as 50% were seen in performance-based measures at 12 weeks and persisted at 2.5 years, and the patient reported recurrent falls, cane use, and mobility-related disability. Discussion This case highlights the extent to which function can decline in an older individual receiving neurotoxic chemotherapy, the potential for these deficits to persist years after treatment is stopped, and the need for physical therapy intervention and further research in this population.

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study HIROI KAKU et al:

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel / carboplatin therapy: A multicenter collaborative study HIROI KAKU et al Exp Ther Med. 2012 January; 3(1): 60–65 Paclitaxel / carboplatin chemotherapy for cancer (TC therapy) exhibits neurotoxicity and causes peripheral neuropathy at a high frequency, which is difficult to cope with. In this study, we investigated the efficacy of Goshajinkigan , a traditional Japanese herbal medicine, for TC therapy-induced peripheral neuropathy. The subjects included in our study were patients with ovarian or endometrial cancer who underwent TC therapy and developed peripheral neuropathy. The patients were randomly divided into Group A, comprising of 14 patients (vitamin B12 treatment), and Group B, comprising of 15 patients (vitamin B12 + Goshajinkigan treatment). The observation period was 6 weeks following treatment initiation, and the evaluation items were as follows: i ) the current perception threshold (CPT value) of the peripheral nerve, ii) visual analogue scale for numbness, iii) National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade of neurotoxicity, and iv) a questionnaire on the subjective symptoms of peripheral neuropathy (functional assessment of cancer therapy- taxane ). These were compared between the groups and no significant differences were noted in any item. However, CTCAE grade 3 neurotoxicity developed in 2 patients (14.3%) after 6 weeks of administration in Group A, whereas no neurotoxicity was observed in Group B. When the change in the frequency of abnormal CPT ratio at 6 weeks of administration from that before treatment was compared between the groups, the frequency of abnormal value was significantly lower in Group B than in Group A (p<0.05). This suggests that Goshajinkigan inhibits the progression of peripheral neuropathy.

A Model of Toxic Neuropathy in Drosophila Reveals a Role for MORN4 in Promoting Axonal Degeneration:

A Model of Toxic Neuropathy in Drosophila Reveals a Role for MORN4 in Promoting Axonal Degeneration J Neurosci. 2012 April 11; 32(15): 5054–5061. MRC Bhattacharya et al Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication of Drosophila larvae with paclitaxel ( taxol ), a chemotherapeutic agent that causes neuropathy in cancer patients. In Drosophila , taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol -induced axonal degeneration in Drosophila shares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT expression and loss of wallenda /DLK. In a pilot RNAi -based screen we found that knockdown of retinophilin ( rtp ), which encodes a MORN-repeat containing protein, protects axons from degeneration in the presence of taxol . Loss-of-function mutants of rtp replicate this axonal protection. Knockdown of rtp also delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog of rtp , MORN4, promotes axonal degeneration in mouse sensory axons following axotomy , illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies .

Indian J Palliat Care. 2010 Jan-Apr; 16(1): 48–51:

Indian J Palliat Care. 2010 Jan-Apr; 16(1): 48–51 Radio Frequency Ablation in Drug Resistant Chemotherapy-induced Peripheral Neuropathy: A Case Report and Review of Literature Chemotherapy-induced peripheral neuropathy (CIPN) is a frequently encountered complication. It can result from a host of agents. Various modalities of treatment have been advocated, of which a novel method is radio frequency ablation. A 63-year-old male, a case of carcinoma prostrate with bone metastases, presented with tingling and numbness in right upper limb. He was given morphine, gabapentin and later switched to pregabalin , but medications provided only minor relief. Initially he was given stellate ganglion block, then radiofrequency ablation of dorsal root ganglion was done, but it failed to provide complete relief. Pulsed radiofrequency ablation (PRF) was then done for 90 seconds; two cycles each in both ulnar and median nerve. After the procedure the patient showed improvement in symptoms within four to five hours and 80% relief in symptoms. We conclude that PRF can be used for the treatment of drug resistant CIPN

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA:

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA Debra L. Barton Background Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. Methods Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory ( p =0.053) and motor subscales ( p =0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. Conclusion Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel:

Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel J Pain. 2009 November; 10(11): 1146–1150. Abstract Neuropathic pain (NP) remains difficult to control for a significant number of patients with cancer. Chemotherapy-induced peripheral neuropathy (CIPN) has been postulated as an initial stage in the development of NP. To assess whether CIPN (defined as National Cancer Institute Common Toxicity Criteria grade 2 or higher) was associated with NP, we conducted a survey of breast cancer patients who had participated in clinical trials of paclitaxel . Of the 430 potential respondents, 240 responded to the survey. Results showed that 64% experienced CIPN during paclitaxel treatment. Follow-up survey data revealed that 27% of those with CIPN were subsequently diagnosed with NP. Logistic regression analyses showed that those who had experienced CIPN were 3 times more likely to develop NP (95% confidence interval=1.2-7.2; p<0.001), which persisted in the multivariate logistic model. In addition, NP patients reported twice as many visits to their health care provider (p=0.02) and had taken more prescription (50% versus 19%; p=0.001) and over-the-counter medications (62.5% versus 45%; p=0.08) for pain than those without NP. The results of this study confirm that CIPN is a predictor of NP, suggesting that survivors treated with paclitaxel should be regularly monitored for NP beyond treatment.

