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Microneurosurgical treatment options in peripheral nerve compression syndromes after chemotherapy and radiation treatment: CHANG et al.
Abstract
Chemotherapy‐induced peripheral neuropathy and radiation‐induced brachial plexopathy are extremely debilitating conditions which can occur after treatment of malignancy. Unfortunately, the diagnosis can be elusive, and this dilemma is further compounded by the lack of efficacious therapeutics to prevent the onset of neurotoxicity before initiating chemotherapy or radiation or to treat these sequelae after treatment. However, microsurgical nerve decompression can provide these patients with a viable option to treat this complication.
... For metastatic brachial plexus involvement, treatment also includes radiation therapy, chemotherapy, or hormonal therapy, depending on cancer type [83]. Treatment of neurolymphomatosis, a rare and often missed manifestation of lymphoma and leukemia thought to be in part of paraneoplastic origin [87,90], includes systemic chemotherapy, sometimes combined with intrathecal chemotherapy and external-beam radiotherapy. Prognosis is generally poor, unless paraneoplastic symptoms predominate. ...
... Unfortunately, conservative measures do not ameliorate RIP [87]. Surgical therapies are more helpful, with microsurgical neurolysis of the brachial plexus to release extensive radiation fibrosis, use of vascularized flap coverage to improve blood supply, and restore some degree of limb function [87] and nerve grafting and muscle and tendon transfers to restore function in paralyzed states. ...
... Unfortunately, conservative measures do not ameliorate RIP [87]. Surgical therapies are more helpful, with microsurgical neurolysis of the brachial plexus to release extensive radiation fibrosis, use of vascularized flap coverage to improve blood supply, and restore some degree of limb function [87] and nerve grafting and muscle and tendon transfers to restore function in paralyzed states. ...
Purpose of review
Brachial plexopathies (BPs) are a heterogeneous group of diseases which can profoundly affect person’s function and quality of life. This review targets current approaches to treatment of different BP types.
Recent findings
Although there are multiple BP etiologies, non-traumatic causes are particularly unrecognized by clinicians, leading to misdiagnoses and delay in appropriate therapies. Recent data suggests that idiopathic neuralgic amyotrophy may be 50-fold more common than previously thought, with poorer outcomes than reported unless rapid diagnosis is followed by a multidisciplinary approach to treatment, including surgery for refractory cases. Advances in diagnostic imaging reduce time to treatment, if proper recognition by primary providers leads to rapid referral to neurologists. Due to rarity, heterogeneity, and overlap of different BP syndromes, development of treatment strategies is still based on case series and retrospective studies. Despite advances in surgical therapies, there are no randomized trials to guide optimal approaches to treatment in either traumatic or non-traumatic cases.
Summary
Recent advances in imaging and surgical therapies may significantly improve clinical outcomes for patients with BPs, if rapid diagnosis of these often under-recognized conditions can be substantially improved to optimize approach to management. Controlled trials are still needed to optimize therapeutic strategies.
... К ранним проявлениям последствий лучевой терапии относятся изменения кожи, потеря волосяного покрова, различные алгические синдромы. К поздним эффектам -скованность, нарушение чувствительности и слабость мышц, контрактуры, сопровождающиеся выраженным болевым синдромом, [12,13]. Клиническая картина постлучевого фиброза варьируется в зависимости от локализации и дозы облучения, а также тяжести поражения анатомических структур. ...
Postradiation epidural fibrosis is one of the rare complications of cancer treatment in patients receiving radiation therapy, leads to a mosaic clinical picture, including manifestations of polyneuropathy, caudogenic intermittent lameness syndrome and can significantly affect the quality of life of patients. Depending on the type of cancer, the volume of the affected tissues and the level of damage to the spine, radiation fibrosis syndrome is characterized by a diverse clinical picture. The main clinical manifestations of post-radiation fibrosis of the spinal canal at the level of the lumbar spine are pain, numbness, paresthesia in the lower extremities. A thorough history and physical examination, combined with the use of neuroimaging data, help establish an accurate diagnosis and select an effective treatment. When studying the problem of post-radiation fibrosis, it is extremely difficult to predict the time, risk group and specificity of characteristic symptoms, given the development of pathology in elderly and senile patients, against the background of existing degenerative changes in the spine. However, there is a close relationship with dosage, anatomical impact, nature of damage and clinical symptoms. Conservative methods of treating post-radiation fibrosis with spinal canal stenosis include the use of analgesic, antiinflammatory therapy. With a prolonged course of pain syndrome, insufficient effectiveness of conservative treatment, local blockades or epidural injections are carried out. In the absence of the effect of conservative treatment, indications for surgical intervention arise.
... This surgery may be paired with a vascularized flap coverage to improve blood supply and decrease the risk of recurrent fibrosis. Some patients may also require nerve grafting and muscle and tendon transfers to restore function, particularly with long-standing plexopathy [34]. Dorsal root entry zone lesioning can be used to destroy nociceptive neural structures to relieve intractable neuropathic pain [6]. ...
Purpose of Review
Radiation fibrosis syndrome is a complication of cancer treatment in patients receiving radiation therapy. This article explores the clinical manifestations of this syndrome which cause pain, and treatment strategies that can be used to ameliorate pain and improve function and quality of life.
Recent Findings
Depending on the cancer type and tissues affected, radiation fibrosis syndrome exhibits a varied clinical picture. Taking a thorough history and physical exam coupled with the use of validated outcome measures can provide an accurate assessment of the patient. Treatment frequently involves the use of rehabilitation, medications, injections, and/or surgery, as appropriate for each patient.
Summary
Radiation fibrosis syndrome can cause pain and affect function and quality of life for cancer patients. Several treatment modalities are currently used for pain reduction and there is hope for future developments in interventions that target molecular pathways.
... However, surgical treatment (including microsurgical neurolysis, vascular flap cover, nerve grafts and transfer of muscles or tendons) is quickly gaining favour, particularly in advanced cases. [4][5][6] ...
The late-onset variant of radiation-induced brachial plexopathy is most often seen after treatment for breast or lung cancers. It has an insidious onset, with symptoms noted years after receiving radiotherapy, and the condition gradually continues to deteriorate with time. We present the case of an elderly man who we saw in view of worsening paraesthesias and weakness of his left arm with associated prominent muscle wasting along the left shoulder girdle. Fifteen years prior to this, he had received radiotherapy for the treatment of nasopharyngeal carcinoma.
... An alternative option is microsurgical neurolysis, which can be considered when progressive motor weakness is present and conservative modalities have failed. This method allows for nerve decompression caused by radiation fibrosis; moreover, a vascularized flap coverage restores some degree of function to the affected limb, restores blood supply to the irradiated areas, and decreases the risk of recurrent fibrosis (13). There is limited evidence to support the use of anticoagulant therapy or hyperbaric oxygen in the treatment of RIPN (7). ...
Cancer itself can have lifelong devastating effects, but radiation treatment can often also result in long-lasting neurological and musculoskeletal complications, leading to subsequent severe functional impairments. Physiatrists caring for the cancer rehabilitation population must be able to recognize and treat radiation-induced peripheral nerve injuries. This report presents a rare case of radiationinduced obturator neuropathy in a patient with recurrent cervical cancer.
LAY ABSTRACT
The number of cancer survivors is increasing annually. Many of these survivors will have received some form of radiation therapy. Whether their last dose was 6 months or 20 years ago, radiation can cause injury to nerves and muscles at any point after treatment. If physicians do not recognize these complications at an early stage, radiation injuries can result in progressive pain and functional impairments that can be lifelong. We report here a rare case of nerve injury in a patient following radiation, emphasizing the key findings of presentation and the testing and management needed in order to prevent long-term pain and improve overall quality of life in cancer survivors.
