Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

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.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

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 METHODS: After 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. RESULTS: Good 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.

Advanced age and liability to oxaliplatin-induced peripheral neuropathy: post hoc analysis of a prospective study.

BACKGROUND AND PURPOSE: The aim of this post hoc analysis of data extracted from a prospective, multicenter study is to test in a large homogenous population of chemotherapy-naïve patients with colorectal cancer (CRC) treated with oxaliplatin (OXA)-based chemotherapy whether advanced age increases the risk of developing OXA-induced peripheral neuropathy (OXAIPN). METHODS: One-hundred and forty-five patients with CRC, without other significant co-morbidities predisposing to peripheral neuropathy, were divided according to their age into two groups: patients aged between 50 and 68 years (group I, n = 75); and patients aged ≥ 69 years (group II, n = 70). Patients were prospectively monitored at baseline and followed-up during chemotherapy using the motor and neurosensory National Cancer Institute Common Toxicity criteria, the clinical version of the Total Neuropathy Score and neurophysiology. The incidence and severity of both the acute and cumulative OXAIPN was thoroughly determined and then compared between age groups. RESULTS: No statistically significant difference was observed in the incidence of both the acute (n = 64/75 vs. 56/70; P = 0.510) and cumulative OXAIPN (n = 51/75 vs. 49/70; P = 0.858) between age groups. The severity of OXAIPN was also similar between age groups. In line with the clinical data, the neurophysiological results between age groups were also comparable. CONCLUSION: The results of this study indicate that advanced age does not seem to represent a significant risk factor of OXAIPN in patients with CRC without any other significant co-morbidities.

Serum neurofilament levels correlate with electrodiagnostic evidence of axonal loss in paclitaxel-induced peripheral neurotoxicity.

INTRODUCTION: Paclitaxel-induced peripheral neurotoxicity (PIPN) typically manifests as a predominantly sensory axonopathy. Nerve conduction studies (NCS) represent the gold standard method to quantify axonal impairment in PIPN. Serum neurofilament light chain (sNfL) levels are emerging biomarkers for quantifying axonal damage in peripheral neuropathies. To date, the association between NCS abnormalities and sNfL levels during paclitaxel-based chemotherapy has not been specifically addressed. METHODS: We prospectively conducted longitudinal measurement of sNfL levels in 27 chemotherapy-naïve breast cancer patients and correlated conventional NCS recordings with sNfL in 22 of them, before (T0) and after (T1) 12 cycles of weekly paclitaxel-based therapy. RESULTS: PIPN was diagnosed in 24/27 patients (88%) after completion of the 12-week paclitaxel-based chemotherapy regimen. Serum NfL levels (pg/mL) were significantly higher at T1 compared to T0 (T0: 18.50 ± 12.88 vs T1: 255.80 ± 194.16; p < 0.001). The increase of sNfL levels at T1 significantly correlated with the decrease or abolishment of amplitudes recorded from the sural nerve (r = 0.620; p = 0.0035), sensory radial (r = 0.613; p = 0.005), sensory ulnar (r = 0.630; p = 0.005), and peroneal motor (r = 0.568; p = 0.024) nerves. CONCLUSION: sNfL levels proportionally increase during chemotherapy administration and significantly correlate with NCS axonal abnormalities in patients with PIPN. A multimodal testing approach employing both sNfL and NCS might improve the PIPN diagnostic accuracy.

Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients.

BACKGROUND: To report our prospective experience on the incidence and pattern of oxaliplatin (OXA)-induced peripheral neuropathy (OXA-IPN) in patients with colorectal cancer (CRC) treated with either FOLFOX-4 or XELoda + OXaliplatin (XELOX). PATIENTS AND METHODS: One hundred and fifty patients scheduled to be treated with either FOLFOX or XELOX for CRC were prospectively monitored at baseline and followed-up during chemotherapy. The incidence and severity of symptoms secondary to OXA-IPN were recorded using three different types of assessment, i.e. the motor and neurosensory National Cancer Institute common toxicity criteria, version 3.0 (NCI-CTCv3), the clinical version of the total neuropathy score (TNSc) and electrophysiological scores. RESULTS: Patients treated with either FOLFOX-4 or XELOX manifested similar incidence rates and severities of acute OXA-IPN. However, FOLFOX-4 was associated with increased incidence of chronic neurotoxicity, compared with XELOX-treated patients (n = 64/77 versus 44/73; P = 0.002), at a very similar OXA median cumulative dose during both regimens. Both the NCI-CTCv3 and TNSc demonstrated that the severity of cumulative OXA-IPN in FOLFOX-4-treated patients is higher than in those treated with XELOX. CONCLUSION: The incidence of acute neurotoxicity during FOLFOX-4 therapy is similar to XELOX. However, it seems that FOLFOX-4 is more neurotoxic than XELOX in terms of cumulative OXA-IPN, despite comparable OXA cumulative dose.