Vincristine Induced Neurotoxicity in Cancer Patients Sunil Gomber, Pooja Dewan and Devender Chhonker :

Vincristine Induced Neurotoxicity in Cancer Patients Sunil Gomber , Pooja Dewan and Devender Chhonker Ten out of 20 children, treated with usual doses of vincristine for various types of childhood cancers, developed neurotoxicity during treatment. Peripheral neurotoxicity (mixed motor-sensory 4/10, pure motor 3/10, pure sensory 3/10) was seen in the form of weakness of lower limbs, areflexia , neuropathic pain, or sensory loss. Autonomic neuropathy presented as constipation and urinary retention in 2 children, while 2 children developed encephalopathy in form of seizures, confusion, aphasia, and transient blindness. In children with severe neuropathy, vincristine administration was withheld/dose reduced till clinical improvement started, which took about 2-3 weeks time. Nerve conduction velocity showed motor-sensory axonal polyneuropathy . Electrophysiological abnormalities were found to persist even six months after clinical recovery in children with neurotoxicity. We found a relatively higher incidence of vincristine induced neuropathy in Indian children, which was probably due to coexistence of severe malnutrition in them. [Indian J Pediatr 2010; 77 (1) : 97-100] E-mail: poojadewan @ hotmail.com

Neurological monitoring reduces the incidence of bortezomib-induced peripheral neuropathy in multiple myeloma patients :

Neurological monitoring reduces the incidence of bortezomib -induced peripheral neuropathy in multiple myeloma patients Journal of the Peripheral Nervous System 15:17–25 (2010 Roser Velasco et al

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Abstract Bortezomib (BTZ) is a proteasome inhibitor approved in the treatment of multiple myeloma (MM). Bortezomib -induced peripheral neuropathy (BIPN) is an unpredictable dose-limiting adverse event in one-third of patients. In the present study, 58 relapsed/refractory MM patients treated with BTZ were analyzed. The study’s aim was to compare BIPN incidence and severity between both groups and to identify risk factors of BIPN. Twenty-four MM patients were evaluated by a neurologist periodically during BTZ treatment in order to prevent high-grade BIPN. Thirty-five MM patients previously treated with BTZ were reviewed. Seven (29%) patients in the monitored group and 19 (56%) in the historical cohort developed BIPN (p = 0 .044). In the univariate analysis, factors related to BIPN in the whole series were age, number of vincristine and BTZ cycles, lactate dehydrogenase and neurological monitoring. Multivariate analysis revealed that absence of neurological monitoring (Hazard Ratio [HR]: 4.94 IC 95% [1.31–18.68], p = 0 .019) and prior treatment with vincristine (HR: 1.34 IC 95% [1.04–1.74], p = 0 .026) were associated with greater risk of BIPN. Baseline total neuropathy score-clinical version ( TNSc ) was a good predictor of BIPN, with higher risk for patients with TNSc >2 (p = 0.038). Neurological monitoring is useful for diminishing BIPN. Neurological monitoring of patients with baseline TNSc >2 should be considered.

J Clin Oncol. 2006 Jul 1;24(19):3113-20. Epub 2006 Jun 5. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. :

J Clin Oncol . 2006 Jul 1;24(19):3113-20. Epub 2006 Jun 5. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib . Abstract PURPOSE: To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS: Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG- Ntx ) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS: Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG- Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG- Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION: Bortezomib -associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

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Leukemia Research Volume 34, Issue 4 , Pages 471-474, April 2010 Bortezomib -induced peripheral neuropathy in multiple myeloma: A comparison between previously treated and untreated patients Alessandro Corso Affiliations Corresponding author. Tel.: +39 0382 503595; fax: +39 0382 502250. ,Silvia Mangiacavalli , Marzia Varettoni , Cristana Pascutto , Patrizia Zappasodi , Mario Lazzarino Division of Hematology, Fondazione IRCCS Policlinico San Matteo , University of Pavia, Viale Golgi 19, 27100 Pavia, Italy Abstract Peripheral neuropathy (PN), with neuropathic pain as main symptom, represents the dose-limiting toxicity of the proteasome inhibitor bortezomib . Aim of this study was to compare the incidence, risk factors, severity and outcome of PN and neuropathic pain in patient treated with bortezomib up-front or at relapse. We studied 55 patients with multiple myeloma (MM) who received bortezomib as first line therapy and 70 pre-treated patients who received bortezomib in relapse or progression. Regarding PN, no differences were found among untreated and pre-treated patients in the incidence (55% vs 52%, p = 0.43), severity (NCI grade 3–4 9% vs 14%, p = 0.27), and outcome (improved/resolved 90% vs 91%, p = 0.58). Concerning neuropathic pain, the incidence was lower (50% vs 81%, p = 0.008) and solved earlier (35 days vs 91 days, p = 0.02) in untreated compared with pre-treated patients. Untreated patients needed dose modification less frequently (36% vs 73%, p = 0.012). No correlation was found between development of PN and prior exposure to potentially neurotoxic drugs such as thalidomide, vincristine , and cysplatin . Age represented the main risk factor for PN ( p = 0.036) with an increase in risk of PN amounting to 6% per year of age. In conclusion, incidence, severity and outcome of bortezomib -related PN are similar in untreated and pre-treated MM patients except for neuropathic pain which has lower incidence and shorter duration in untreated patients with less frequent need for bortezomib discontinuation. Age emerges as the most relevant risk factor for peripheral neuropathy, with a risk increase for PN of 6% per year of age

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