Significance:
Chemotherapy is a primary method to treat cancer. While chemotherapeutic drugs are designed to target rapidly dividing cancer cells, they can also affect other cell types. In the case of dermal cells and macrophages involved in wound healing, cytotoxicity often leads to the development of chronic wounds. The situation becomes even more severe when chemotherapy is combined with surgical tumor excision.
Recent advances:
Despite its significant impact on patients' recovery from surgery, the issue of delayed wound healing in individuals undergoing chemotherapy remains inadequately explored.
Critical issues:
This review aims to analyze the harmful impact of chemotherapy on wound healing. The analysis showed that chemotherapy drugs could inhibit cellular metabolism, cell division, and angiogenesis and lead to nerve damage. They impede the migration of cells into the wound and reduce the production of extracellular matrix. At the molecular level, they interfere with replication, transcription, translation, and cell signaling. This work reviews skin problems that patients may experience during and after chemotherapy and demonstrates insights into the cellular and molecular mechanisms of these pathologies.
Future directions:
In the future, the problem of impaired wound healing in patients treated with chemotherapy may be addressed by cell therapies like autologous keratinocyte transplantation, which has already proved effective in this case. Epigenetic intervention to mitigate the side effects of chemotherapy is also worth considering, but epigenetic consequences of chemotherapy on skin cells are largely unknown and should be investigated.
Musculoskeletal physicians often encounter disorders of the peripheral nervous system, whether plexopathies and neuropathies. In this chapter, we discussed a variety and perhaps the most common peripheral nervous system disorders that an MSK clinician may encounter in acute or in chronic clinical scenarios. Conditions such as rib fracture may result in intercostal neuralgia. Posttraumatic cases that require amputation may experience phantom limb pain. Idiopathic and iatrogenic peripheral nerve disorders including genitofemoral neuropathy, ilioinguinal neuropathy, and lateral femoral cutaneous neuropathy are seen commonly in musculoskeletal clinics. In the context of trauma or other associated disorders, lumbosacral plexopathy, brachial plexopathy, thoracic outlet syndrome, and complex regional pain syndrome may present for evaluation. Proper identification and treatment of such patients will result in substantial symptom relief and improvement of quality of life and function.
Background
Dosimetric constraints of the brachial plexus have not yet been well-established for patients undergoing stereotactic body radiotherapy (SBRT). This study evaluated long-term experience with the treatment of early stage apical lung tumors with SBRT and reports on dosimetric correlates of outcome.
Methods
Between 2009 and 2018, a total of 78 consecutive patients with 81 apical lung tumors underwent SBRT for T1-3N0 non-small cell lung cancer. Apical tumors were those with tumor epicenter superior to the aortic arch. The brachial plexus (BP) was anatomically contoured according to the Radiation Therapy Oncology Group (RTOG) atlas. Patient medical records were retrospectively reviewed to determine incidence of brachial plexus injury (BPI) and a normal tissue complication probability model (NTCP) was applied to the dosimetric data.
Results
Five patients (6.4%) reported neuropathic symptoms consistent with BPI and occurred a median 11.9 months after treatment (range, 5.2 to 28.1 months). Most common dose and fractionation in those developing BPI were 50 Gy in 5 fractions (4 patients). Symptoms consisted of pain in 2 patients (40.0%), numbness in the hand or axilla in 4 patients (80.0%), and ipsilateral hand weakness in 1 patient (20.0%). In the overall cohort the median BP Dmax (EQD23 Gy) was 5.13 Gy (range, 0.18 to 217.2 Gy) and in patients with BPI the median BP Dmax (EQD23 Gy) was 32.14 Gy (range, 13.4 to 99.9 Gy). The NTCP model gave good fit with an area under the curve (AUC) of 0.75 (OR 7.3, 95% CI: 0.8-68.3) for BP Dmax (EQD23 Gy) threshold of 20 Gy.
Conclusion
Significant variation exists in the dose delivered to the brachial plexus for patients treated by SBRT for apical lung tumors. The incidence of neuropathic symptoms in the post-SBRT setting was appreciable and prospective clinical correlation with dosimetric information should be utilized in order to develop evidence-based dose constraints.
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018. © 2018 American Cancer Society.
Objective:
To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial.
Methods:
Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis.
Results:
The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness.
Conclusion:
First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.
Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.
Up to 20% of patients with multiple myeloma (MM) show signs of peripheral neuropathy (PN) at primary diagnosis.[1][1] Treatment with neurotoxic agents such as bortezomib or thalidomide increases rates of PN in newly diagnosed patients by up to 50%.[2][2] Since subcutaneous (SC) administration
Radiation-induced brachial plexopathy (RIBP) is one of the late complications in nasopharyngeal carcinoma (NPC) patients who received radiotherapy. We conducted a retrospective study to investigate its clinical characteristics and risk factors.Thirty-onepatients with RIBP after radiotherapy for NPC were enrolled. Clinical manifestations of RIBP, electrophysiologic data, magnetic resonance imaging (MRI), and the correlation between irradiation strategy and incidence of RIBP were evaluated. The mean latency at the onset of RIBP was 4.26 years. Of the symptoms, paraesthesia usually presented first (51.6%), followed by pain (22.6%) and weakness (22.6%). The major symptoms included paraesthesia (90.3%), pain (54.8%), weakness (48.4%), fasciculation (19.3%) and muscle atrophy (9.7%). Nerve conduction velocity (NCV) and electromyography (EMG) disclosed that pathological changes of brachial plexus involved predominantly in the upper and middle trunks in distribution. MRI of the brachial plexus showed hyper-intensity on T1, T2, postcontrast T1 and diffusion weighted whole body imaging with background body signal suppression (DWIBS) images in lower cervical nerves. Radiotherapy with Gross Tumor volume (GTVnd) and therapeutic dose (mean 66.8±2.8Gy) for patients with lower cervical lymph node metastasis was related to a significantly higher incidence of RIBP (P < 0.001).Thus, RIBP is a severe and progressive complication of NPC after radiotherapy. The clinical symptoms are predominantly involved in upper and middle trunk of the brachial plexus in distribution. Lower cervical lymph node metastasis and corresponding radiotherapy might cause a significant increase of the RIBP incidence.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and debilitating complications of cancer treatment. Due to a lack of effective management options for patients with CIPN, the National Cancer Institute (NCI) sponsored a series of trials aimed at both prevention and treatment. A total of 15 such studies were approved, evaluating use of various neuro-modulatory agents which have shown benefit in other neuropathic pain states. Aside from duloxetine, none of the pharmacologic methods demonstrated therapeutic benefit for patients with CIPN. Despite these disappointing results, the series of trials revealed important lessons that have informed subsequent work. Some examples of this include the use of patient-reported symptom metrics, the elimination of traditional-yet unsubstantiated-practice approaches, and the discovery of molecular genetic predictors of neuropathy. Current inquiry is being guided by the results from these large-scale trials, and as such, stands better chance of identifying durable solutions for this treatment-limiting toxicity.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and relevant side effect of antineoplastic agents such as cisplatin, paclitaxel, vincristine and bortezomib. Over the last years, significant progress has been achieved in elucidating the underlying pathomechanisms of CIPN using both in vivo and in vitro models. These studies suggest that mitochondrial toxicity, disturbed axonal transport, toxic effects on Schwann cells and activation of the immune system contribute to the pathogenesis of CIPN. This review provides an overview of the current pathogenetic concepts of CIPN. In addition, experimental approaches that aim at preventing or ameliorating neurotoxic effects of antineoplastic agents are discussed.