Informal educational interventions for caregivers of adult cancer survivors.

This review study explores the available data relating to the informal education aspects of effective interventions applied in caregivers of adult cancer survivors to maintain their own health and quality of life (QoL) and as such to provide the optimal care to the cancer patient. The implications of these interventions in oncology practice are also discussed. Available data show that, over the last years, a significant proportion of caregivers of cancer survivors are increasingly offered informal education interventions towards the reduction of their burden. More specifically, educational, skills training, and therapeutic counseling interventions seem to positively affect caregivers' well-being and overall QoL. However, based on available data, one cannot generalize these interventions on improving caregivers' outcomes of daily living activities and QoL. As such, available intervention strategies should be further tested and validated in larger samples, whereas novel health promotion educational approaches are expected to be designed to effectively address and comply with the appropriate needs of caregivers of cancer patients.

Informal education and health promoting approaches in adult cancer survivors.

This review looks at the available data relating to the informal education aspects and other health promoting approaches applied by adult cancer survivors to reduce the risk of cancer. The implications of such behavioral interventions on oncology practice are discussed. We also highlight areas of future research to pursue. Available data show that many cancer survivors remain engaged in risky health behaviors post-diagnosis, which are associated with an increased risk of disease's recurrence. However, over the last years patients seem to increasingly receive adequate risk-based medical care. The application of appropriate informal education approaches, such as diet, exercise, and cessation of former unhealthy habits, such as smoking and alcohol has facilitated behavioral changes in cancer survivors, thoroughly improving their well being and overall quality of life (QOL). Most of the research studies published to date have applied structured lifestyle interventions on intensive, individualized counseling sessions delivered by trained personnel or psychosocial-based mediations and reported that these approaches are largely effective in promoting the adoption of a healthier lifestyle in cancer survivors. These interventions have been reported to reduce the risk of cancer recurrence and thus to obtain an obvious positive impact on their well-being and overall QOL. However, there is still insufficient evidence to conclude and support with confidence the effectiveness of any of these behavioral interventions and therefore future interventions should be initiated to assess the long-term effects and validating outcomes of lifestyle and other psychosocial interventions.

Integrin beta-3 L33P: a new insight into the pathogenesis of chronic oxaliplatin-induced peripheral neuropathy?

AIM: To assess the significance of the ITGB3 polymorphism at residue 33 (ITGB3 L33P) in the development of chronic oxaliplatin-induced peripheral neuropathy (OXLIPN). METHODS: Fifty-five patients with advanced colorectal cancer were genotyped, using allele-specific primers and sybr green in real-time PCR. Patients had received adjuvant oxaliplatin-based chemotherapy. The severity of the OXLIPN was defined by means of the clinical total neuropathy score (TNSc). Following the discontinuation of treatment, 34/55 patients (61.8%) developed OXLIPN. Grade I neurotoxicity was revealed in 13 (38.2%) patients and grade II neurotoxicity in 21 (61.8%) patients. RESULTS: Patients without OXLIPN (n = 21) were 19% homozygous for C, 33.3% were heterozygous, and 47.7% were homozygous for T. The corresponding percentages for patients developing any grade of OXLIPN (n = 34) were similar. About half of patients (46.1%) with grade I OXLIPN were heterozygotes (CT), 23.1% were CC, and 30.8% were TT. The majority of patients with grade II OXLIPN were TT (66.7%) with the remaining 33.3% being CT. The TT genotype was associated with increased severity of OXLIPN compared to the genotypes containing the C allele (P = 0.044). CONCLUSION: The ITGB3 L33P seems to be unrelated to the development of OXLIPN, but it appears to be related to its severity.

Toxic peripheral neuropathy associated with commonly used chemotherapeutic agents.

