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.
Bortezomib has demonstrated significant activity in clinical trials, mainly against recurrent or newly diagnosed multiple myeloma (MM). Peripheral neuropathy is a significant toxicity of bortezomib, ...requiring dose modification and potential changes in the treatment plan when it occurs. The mechanism underlying bortezomib-induced peripheral neuropathy (BIPN) is unknown. Metabolic changes resulting from the accumulation of bor-tezomib in the dorsal root ganglia cells, mitochondrial-mediated disregulation of Ca++ homeostasis, and disregulation of neurotrophins may contribute to the pathogenesis of BIPN. It is increasingly recognized that BIPN may be a proteasome inhibitor class effect, producing primarily a small fiber and painful, axonal, sensory distal neuropathy. Incidence of BIPN is mainly related to various risk factors, including cumulative dose and evidence of preexisting neuropathy. Assessment of BIPN is based primarily on neurologic clinical examination and neurophysiologic methods. To date, apart from the use of dose reduction and schedule change algorithm, there is no effective treatment with neuroprotective agents for BIPN. Analgesics, tricyclic antidepressants, anticonvulsants, and vitamin supplements have been used as symptomatic treatment against bortezomib-associated neuropathic pain with some success. This review looks critically at the pathogenesis, incidence, risk factors, diagnosis, characteristics, and management of BIPN, and highlights areas for future research.
Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.
...In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.
Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval CI, 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.
Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck Darmstadt, Germany; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).
Thirty-four years since its discovery, NF-κB remains a transcription factor with great potential for cancer therapy. However, NF-κB-targeted therapies have yet to find a way to be clinically ...translatable. Here, we focus exclusively on the role of NF-κB in non-small cell lung cancer (NSCLC) and discuss its contributing effect on cancer hallmarks such as inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial-mesenchymal transition, metastasis, stemness, metabolism, and therapy resistance. In addition, we present our current knowledge of the clinical significance of NF-κB and its involvement in the treatment of patients with NSCLC with chemotherapy, targeted therapies, and immunotherapy.
Abstract Context In recent years, there is growing evidence in the medical literature to support an association between administration of commonly used chemotherapeutic agents and an increased risk ...for cognitive impairment. Objectives We herein critically summarize data relating to the pathophysiological mechanisms by which chemotherapy may induce cognitive impairment in patients surviving from solid tumors. The clinical and epidemiological characteristics and the proposed management strategies to counter chemotherapy-induced cognitive impairment (CICI) also are presented. Methods References for this review were identified by searches of PubMed from 1995 until December 2009 with related terms. Results Both the pathogenetic mechanisms and the overall clinical nature of CICI remain vaguely defined. Findings indicate that CICI is a relatively common event that, in most of the cases, remains underdiagnosed, thereby adversely affecting the quality of life of patients with cancer. Effective pharmacological interventions toward the symptomatic or prophylactic management of CICI also are lacking. Conclusion Either called “chemobrain” or “chemofog,” the long-term CICI in cancer survivors is real. The need for multidisciplinary care interventions toward a timely diagnosis and management of CICI is clearly warranted.
Abstract This review study explores the available data relating to the impact of financial crisis and subsequently applied austerity measures on the health care, social services and health promotion ...policies in Greece. It is evident that Greece is affected more than any other European country by the financial crisis. Unemployment, job insecurity, income reduction, poverty and increase of mental disorders are among the most serious consequences of crisis in the socioeconomic life. The health system is particularly affected by the severe austerity measures. The drastic curtailing of government spending has significantly affected the structure and functioning of public hospitals that cope with understaffing, deficits, drug shortage and basic medical supplies. Moreover, health promotion policies are constrained, inhibiting thus the relevant initiatives toward disease prevention and health promotion education practices. Overall, the current economic situation in Greece and its impact on real life and health care is quite concerning. Policy makers should not disregard the implications that austerity and fiscal policies have on the health sector. Greater attention is needed in order to ensure that individuals would continue getting public health care and having access to preventive and social support services. To face the economic hardship, policy makers are expected to implement human-centered approaches, safeguarding the human dignity and the moral values.
The objective of the current prospective, multicenter, international study was to trace the incidence and severity of acute oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its ...clinical pattern. The authors also specifically tested whether patients who had more symptoms of acute OXLIPN eventually would develop a more severe chronic, cumulative form of OXLIPN.