Peroneal nerve entrapment neuropathy (PNEN) is one cause of numbness and pain in the lateral lower thigh and instep, and of motor weakness of the extensors of the toes and ankle. We report a less invasive surgical procedure performed under local anesthesia to treat PNEN and our preliminary outcomes. We treated 22 patients (33 legs), 7 men and 15 women, whose average age was 66 years. The mean postoperative follow-up period was 40 months. All patients complained of pain or paresthesia of the lateral aspect of affected lower thigh and instep; all manifested a Tinel-like sign at the entrapment point. As all had undergone unsuccessful conservative treatment, we performed microsurgical decompression under local anesthesia. Of 19 patients who had undergone lumbar spinal surgery (LSS), 9 suffered residual symptoms attributable to PNEN. While complete symptom abatement was obtained in the other 10 they later developed PNEN-induced new symptoms. Motor weakness of the extensors of the toes and ankle [manual muscle testing (MMT) 4/5] was observed preoperatively in 8 patients; it was relieved by microsurgical decompression. Based on self-assessments, all 22 patients were satisfied with the results of surgery. PNEN should be considered as a possible differential diagnosis in patients with L5 neuropathy due to lumbar degenerative disease, and as a causative factor of residual symptoms after LSS. PNEN can be successfully addressed by less-invasive surgery performed under local anesthesia.
Purpose
We aimed to study the radiation induced brachial plexopathy in patients with head and neck squamous cell carcinoma (HNSCC) treated with Sequential Intensity Modulated Radiation Therapy (S-IMRT).
Methods and materials
This IRB approved study included 68 patients with HNSCC treated consecutively. Detailed dose volume histogram data was generated for ipsilateral and contralateral brachial plexus (BP) volumes receiving a specified dose (Vds) i.e. V50-V75 and dose in Gray covering specified percent of BP volume (Dvs) i.e. D5-D30 and maximum point doses (Dmax). To assess BP injury all patients’ charts were reviewed in detail for sign and symptoms of BP damage. Post-hoc comparisons were done using Tukey-Kramer method to account for multiple significance testing.
Results
The mean and maximum doses to BP were significantly different (p < .05) based on tumor site, nodal status and tumor stage. The mean volume to the ipsilateral BP for V50, V60, V70, and V75 were 7.01 cc, 4.37 cc, 1.47 cc and 0.24 cc, respectively. The mean dose delivered to ≤5% of ipsilateral BP was 68.70 Gy (median 69.5Gy). None of the patients had acute or late brachial plexopathy or any other significant neurological complications, with a minimum follow up of two years (mean 54 months).
Conclusions
In this study cohort, at a minimum of two-years follow up, the mean dose of 68.7Gy, a median dose to 69.5Gy to ≤5% of ipsilateral BP, and a median Dmax of 72.96Gy did not result in BP injury when patients were treated with S-IMRT technique. However, longer follow up is needed.
Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.
©AlphaMed Press.
With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment.
To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL.
Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity.
Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2.
Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4).
Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10(-9)). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.
In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.
To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors.
A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life.
A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms.
On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.
Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In any case, it is acknowledged that the dorsal root ganglia of the primary sensory neurons are the most common neural targets of CIPN. Both the incidence and severity of CIPN are clinically under- and misreported, and it has been demonstrated that scoring CIPN with common toxicity scales is associated with significant inter-observer variability. Only a proportion of chemotherapy-treated patients develop treatment-emergent and persistent CIPN, and to date it has been impossible to predict high-and low-risk subjects even within groups who receive the same drug regimen. This issue has recently been investigated in the context of pharmacogenetic analyses, but these studies have not implemented a proper methodological approach and their results are inconsistent and not really clinically relevant. As such, a stringent approach has to be implemented to validate that information. Another open issue is that, at present, there is insufficient evidence to support the use of any of the already tested chemoprotective agents to prevent or limit CIPN. The results of comprehensive interventions, including clinical, neurophysiological, and pharmacogenetic approaches, are expected to produce a consistent advantage for both doctors and patients and thus allow the registration and analysis of reliable data on the true characteristics of CIPN, eventually leading to potential preventive and therapeutic interventions.
Background:
The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment.
Patients and methods:
A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20).
Results:
Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores.
Conclusion:
None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.
Docetaxel-induced peripheral neuropathy (PN) can lead to sub-optimal treatment in women with early breast cancer. Here, we compare the frequency of dose reduction as a result of PN in two different adjuvant regimens. From the Danish Breast Cancer Cooperative Group READ trial we included 1,725 patients with early stage breast cancer who randomly were assigned to three cycles of epirubicin and cyclophosphamide followed by three cycles docetaxel (D100) or six cycles of cyclophosphamide and docetaxel (D75). Eligible patients completed chemotherapy, received docetaxel, and provided information on patient-reported outcome (secondary outcome of trial) including PN. Associations between PN and risk factors were analyzed by multivariate logistic regression. Overall 597 patients (34 %) reported PN, grades 2-4, during treatment, 194 (11 %) after the first cycle [early onset peripheral neuropathy (EPN)] and 403 (23 %) after subsequent cycles [later-onset peripheral neuropathy (LPN)]. The odds ratio (OR) of EPN was significantly increased for the D100 regimen (OR 3.10; 95 % CI 2.18-4.42) while this regimen was associated with reduced OR of LPN (OR 0.69; 95 % CI 0.54-0.88). Patients with PN received significantly lower cumulative doses of docetaxel than patients with no PN. Explorative analysis showed that OR of PN was significantly reduced if patients wore frozen gloves and socks during treatment (OR 0.56; 95 % CI 0.38-0.81) in the EPN group. Patients developing PN after the first cycle are less likely to receive docetaxel at the planned dose intensity and usage of frozen gloves and socks may modify the risk.
There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy.
To determine the effect of duloxetine, 60 mg daily, on average pain severity.
Randomized, double-blind, placebo-controlled crossover trial at 8 National Cancer Institute (NCI)-funded cooperative research networks that enrolled 231 patients who were 25 years or older being treated at community and academic settings between April 2008 and March 2011. Study follow-up was completed July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment.
The initial treatment consisted of taking 1 capsule daily of either 30 mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of duloxetine or placebo daily for 4 additional weeks.
The primary hypothesis was that duloxetine would be more effective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain. Pain severity was assessed using the Brief Pain Inventory-Short Form "average pain" item with 0 representing no pain and 10 representing as bad as can be imagined.
Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95% CI, 0.01-0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount. CONCLUSION AND RELEVANCE: Among patients with painful chemotherapy-induced peripheral neuropathy, the use of duloxetine compared with placebo for 5 weeks resulted in a greater reduction in pain.
clinicaltrials.gov Identifier: NCT00489411.