Peripheral neuropathy ranks among the most common non-haematological adverse effects of a number of effective chemotherapeutic agents, including platinum compounds, taxanes and vinca alkaloids. Newer agents, such as bortezomib, thalidomide and lenalidomide, frequently exert similar neurotoxic effects on peripheral nerves. Chemotherapy-induced peripheral neuropathy (CIPN) may result from a variety of mechanisms and may be related to causal factors, such as single dose per course, cumulative dose and risk factors including treatment schedule, prior or concomitant administration of other neurotoxic agents, age and pre-existing peripheral neuropathy of other causes. The symptoms usually begin during chemotherapy and they may even worsen after cessation of treatment. In most of the cases, patients experience positive (pain, paresthesias) or negative (numbness) sensory symptoms in distal extremities in a stocking-and-glove distribution with less prominent motor and autonomic involvement. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested in preclinical models and clinical open label or randomized controlled trials for their ability to prevent or treat symptoms of CIPN. Although several of these agents hold promise as possible neuroprotective factors, clinical data are still controversial and none have as yet robustly been proven effective against CIPN. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of peripheral neuropathy associated with commonly used chemotherapeutic agents. We also highlight areas of future research to pursue.

The significance of second lumbrical-interosseous latency comparison in the diagnosis of carpal tunnel syndrome.

AIM: To assess the significance of the second lumbrical-interosseous latency (2LI-DML) comparison in the diagnosis of carpal tunnel syndrome (CTS). PATIENTS AND METHODS: We examined 150 consecutive hands of patients referred with suspected CTS, using the 2LI-DML test and other standard measures of median nerve function. Correlations of the 2LI-DML test with standard tests were computed. RESULTS: Hundred and four hands were electrophysiologically confirmed to have CTS. The 2LI-DML test was abnormal in 99/104 (95.2%) hands with CTS with a mean value of 1.54 +/- 1.12 ms. Among the other measures, the orthodromic median-ulnar palmar velocity comparison was the most frequently abnormal test (95/104 hands, 91.3%), followed by the double-peak morphology of orthodromic sensory action potential from digit 4 (94/104, 90.4%). The 2LI-DML test significantly correlated, either positively or negatively, with all other standard tests. CONCLUSION: The 2LI-DML comparison is highly sensitive in diagnosing CTS, even in mild cases in which standard tests fail to detect abnormalities.

Neuromyelitis optica: a distinct demyelinating disease of the central nervous system.

OBJECTIVES: We review and discuss the pathogenesis, epidemiology, diagnosis as well as recent advances in the treatment of NMO. We also highlight areas of future research. METHODS: A review was carried out on reports drawn from MEDLINE until 2007. RESULTS: Neuromyelitis optica (NMO) is a relative uncommon demyelinating disease of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. NMO follows an unpredictable course, being either monophasic or relapsing. The relapsing form of NMO primarily affects women with onset varying from childhood to adults in their 40s or elderly. Until recently, NMO was considered to be a variant of multiple sclerosis. However, in contrast to multiple sclerosis, NMO attacks are not mediated by T cells but rather by B cells and NMO-immunoglobulin G antibodies that target aquaporin-4. Humoral immune mechanisms, including complement activation plays an important role in the pathogenesis of NMO. At present, parenteral corticosteroids are widely employed as first-line treatment of optic neuritis and myelitis attacks, whereas therapeutic plasmapheresis is applied in the case of corticosteroids failure. Various strategies for the prevention of NMO relapses have been employed in small case series with modest activity. CONCLUSION: Recent advances in the clinical, neuroimaging, laboratory and pathological hallmarks have established that NMO is a distinct demyelinating disease of the CNS.

Painful limbs/moving extremities.

Painful limbs/moving extremities (PLME) is a disorder characterized by spontaneous, complex, slow (1-2 Hz) involuntary toe or finger movements. The movements that can be bilateral or unilateral are usually accompanied by pain in the affected limbs. Painless variants are less common. PLME has been associated with peripheral and central nervous system disease although idiopathic cases have been reported. Its etiopathogenesis is unknown and treatment approaches remain largely empirical. Nerve blocks and botulinum toxin type A injections as well as oral medication have had some measure of success. Current theories suggest that central oscillator(s) at the spinal or supraspinal levels may be involved. Future research in PLME should include prospective electrophysiological and functional imaging studies as well as clinical trials with botulinum toxin injections and oral pharmacological agents.

Co-occurrence of brain tumours and demyelination of the central nervous system: coincidence or interrelation?