One hundred seventy patients (mean ± standard deviation age, 63.7 ± 8.7 years) who were scheduled to receive either combined leucovorin, 5-fluoruracil, and oxaliplatin (FOLFOX) or combined capecitabine and oxaliplatin (XELOX) for metastatic colorectal cancer were monitored prospectively at baseline and were followed in 4 European sites. The incidence of hyperexcitability symptoms secondary to acute OXLIPN was assessed by using a descriptive questionnaire (yes/no question) at each clinical evaluation. Motor and neurosensory criteria according to version 3 of the National Cancer Institute's Common Toxicity Criteria were applied to clinically grade the severity of OXLIPN.
Acute OXLIPN was present in 146 of 170 patients (85.9%). The vast majority of these patients manifested cold-induced perioral (95.2%) or pharyngolaryngeal (91.8%) dysesthesias. Severe acute OXLIPN that required prolongation of oxaliplatin infusion from 2 hours to 4 to 6 hours occurred in 32 of 146 patients (21.9%). The increased number of acute OXLIPN symptoms was correlated significantly (Spearman rho correlation coefficient r) with both the development (r = 0.602; P < .001) and the degree of the chronic, cumulative form (r = 0.702; P < .001).
The current results indicated that the vast majority of patients with colorectal cancer who receive oxaliplatin-based chemotherapy will manifest symptoms of a transient acute syndrome soon after oxaliplatin administration. Patients who have a more complex combination of acute phenomena related to axonal hyperexcitability are those who eventually develop more severe OXLIPN. Therefore, it may be advisable to test agents against acute OXLIPN to verify their effects on the chronic form.
Cofilin phospho-regulation is important for actin filament turnover and is implicated in cancer. Phosphorylation of cofilin is mediated by LIM kinases (LIMKs) and dephosphorylation by Slingshot ...phosphatases (SSH). LIMKs and SSH promote cancer cell invasion and metastasis and represent novel anti-cancer targets. However, little is known regarding LIMK/cofilin and SSH in human colorectal cancer (CRC). In this study, we aimed to address their expression and significance in human CRC. We evaluated expression of non-phosphorylated (active) and phosphorylated cofilin, LIMK1, LIMK2, and SSH1 by immunohistochemistry in 143 human CRC samples in relation to clinicopathologic parameters, response of metastatic disease to chemotherapy, and epithelial-mesenchymal transition (EMT) markers β-catenin, E-cadherin, and ZEB. We show that active cofilin, LIMK1, LIMK2, and SSH1 are overexpressed in human CRC and are associated with tumor progression parameters. SSH1 is an independent predictor of lymph node metastasis by multivariate analysis. LIMK1 and SSH1 expression is also higher in non-responders to chemotherapy, and SSH1 is shown by multivariate analysis to independently predict response of metastatic disease to chemotherapy. Active cofilin, LIMK1, LIMK2, and SSH1 also correlated with the EMT markers examined. In addition, immunofluorescence analysis showed increased expression of active cofilin, LIMK1, LIMK2, and SSH1 in HT29 colon cancer cells resistant to 5-fluorouracil compared to parental HT29 cells. Our results suggest that F-actin regulators LIMK/cofilin pathway and SSH1 are associated with CRC progression and chemoresistance representing promising tumor biomarkers and therapeutic targets in CRC.
Summary Platinum compounds are a class of chemotherapy agents that posses a broad spectrum of activity against several solid malignancies. Oxaliplatin (OXL) is a third-generation organoplatinum ...compound with significant activity mainly against colorectal cancer (CRC). Peripheral neuropathy is a well recognized toxicity of OXL, usually resulting in dose modification. OXL induces two types of peripheral neuropathy; acute and chronic. The acute oxaliplatin-induced peripheral neuropathy (OXLIPN) may be linked to the rapid chelation of calcium by OXL-induced oxalate and OXL is capable of altering the voltage-gated sodium channels through a pathway involving calcium ions. On the other hand, decreased cellular metabolism and axoplasmatic transport resulting from the accumulation of OXL in the dorsal root ganglia cells is the most widely accepted mechanism of chronic oxaliplatin-induced peripheral neuropathy (OXLIPN). As a result, OXL produces a symmetric, axonal, sensory distal primary neuronopathy without motor involvement. The incidence of OXLIPN is usually related to various risk factors, including treatment schedule, dosage, cumulative dose and time of infusion. The assessment of OXLIPN is primarily based on neurologic clinical examination and quantitative methods, such as nerve conduction study. To date, several neuroprotective agents including thiols, neurotrophic factors, anticonvulsants and antioxidants have been tested for their ability to prevent OXLIPN. However, the clinical data are still controversial. We herein review and discuss the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of OXLIPN. We also highlight areas of future research.
PDF