Radiation-induced peripheral neuropathy is a chronic handicap, frightening because progressive and usually irreversible, usually appearing several years after radiotherapy. Its occurrence is rare but increasing with improved long-term cancer survival. The pathophysiological mechanisms are not yet fully understood. Nerve compression by indirect extensive radiation-induced fibrosis plays a central role, in addition to direct injury to nerves through axonal damage and demyelination and injury to blood vessels by ischaemia following capillary network failure. There is great clinical heterogeneity in neurological presentation since various anatomic sites are irradiated. The well-known frequent form is radiation-induced brachial plexopathy (RIBP) following breast cancer irradiation, while tumour recurrence is easier to discount today with the help of magnetic resonance imaging and positron emission tomography. RIBP incidence is in accordance with the irradiation technique, and ranges from 66% RIBP with 60Gy in 5Gy fractions in the 1960s to less than 1% with 50Gy in 2Gy fractions today. Whereas a link with previous radiotherapy is forgotten or difficult to establish, this has recently been facilitated by a posteriori conformal radiotherapy with 3D-dosimetric reconstitution: lumbosacral radiculo-plexopathy following testicular seminoma or Hodgkin's disease misdiagnosed as amyotrophic lateral sclerosis. Promising treatments via the antioxidant pathway for radiation-induced fibrosis suggest a way to improve the everyday quality of life of these long-term cancer survivors.
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study.Patients and methodsAfter literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out.ResultsGood inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures.Conclusion
Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.
The purpose of this retrospective study was to determine tumor factors contributing to brachial plexus (BP) dose in head-and-neck cancer (HNC) patients treated with intensity-modulated radiotherapy (IMRT) when the BP is routinely contoured as an organ at risk (OAR) for IMRT optimization.
From 2004 to 2011, a total of 114 HNC patients underwent IMRT to a total dose of 69.96 Gy in 33 fractions, with the right and left BP prospectively contoured as separate OARs in 111 patients and the ipsilateral BP contoured in 3 patients (total, 225 BP). Staging category T4 and N2/3 disease were present in 34 (29.8%) and 74 (64.9%) patients, respectively. During IMRT optimization, the intent was to keep the maximum BP dose to ≤60 Gy, but prioritizing tumor coverage over achieving the BP constraints. BP dose parameters were compared with tumor and nodal stage.
With a median follow-up of 16.2 months, 43 (37.7%) patients had ≥24 months of follow-up with no brachial plexopathy reported. Mean BP volume was 8.2 ± 4.5 cm(3). Mean BP maximum dose was 58.1 ± 12.2 Gy, and BP mean dose was 42.2 ± 11.3 Gy. The BP maximum dose was ≤60, ≤66, and ≤70 Gy in 122 (54.2%), 185 (82.2%), and 203 (90.2%) BP, respectively. For oropharynx, hypopharynx, and larynx sites, the mean BP maximum dose was 58.4 Gy and 63.4 Gy in T0-3 and T4 disease, respectively (p = 0.002). Mean BP maximum dose with N0/1 and N2/3 disease was 52.8 Gy and 60.9 Gy, respectively (p < 0.0001).
In head-and-neck IMRT, dose constraints for the BP are difficult to achieve to ≤60 to 66 Gy with T4 disease of the larynx, hypopharynx, and oropharynx or N2/3 disease. The risk of brachial plexopathy is likely very small in HNC patients undergoing IMRT, although longer follow-up is required.
As the recommended radiation dose for non-small-cell lung cancer (NSCLC) increases, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging, particularly for tumors in the superior sulcus. In this retrospective analysis, we compared dose-volume histogram information with the incidence of plexopathy to establish the maximum dose tolerated by the brachial plexus.
We identified 90 patients with NSCLC treated with definitive chemoradiation from March 2007 through September 2010, who had received >55 Gy to the brachial plexus. We used a multiatlas segmentation method combined with deformable image registration to delineate the brachial plexus on the original planning CT scans and scored plexopathy according to Common Terminology Criteria for Adverse Events version 4.03.
Median radiation dose to the brachial plexus was 70 Gy (range, 56-87.5 Gy; 1.5-2.5 Gy/fraction). At a median follow-up time of 14.0 months, 14 patients (16%) had brachial plexopathy (8 patients [9%] had Grade 1, and 6 patients [7%] had Grade ≥2); median time to symptom onset was 6.5 months (range, 1.4-37.4 months). On multivariate analysis, receipt of a median brachial plexus dose of >69 Gy (odds ratio [OR] 10.091; 95% confidence interval [CI], 1.512-67.331; p = 0.005), a maximum dose of >75 Gy to 2 cm(3) of the brachial plexus (OR, 4.909; 95% CI, 0.966-24.952; p = 0.038), and the presence of plexopathy before irradiation (OR, 4.722; 95% CI, 1.267-17.606; p = 0.021) were independent predictors of brachial plexopathy.
For lung cancers near the apical region, brachial plexopathy is a major concern for high-dose radiation therapy. We developed a computer-assisted image segmentation method that allows us to rapidly and consistently contour the brachial plexus and establish the dose limits to minimize the risk of brachial plexopathy. Our results could be used as a guideline in future prospective trials with high-dose radiation therapy for unresectable lung cancer.
Predictive ability of a positive Tinel sign over the tibial nerve in the tarsal was evaluated as a prognostic sign in determining sensory outcomes after distal tibial neurolysis in diabetics with chronic nerve compression at this location. Outcomes were evaluated with a visual analog score (VAS) for pain and measurements of the cutaneous pressure threshold/two-point discrimination. A multicenter prospective study enrolled 628 patients who had a positive Tinel sign. Of these patients, 465 (74%) had VAS >5. Each patient had a release of the tarsal tunnel and a neurolysis of the medial and lateral plantar and calcaneal tunnels. Subsequent, contralateral, identical surgery was done in 211 of the patients (152 of which had a VAS >5). Mean VAS score decreased from 8.5 to 2.0 (p <0.001) at 6 months, and remained at this level for 3.5 years. Sensibility improved from a loss of protective sensation to recovery of some two-point discrimination during this same time period. It is concluded that a positive Tinel sign over the tibial nerve at the tarsal tunnel in a diabetic patient with chronic nerve compression at this location predicts significant relief of pain and improvement in plantar sensibility.
Neuropathy is a common, often debilitating complication of cancer and its treatment. Effective management of this disorder depends on early diagnosis and an understanding of its underlying causes in the individual patient. In January 2009, NCCN gathered a multidisciplinary group to review the literature and discuss intervention strategies currently available to patients as well as areas that require research efforts. The task force, which comprised experts in anesthesiology, medical oncology, neurology, neuro-oncology, neurophysiology, nursing, pain management, and rehabilitation, was charged with the goal of outlining recommendations for the possible prevention, diagnosis, and management of neuropathy. This report documents the proceedings of this meeting with a general background on neuropathy and neuropathy in oncology, followed by discussions on challenges and research issues, evaluation criteria, and management of different symptoms associated with this disorder.
Radiation-induced fibrosis (RIF) and radionecrosis (RN) are late complications that are usually considered irreversible. Usual management strategy includes eliminating local and general aggravating factors and controlling acute and chronic inflammation with steroids. Thanks to progress in understanding the pathophysiology of these lesions, several lines of treatment have been developed in clinical practice. However, results of clinical studies are difficult to compare because of variations in severity of RIF, method of RIF assessment, availability of efficient therapeutic drugs, treatment duration, and quality of trial design. For moderate established RIF, current management strategy mainly includes (1) anti-inflammatory treatment with corticosteroids or interferon gamma; (2) vascular therapy with pentoxifylline (PTX) or hyperbaric oxygen (HBO); and (3) antioxidant treatment with superoxide dismutase, tocopherol (vitamin E), and, most successfully, with a PTX-vitamin E combination. On the basis of etiology, RN can be managed by (1) anti-inflammatory treatment with corticosteroids and possibly clodronate, (2) vascular therapy with HBO and PTX, (3) antioxidant treatment with a PTX-vitamin E combination, and (4) a PTX-vitamin E-clodronate combination. Controlled randomized trials are now necessary to identify the best treatment at each step of RIF. In the future, these treatments of fibrosis and necrosis should include targeted drugs (such as growth factors) to take organ specificities into account.