The co-occurrence of a brain tumour and demyelinating disease of the central nervous system (CNS) constitutes a rare clinical entity. We herein report the incidence of meningioma and CNS non-specific demyelination in a patient with a 6-year history of operated brain tumour (meningioma). Our case bolsters the argument that in at least some cases, the occurrence of a brain tumour could predispose to CNS non-specific demyelination.

Effect of epoetin alpha therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy.

The primary aim of this study was to assess whether epoetin alpha (Ea) would improve cognitive performance in a group of anaemic cancer patients receiving chemotherapy. The secondary aim was to confirm the positive impact of Ea on haematological parameters, and quality of life (QOL). Fifty patients with solid tumours and haemoglobin (Hb) <11.0 g/dL received Ea 40,000 units once weekly for 12 weeks and were administered the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire prior to Ea therapy and at study completion. No clinically significant alterations were observed on cognitive function during Ea treatment. Changes in cognitive function were unrelated to Hb change and there were no significant differences in cognitive performance between Ea responders and non-responders. The analyses revealed clinically significant improvements in Hb levels, physical and role function, and clinically meaningful reductions in fatigue. Hb changes were significantly associated with the magnitude of improvement in QOL parameters. The lack of a clinical benefit in cognition observed in this study during Ea treatment may redirect the focus of research from enhancing to maintaining cognitive function, since stability in cognitive performance through time may be as well clinically important.

Emotional distress in cancer patients at the beginning of chemotherapy and its relation to quality of life.

PURPOSE: The present study sought to determine the prevalence of emotional distress and evaluate demographic and clinical factors related to anxiety and depression in treatment-naïve cancer patients at the beginning of chemotherapy. Another objective was to explore the associations between emotional distress and quality of life (QoL), an endpoint of great importance in current cancer care. PATIENTS AND METHODS: Adult outpatients with a variety of cancer diagnoses were administered the Hospital Anxiety and Depression Scale (HADS) and the European Organization for Research and Treatment of Cancer (EORTC QLQC30) questionnaire prior to the initiation of treatment. RESULTS: A total of 265 patients took part in the study. A sizeable minority of our patients reported intense levels of anxiety (27.2%) and depression (19.6%). Patients without a partner, females, and patients with advanced disease or lower physician-rated performance status (PS) were more likely to experience clinically significant emotional distress. Levels of anxiety and mainly depression were negatively related to all QoL domains. CONCLUSION: Our results indicate that a significant proportion of Greek cancer patients experience intense anxiety and depression prior to chemotherapy, and confirm the adverse impact of psychological morbidity on patients' QoL. Standardized and timely screening of emotional distress across all phases of cancer will help to effectively identify patients whose symptoms warrant attention. Future studies should continue to develop and evaluate rapid measures for detecting significant emotional distress in cancer patients, and to devise appropriate interventions to treat distress and enhance patients' QoL.

Effects of carotid endarterectomy on motor evoked potentials elicited by transcranial magnetic stimulation.

PURPOSE: To investigate the within 3 days effects of carotid endarterectomy (CEA) on functional status of the central motor system in patients with carotid stenosis by means of transcranial magnetic stimulation (TMS). PATIENTS AND METHOD: We studied 30 consecutive patients, 20 males and 10 females with a mean age of 69.2+/-7.1 years, who underwent CEA for symptomatic carotid stenosis. All patients had suffered an ischemic attack 6 months prior to the operation. Two TMS studies, one before and one shortly after CEA were performed on both sides in each of the patients. Resting motor threshold, motor evoked potentials (MEP) amplitude at rest, MEP latency at rest and during contraction and silent period duration (SPD) were recorded and analyzed. Two groups of data were collected. Group 1 consisted of data from the operated side in all 30 patients. Group 2 consisted of data from the contralateral side and served as a control. RESULTS: Motor resting thresholds were similar in the two groups. Intragroup pre and post CEA comparisons showed no difference in the operated group and significant increased threshold after CEA on the non-operated side. There was no significant difference of TMS intensity for maximal MEP in either side before or after CEA. Latency at rest and during voluntary contraction and amplitude at rest showed no significant differences between or within groups' comparisons. In group 1 SPD showed a statistically significant increase after CEA as opposed to baseline. In group 2 SPD showed a non significant increase after CEA. CONCLUSION: In the absence of other MEP changes, our finding of prolonged SPD post-operatively suggests preferential influence of the inhibitory cortical circuits. The potential favorable effect of CEA in patients with hyperexcitability such as disabling spasticity after stroke should be further studied.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.