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Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes that leads to suboptimal treatment and adversely affects quality of life. Acetyl-L-Carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients enrolled in this trial. Methods: S0715 was a randomized, double-blind, multi-center trial comparing ALC (1000 mg TID) versus placebo for 24 weeks in women with stage I-III breast cancer undergoing taxane-based chemotherapy. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at 12 weeks. Additional assessments were conducted at weeks 24, 36, 52 and 104. We examined the reduction of NTX score over 2 years using linear mixed models for longitudinal data, adjusting for stratification factors and the baseline NTX score. Individual assessment time-points were examined using linear regression. Results: SWOG S0715 registered 437 patients, of whom 409 were eligible and evaluable, including 208 assigned to receive ALC and 201 to placebo. Patterns of evaluability were similar over time by arm. The results for the primary outcome of interest, NTX, show a statistically significant (p = 0.01) average difference of -1.39 (95% CI: -2.47 to -0.31) between treatment groups, with the ALC group having lower scores (worse CIPN) on average than the placebo group. These differences were particularly evident at Weeks 24 (p = 0.02), 36 (p = 0.04), and 52 (p = 0.02). A clinically meaningful (≥5 points) reduction in NTX score over baseline was observed more frequently for the ALC vs. control arm (week 24, 41% vs. 34%; week 36, 41% vs. 28%; 1 year, 41% vs. 32%; 2 years, 40% vs. 34%). For both treatment groups 2 year NTX scores were significantly different compared to baseline (p < 0.001). Conclusions: For both groups NTX scores were reduced with taxane-therapy and remained persistently low 2-years following treatment. Twenty-four weeks of ALC therapy resulted in significantly worse CIPN at weeks 24 36 and 52. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Clinical trial information: NCT00775645.
Background:
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes. Acetyl-L-carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients in this trial.
Methods:
S0715 was a randomized, double-blind, multicenter trial comparing ALC (1000 mg three times a day) with placebo for 24 weeks in women undergoing adjuvant taxane-based chemotherapy for breast cancer. CIPN was measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at weeks 12, 24, 36, 52, and 104. We examined NTX scores over two years using linear mixed models for longitudinal data. Individual time points were examined using linear regression. Regression analyses included stratification factors and the baseline score as covariates. All statistical tests were two-sided.
Results:
Four-hundred nine subjects were eligible for evaluation. Patients receiving ALC had a statistically significantly (P = .01) greater reduction in NTX scores (worse CIPN) of -1.39 points (95% confidence interval [CI] = -2.48 to -0.30) than the placebo group. These differences were particularly evident at weeks 24 (-1.68, 95% CI = -3.02 to -0.33), 36 (-1.37, 95% CI = -2.69 to -0.04), and 52 (-1.83, 95% CI = -3.35 to -0.32). At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline. For both treatment groups, 104-week NTX scores were statistically significantly different compared with baseline (P < .001).
Conclusions:
For both groups, NTX scores were reduced from baseline and remained persistently low. Twenty-four weeks of ALC therapy resulted in statistically significantly worse CIPN over two years. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Until then, the potential efficacy and harms of commonly used supplements should be rigorously studied.
Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.
Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of many cancer treatments. The hallmark of CIPN is degeneration of long axons required for transmission of sensory information; axonal degeneration causes impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that the chemotherapeutic agent paclitaxel triggers CIPN by altering IP3 receptor phosphorylation and intracellular calcium flux, and activating calcium-dependent calpain proteases. Concomitantly paclitaxel impairs axonal trafficking of RNA-granules and reduces synthesis of Bclw (bcl2l2), a Bcl2 family member that binds IP3R1 and restrains axon degeneration. Surprisingly, Bclw or a stapled peptide corresponding to the Bclw BH4 domain interact with axonal IP3R1 and prevent paclitaxel-induced degeneration, while Bcl2 and BclxL cannot do so. Together these data identify a Bclw-IP3R1-dependent cascade that causes axon degeneration and suggest that Bclw-mimetics could provide effective therapy to prevent CIPN.
Background:
The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL).
Methods:
The National Surgical Adjuvant Breast and Bowel Project Protocol B-30 was a randomized trial comparing sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T) (AC→T), concurrent ACT, or AT in women with node-positive, early-stage breast cancer. The AC→T group had a higher cumulative dose of T. PN was one of the symptoms assessed in a QOL substudy. Statistical methods included simple and mixed ordinal logistic regression and general linear models. All statistical tests were two-sided.
Results:
Of 1512 patients, 41.9% reported PN two years after treatment initiation. Treatment with AT and ACT was associated with less severe long-term PN compared with AC→T (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.35 to 0.58; OR = 0.59, 95% CI = 0.46 to 0.75). Preexisting PN, older age, obesity, mastectomy, and greater number of positive nodes were also associated with higher risk of long-term PN. Patients who reported worse PN symptoms at 24 months had statistically significantly worse QOL (Ptrend < .001).
Conclusions:
The administration of docetaxel is associated with long-term PN. The lower rate of long-term PN in AT and ACT patients might be an important consideration in supporting choosing these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy.
Purpose
Carpal tunnel and cubital tunnel syndrome are the 2 most common upper-limb compressive neuropathies. However, whether the characteristics of patient populations undergoing surgery for these conditions are similar is unclear in terms of demographics and concomitant pathologies. Our null hypothesis was that there are no identifiable differences between these patient populations.
Methods
A retrospective cohort study was performed by billing system query using Common Procedural Terminology (CPT) codes for all patients who underwent open carpal tunnel release (CTR) (CPT code 64721) and/or open cubital tunnel surgery (CPT code 64718) by 1 of 4 hand surgeons from August 2008 to July 2013. Application of exclusion criteria of acute trauma, revision surgery, neoplasm, age less than 18 years, and inaccurate or insufficient records resulted in identification of 1,114 patients who underwent CTR, 264 patients who underwent cubital tunnel surgery, and 76 patients who underwent both. Computerized medical records were analyzed for demographic variables, medical comorbidities, and other procedures performed under the same anesthetic.
Results
In the multivariable analysis, older age, female sex, higher body mass index, trigger finger, and de Quervain tenosynovitis were associated with CTR. Prior trauma to the anatomic site was more common in the cubital tunnel group. Diabetes mellitus was associated with patients who had both procedures.
Conclusions
The populations of patients who undergo surgery for different upper-extremity compressive neuropathies are not homogenous: CTR is associated with older age, female sex, higher body mass index, and hand tendinopathies. Cubital tunnel decompression is associated with prior trauma to the anatomic site. Diabetic patients are more likely to have both procedures. Diabetic patients undergoing either procedure should be evaluated for other peripheral nerve compression pathologies.
Type of study/level of evidence
Diagnostic IV.
Objective:
To assess the design characteristics and reporting quality of published randomized controlled trials (RCTs) for treatments of chemotherapy-induced peripheral neuropathy (CIPN) initiated before or during chemotherapy.
Methods:
In this systematic review of RCTs of preventive or symptomatic pharmacologic treatments for CIPN initiated before or during chemotherapy treatment, articles were identified by updating the PubMed search utilized in the CIPN treatment guidelines published in the Journal of Clinical Oncology in 2014.
Results:
Thirty-eight articles were identified. The majority included only patients receiving platinum therapies (61%) and used a placebo control (79%). Common exclusion criteria were preexisting neuropathy (84%), diabetes (55%), and receiving treatments that could potentially improve neuropathy symptoms (45%). Ninety-five percent of studies initiated the experimental treatment before CIPN symptoms occurred. Although 58% of articles identified a primary outcome measure (POM), only 32% specified a primary analysis. Approximately half (54%) of the POMs were patient-reported outcome measures of symptoms and functional impairment. Other POMs included composite measures of symptoms and clinician-rated signs (23%) and vibration tests (14%). Only 32% of articles indicated how data from participants who prematurely discontinued chemotherapy were analyzed, and 21% and 29% reported the number of participants who discontinued chemotherapy due to neuropathy or other/unspecified reasons, respectively.
Conclusions:
These data identify reporting practices that could be improved in order to enhance readers' ability to critically evaluate RCTs of CIPN treatments and use the findings to inform the design of future studies and clinical practice. Reporting recommendations are provided.
The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib-induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome-wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug-induced PNP and to functionally validate our in silico predictions.
Background Over the last decade, surgical decompression procedures have been commonly used in the treatment of diabetic peripheral neuropathy. However, the effectiveness of them remains to be proved.
Methods A comprehensive literature search of databases including PubMed-Medline, Ovid-EMBASE, and Cochrane Library was performed to collect the related literatures. The Medical Subject Headings used were “diabetic neuropathy,” “surgical decompression,” and “outcomes.” The methodological index for nonrandomized studies was adopted for assessing the studies included in this review. Analyses were performed with Review Manager (Version 5.3, Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014).
Results A total of 12 literatures (including 8 prospective and 4 retrospective) encompassing 1,825 patients with DPN were included in the final analysis. Only one literature was identified as a randomized controlled trial. The remaining 11 literatures were observational studies; 7 of them were classified as upper-extremity nerve decompression group and 4 of them were classified as lower-extremity nerve decompression group. Meta-analysis shows that Boston questionnaire symptom severity and functional status of upper extremities, and distal motor latency and sensory conduction velocity of median nerve of DPN patients are significantly improved after carpal tunnel release. Besides, visual analog scale and two-point discrimination are considered clinically and statistically significant in lower extremities after operation.
Conclusions The findings from our review have shown the efficacy of surgical decompression procedures in relieving the neurologic symptoms and restoring the sensory deficits in DPN patients. As there are few high-quality randomized controlled trials or well-designed prospective studies, more data are needed to elucidate the role of surgical procedures for DPN treatment in the future.
Purpose:
To evaluate the effect of hypofractionated radiation therapy (HFRT) of the breast/chest wall and regional nodes on overall survival (OS), disease-free survival (DFS), locoregional control and on treatment-related toxicity in patients with breast cancer and nodal involvement.
Methods and materials:
Two hundred fifty-seven patients treated between October 2009 and June 2011 with hypofractionated locoregional radiation therapy (42 Gy in 15 fractions) were retrospectively reviewed, 51 (19.8%) after breast-conserving surgery and 206 (80.2%) after radical surgery. Patients treated with breast-conserving surgery received a boost dose to the tumor bed (delivered by photons, electrons, or interstitial high-dose-rate brachytherapy). Two hundred fifty-six (99.6%) patients underwent chemotherapy, 209 (81.3%) had hormonal treatment, and 65 (25.3%) had anti-HER2 targeted therapy.
Results:
The median follow-up time was 64 months (range, 11-88 months). The rates of 5-year OS, DFS, locoregional recurrence (LRR)-free survival, and distant metastasis (DM)-free survival were 86.6%, 84.4%, 93.9%, and 83.1%, respectively. In multivariate analysis (MVA), lymph node ratio >65%, lymphovascular invasion, and negative hormone receptor status predicted for OS, DSF, and DM. T3 to 4 stage was also associated with worse DFS and DM. Finally, for LRR the independent prognostic factors on MVA were N2 to 3 stage and grade 3. Hyperpigmentation was observed in 19.2% of patients, telangiectasia in 12.3%, and fibrosis in 30.7%. Grade ≥2 lymphedema was recorded in 5.8% of cases. During the study follow-up, no cardiac or symptomatic pneumonitis was observed, nor were plexopathy or rib fractures.
Conclusion:
According to the findings from this retrospective study, HFRT seems to be an acceptable alternative for patients with breast cancer who need regional nodal irradiation. However, prospective randomized trials are necessary to confirm these preliminary results.
Purpose:
To test clinical feasibility, safety, and toxicity of prone hypofractionated breast, chest wall, and nodal radiation therapy.
Methods and materials:
Following either segmental or total mastectomy with axillary node dissection, patients were treated in an institutional review board-approved prospective trial of prone radiation therapy to the breast, chest wall, and supraclavicular and level III axillary lymph nodes. A dose of 40.5 Gy/15 fractions with a concomitant daily boost to the tumor bed of 0.5 Gy (total dose, 48 Gy) was prescribed. In postmastectomy patients, the same treatment was prescribed, but without a tumor bed boost. The primary endpoint was incidence of >grade 2 acute skin toxicity. The secondary endpoints were feasibility of treatment using prone set-up, compliance with protocol-defined dosimetric constraints, and incidence of late toxicity. A dosimetric comparison was performed between protocol plans (prone) and nonprotocol plans (supine), targeting the same treatment volumes.
Results:
Sixty-nine patients with stage IB-IIIA breast cancer enrolled in this trial. Surgery was segmental mastectomy (n = 45), mastectomy (n = 23), and bilateral mastectomy (n = 1), resulting in 70 cases. None experienced >grade 2 acute skin toxicity according to the Common Terminology Criteria for Adverse Events, v 3.0, meeting our primary endpoint. Ninety-six percent of patients could be treated with this technique prone. However, 17 plans (24%) exceeded protocol constraints to the brachial plexus. Maximum long-term toxicity was 1 grade 2 arm lymphedema, 1 grade 3 breast retraction, and no occurrence of brachial plexopathy. Dosimetric comparison of protocol with nonprotocol plans demonstrated significantly decreased lung and heart doses in prone plans.
Conclusions:
Prone hypofractionated breast, chest wall, and nodal radiation therapy is safe and well tolerated in this study. Although the initial pattern of local and regional control is encouraging, longer follow-up is warranted for efficacy and late toxicity assessment, particularly to the brachial plexus.
We aimed to study the radiation induced brachial plexopathy in patients with head and neck squamous cell carcinoma (HNSCC) treated with Sequential Intensity Modulated Radiation Therapy (S-IMRT).
This IRB approved study included 68 patients with HNSCC treated consecutively. Detailed dose volume histogram data was generated for ipsilateral and contralateral brachial plexus (BP) volumes receiving a specified dose (Vds) i.e. V50-V75 and dose in Gray covering specified percent of BP volume (Dvs) i.e. D5-D30 and maximum point doses (Dmax). To assess BP injury all patients' charts were reviewed in detail for sign and symptoms of BP damage. Post-hoc comparisons were done using Tukey-Kramer method to account for multiple significance testing.
The mean and maximum doses to BP were significantly different (p < .05) based on tumor site, nodal status and tumor stage. The mean volume to the ipsilateral BP for V50, V60, V70, and V75 were 7.01 cc, 4.37 cc, 1.47 cc and 0.24 cc, respectively. The mean dose delivered to ≤5% of ipsilateral BP was 68.70 Gy (median 69.5Gy). None of the patients had acute or late brachial plexopathy or any other significant neurological complications, with a minimum follow up of two years (mean 54 months).
In this study cohort, at a minimum of two-years follow up, the mean dose of 68.7Gy, a median dose to 69.5Gy to ≤5% of ipsilateral BP, and a median Dmax of 72.96Gy did not result in BP injury when patients were treated with S-IMRT technique. However, longer follow up is needed.
Background. Chemotherapy with taxanes and platinum compounds has resulted in substantial survival benefits both in adjuvant and metastatic settings. However, as a side effect, such chemotherapy may cause peripheral neuropathy (CIPN) which may result in discontinuation of treatment, and if it persists after treatment completion, has a negative impact on quality of life (QoL).
Results. Symptoms of CIPN are sensory, like pain, numbness, and tingling, typically located in the hands and feet. For oxaliplatin, there is an acute form of CIPN, resulting in paraesthesias in the mouth and throat during or shortly after the infusion triggered by exposure to cold. Risks factors for CIPN include preexisting neuropathy, either from treatment with other neurotoxic agents, or from comorbid conditions. The incidence of CIPN is related to dose per cycle, cumulative dose, and duration of infusion. While cisplatin-induced neuropathy is irreversible, CIPN induced by taxanes may persist for several years in about 30% of patients. Evidence from the literature is suggestive that CIPN is likely to be negatively associated with QoL. No agents have been identified to be recommended for the prevention of CIPN. For treatment of CIPN, the best available data supports a moderate recommendation for treatment with duloxetine and evidence is inconclusive regarding the use of tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine.
Conclusion. Research is still needed to predict which patients are at high risk of developing CIPN during treatment and in whom CIPN will persist after completion of chemotherapy.
Radiation-induced brachial plexopathy is a delayed complication of radiation treatment for tumors involving the neck and chest area and is progressive. A 56-year-old woman presented to us with loss of elbow flexion and weak wrist and finger extension 15 years after she received external beam radiation to the left chest, axilla, and supraclavicular region for treatment of breast cancer. She was managed with a gracilis free muscle transfer for elbow flexion and hand prehension. By 2 years after surgery she regained elbow range of motion of 40° to 110° and improved in hand function. She was able to perform activities of daily living. Disabilities of the Arm, Shoulder, and Hand score improved from 56 to 20.
With a 3-fold increase in the number of cancer survivors noted since the 1970s, there are now over 28 million cancer survivors worldwide. Accordingly, there is a heightened awareness of long-term toxicities and the impact on quality of life following treatment in cancer survivors. This review will address the increasing importance and challenge of chemotherapy-induced neurotoxicity, with a focus on neuropathy associated with the treatment of breast cancer, colorectal cancer, testicular cancer, and hematological cancers. An overview of the diagnosis, symptomatology, and pathophysiology of chemotherapy-induced peripheral neuropathy will be provided, with a critical analysis of assessment strategies, neuroprotective approaches, and potential treatments. The review will concentrate on neuropathy associated with taxanes, platinum compounds, vinca alkaloids, thalidomide, and bortezomib, providing clinical information specific to these chemotherapies. CA Cancer J Clin 2013;63:419-437. (©) 2013 American Cancer Society, Inc.
Purpose:
Data are limited on the clinical significance of brachial plexopathy in patients with apical non-small cell lung cancers (NSCLC) treated with definitive radiation therapy. We report the rates of radiation-induced brachial plexopathy (RIBP) and tumor-related brachial plexopathy (TRBP) and associated dosimetric parameters in apical NSCLC patients.
Methods and materials:
Charts of NSCLC patients with primary upper lobe or superiorly located nodal disease who received ≥50 Gy of definitive conventionally fractionated radiation or chemoradiation were retrospectively reviewed for evidence of brachial plexopathy and categorized as RIBP, TRBP, or trauma-related. Dosimetric data were gathered on ipsilateral brachial plexuses (IBP) contoured according to Radiation Therapy Oncology Group atlas guidelines.
Results:
Eighty patients were identified with a median follow-up and survival time of 17.2 and 17.7 months, respectively. The median prescribed dose was 66.6 Gy (range, 50.4-84.0), and 71% of patients received concurrent chemotherapy. RIBP occurred in 5 patients with an estimated 3-year rate of 12% when accounting for competing risk of death. Seven patients developed TRBP (estimated 3-year rate of 13%), comprising 24% of patients who developed locoregional failures. Grade 3 brachial plexopathy was more common in patients who experienced TRBP than RIBP (57% vs 20%). No patient who received ≤78 Gy to the IBP developed RIBP. On multivariable competing risk analysis, IBP V76 receiving ≥1 cc, and primary tumor failure had the highest hazard ratios for developing RIBP and TRBP, respectively.
Conclusions:
RIBP is a relatively uncommon complication in patients with apical NSCLC tumors receiving definitive doses of radiation, while patients who develop primary tumor failures are at high risk for developing morbid TRBP. These findings suggest that the importance of primary tumor control with adequate doses of radiation outweigh the risk of RIBP in this population of patients.
Background:
Patients and surgeons recognize the value of procedures that minimize scarring and tissue dissection, but technical standards do not exist with regards to incision lengths needed for tibial nerve decompression. This article introduces reproducible techniques that reliably provide exposure for release of known anatomical compression points of the tibial nerve, while minimizing the length of required skin incisions.
Methods:
The senior author's approach to decompression of the tibial nerve at the soleus arch and the tarsal tunnel is presented. Typical incision lengths and surgical exposure are demonstrated photographically. The safety of using this technique is examined by review of the medical records of all patients undergoing this procedure from 2003 to 2011, looking for technical complications such as unintentional damage to nerves or adjacent structures.
Results:
224 consecutive patients undergoing 252 total procedures underwent release of known anatomical compression points of the tibial nerve at either the tarsal tunnel, inner ankle, or the soleus arch. Typical incision lengths used for these procedures were 5 cm for the proximal calf and 4.5 cm for the tarsal tunnel. Review of medical records revealed no incidences of unintentional injury to nerves or adjacent important structures. Functional and neurological outcomes were not assessed.
Conclusions:
Tibial nerve decompression by release of known anatomical compression points can be accomplished safely and effectively via minimized skin incisions using the presented techniques. With appropriate knowledge of anatomy, this can be performed without additional risk of injury to the patient, making classically-described longer incisions unnecessarily morbid.
Irradiation of the supraclavicular lymph nodes has historically increased the risk of brachial plexopathy. We report long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes.
We collected information from 814 women consecutively treated with adjuvant radiotherapy for breast cancer. The women had breast surgery with axillary dissection (AD) or sentinel node biopsy (SNB). The breast area was treated to 50 Gy in 2.0 Gy fractions. Women with >three lymph node metastases had regional radiotherapy (RRT) to the supraclavicular lymph nodes. Three to eight years after radiotherapy, they received a questionnaire asking about paraesthesia, oedema, pain, and strength in the upper limb.
Paraesthesia was reported by 38/192 (20%) after AD with RRT compared to 68/505 (13%) after AD without RRT (relative risk [RR] 1.47; 95% confidence interval [CI] 1.02-2.11) and by 9/112 (8%) after SNB without RRT (RR 2.46; 95% CI 1.24-4.90). Corresponding risks adjusted for oedema (RR 1.28; 95% CI 0.93-1.76) and (RR 1.75; 95% CI 0.90-3.39). In women ≤ 49years with AD and RRT, 27% reported paraesthesia. No significant pain or decreased strength was reported after RRT.
Radiotherapy to the supraclavicular lymph nodes after axillary dissection increases the occurrence of paraesthesia, mainly among younger women. When adjusted for oedema the contribution from radiotherapy is no longer formally statistically significant indicating that there is also an indirect effect mediated by the oedema.
Both patients and surgeons recognize the value of procedures that minimize scarring and tissue dissection. No previous reports have described a minimally invasive technique for peroneal nerve neurolysis, or evaluated its safety.
The senior author's technique for a minimally invasive approach to neurolysis of the common, superficial, and deep peroneal nerves is presented. Safety of the technique was determined by review of records of all patients undergoing this procedure from 2003-2011, looking for major complications.
Using the minimally invasive approach to peroneal nerve neurolysis, average skin incision size is 3.5 cm for the common peroneal nerve, 4 cm for the superficial peroneal nerve, and 2.5 cm for the deep peroneal nerve. In 400 patients undergoing 679 total procedures, there were no nerve injuries, postoperative neuromas, or adjacent structures harmed.
Peroneal nerve neurolysis can be accomplished safely and effectively via a minimal skin incision, improving aesthetic results and decreasing possible scar-related complications.
Peripheral neuropathy is highly prevalent among patients with diabetes mellitus and demonstrates well-established consequences of limb loss following lower extremity ulceration, infection, and amputation and upper extremity loss of function. Symptomatic neuropathy is recognized by neuropathic pain, paresthesias, and the development of trophic limb changes. The objective of this review is to define the role of peripheral nerve surgery in the treatment of diabetic patients with upper or lower extremity symptomatic peripheral neuropathy and/or chronic postoperative pain.
At locations of decreased anatomical cross-sectional area, compression points impinge on peripheral nerve fascicles, and because of a synergistic effect of the metabolic derangements of diabetes, these points of compression are implicated in nerve abnormality and dysfunction. The surgical outcomes literature following decompression is reviewed, and specific recommendations are made for appropriate surgical candidate selection. In addition, the operative techniques used in peripheral nerve surgery are outlined.
Peripheral nerve surgery for diabetic peripheral neuropathy is indicated when symptoms of pain, allodynia, or trophic changes persist despite optimization of medical management. Surgical treatment is considered an adjunct therapy to medical optimization and should be used when there is clinical and/or electrodiagnostic evidence of compression neuropathy or a postsurgical neuroma-related chronic pain syndrome that is refractory to conservative management.
Review of available reports in the surgical literature demonstrates that the results of peripheral nerve surgery are promising for the prevention of limb loss in chronic diabetes mellitus, for diminishment of pain, and for restoration of sensory/motor function.
As peripheral nerve specialists can have a wide variety of training backgrounds, few standards of care exist with respect to necessary incision length, amount of dissection, and operative technique for common nerve decompressions.
Approaches for the following 12 common peripheral nerve surgeries were minimized using shorter incisions and a simple lighted retractor: zygomatico-temporal and auriculotemporal, greater occipital, brachial plexus, ulnar, radial, median, lateral femoral cutaneous nerve of the thigh, peroneal at the groin, fibular neck and lateral calf, and tibial and inner ankle. The new "minimal" incision length was recorded as was that of the "classical" approach as taught to the senior author and frequently represented in atlases. A Mann-Whiney analysis was independently performed to evaluate for significance between the lengths of incisions for each procedure.
The average length of the "minimal" incisions was 3.9 ± 0.6 cm (range, 3.1-6.1 cm), with an average reduction in length of 51% as compared with the "classical" incisions (range, 30-75%; P < 0.001). There were no perioperative morbidities.
Minimally invasive peripheral nerve surgery applied to the above procedures yields successful surgical outcomes while shortening incision lengths and maximizing patient satisfaction without sacrificing patient safety.
Oxaliplatin use in gastrointestinal malignancies is limited by neurotoxicity. This study aimed to assess the efficacy of pregabalin (LYRICA(R)) in the treatment of oxaliplatin-induced neurotoxicity.
A total of 23 gastrointestinal cancer patients with grade 2 and 3 oxaliplatin-induced sensory neuropathy were treated with pregabalin up to a target dose of 150mg orally (PO) three times a day (tid) based on benefit and tolerance. Neurological symptoms were serially evaluated.
The target dose of 150 mg tid provided the best benefit, but patients benefited even at lower doses. Onset of benefit was observed in 2-6 weeks. In the majority of patients (48%), neuropathy improved by 1 to 2 grades.
Pregabalin significantly reduced the severity of oxaliplatin-induced sensory neuropathy. Being more potent than gabapentin, pregabalin achieved efficacy at lower doses and should lead to fewer dose-related side effects, although this remains to be established in a head-to-head trial.
The anatomical basis for the surgical techniques used to treat tarsal tunnel syndrome is not well studied. The authors sought to evaluate their hypotheses that (1) pronation and pronation with plantar flexion of the intact foot would have higher pressures than the intact foot in other positions; (2) decompression surgery would significantly lower the pressure in all three tunnels in all foot positions, and roof incision plus septum excision would lower the pressure further in some positions; and (3) the pressures in symptomatic patients would be significantly higher than those in an analogous cadaver study.
In 10 patients with tarsal tunnel syndrome, the authors intraoperatively measured pressures in the tarsal, medial plantar, and lateral plantar tunnels in multiple foot positions before and after excision of the tunnel roofs and intertunnel septum.
The authors found that (1) pronation and plantar flexion significantly increased pressures in the medial and lateral plantar tunnels, to levels sufficient to cause chronic nerve compression; (2) tunnel release and septum excision significantly decreased those pressures; and (3) compared with cadaver pressures, patients had similar tarsal tunnel pressures but higher lateral plantar tunnel pressures in some positions.
Many surgeons operating on patients with tarsal tunnel syndrome do not decompress the respective medial plantar and lateral plantar nerves and excise the septum. The authors' study validates the hypotheses that patients who are clinically suspected of having chronic compression of the tibial nerve and its branches at the ankle have higher tunnel pressures and that releasing these structures decreases the pressures.
The aims of the current explorative study were to assess persistent neuropathy in 45 patients up to 6 years after treatment with cisplatin or oxaliplatin and to determine the most adequate method to evaluate neuropathy. Furthermore, the effect of possible determinants on persistent neuropathy was investigated.
The assessment of neuropathy was performed using a questionnaire, by neurological tests, and by vibration threshold (VT) measurements. Because VT determination gives the most objective information, VT measurements were used for further analyses.
The analyses revealed that neuropathy of the hands was related to follow-up time, with an observed recovery half-life of 6.8 (+/- 3.1) years. No significant reversibility of neuropathy of the feet within the observation period could be demonstrated. For cisplatin, the severity of neuropathy was related to the cumulative dose and sodium thiosulfate use. Oxaliplatin induced neuropathy did not appear to be related to the dose within the studied dose range. No relationship with platinum levels, renal function, glutathione transferase genotypes, diabetes mellitus, alcohol use, or co-medication could be demonstrated. This study was performed as an explorative study and the issues discussed need to be investigated further.
Brachial plexus neuropathy can cause progressive pain and disability in patients with breast cancer. Metastatic spread and radiation injury are the most common causes in these patients. We report a case of partial ulnar nerve transfer to the nerve to the biceps muscle to restore elbow flexion in a patient with combined radiation-induced and metastatic brachial plexopathy.