Roma 12-05-2014 NEUROTOSSICITA’ D. Cortinovis S.C. Oncologia Medica H S. Gerardo Monza CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY (cipn) The magnitude Measure Prevention (?) Care (?) Conclusion THE HIDDEN PHENOMENON CT RT SURGERY PATIENT PRE-EXISTING CONDITIONS HOW TO MEASURE DEFINITION A group of neuromuscular symptoms that result from nerve damage caused by drug therapies used in the treatment of cancer. Affects 30-100% of patients getting specific neurotoxic chemotherapy drugs. The most commonly used classes of drugs causing peripheral neuropathy are taxanes (Taxol and Taxotere) and platinum based drugs (cisplatin and oxaliplatin). (Ocean & Vahdat, 2004; Visovsky, 2003) SYMPTOMS WHAT IS THE FEELING? Walking Picking up things Driving Hobbies Sexual Activity Relationships Sleep Chores Exercise Writing Work NUMBERS MECHANISM OF CIPN IS CIPN A UNIQUE EVIDENCE? INFUSION RATE DIFFERENT DAMAGE DIFFERENT AGENTS CUMULATIVE DOSE TYPICAL SYMPTOMS COASTING HOW TO MEASURE The diagnosis of PN is not straightforward PN “grading” can give us an idea as to severity Available grading scales have many limitations (wide variations in ones’ opinion) Peripheral Sensory Neuropathy** Grade 1 Grade 2 Grade 3 Grade 4 Asymptomatic loss of DTRs, paresthesia Moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self care ADL Life-threatening; urgent intervention indicated SECONDARY ANALYSIS SELECTED OUTCOME MEASURES FOR THE PRESENT SECONDARY ANALYSIS  the National Cancer Institute Common-Toxicity-Criteria (NCI-CTC)‫‏‬  the Total Neuropathy Score clinical version (TNSc)‫‏‬  the modified INCAT sensory sumscore (mISS)‫‏‬  the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30  CIPN20 quality of life measures CI- Perinoms Study FUTURE PERSPECTIVE Responsiveness study for outcome measures found as valid in CI-PERINOMS in a multicentric international US/EU study Our Center will be the PROMOTOR At the moment: IRB approval is due to be obtained 250 pts will be enrolled globally PREVENTION/TREATMENT TRIALS 42 RCT 6 RCT Hershman D JCO 2014 THINK‫‏‬DIFFERENT……‫‏‏‬ ACUTE OXAIPN SCN4A-rs2302237 SCN10A-rs1263292 CHRONIC OXAIPN SCN4A rs2302237 Argyriou A Cancer 2013 GENETIC AND EARLY DIAGNOSIS Graphics represent the percentage change of a-SAP or a-CMAP of the nerves at mid-treatment and final assessment compared with baseline data. (a-CMAP, amplitude of compound muscle action potential; a-SAP, amplitude of sensory nerve action potential.) Velasco R JNNP 2012 ESTEVE-SIGM-202 A PROOF-OF-CONCEPT PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE BLIND, MULTICENTRE CLINICAL TRIAL IN 2 PARALLEL GROUPS TO EVALUATE THE EFFICACY AND SAFETY OF E-52862 FOR REDUCING THE INCIDENCE AND SEVERITY OF OXALIPLATIN-INDUCED PERIPHERAL NEUROPATHY IN PATIENTS TREATED FOR COLORECTAL CANCER General Profile of E-52862 Sigma receptor antagonist The σ1R is a unique ligand-regulated molecular chaperone that modulates intracellular signaling cascades by interacting with target proteins only once they have become activated Sigma-1 receptor and Pain Modulation of signal transduction incurred upon the stimulation of different pain-signaling mechanisms Substance P Bradykinin ATP, others Growth factors (BDNF…) Glutamate Ca2+ VGCC TKR GPCR Ca2+ NMDA-R DAG Gαq PIP2 PKC Gβγ σ1R PLC Ca2+ IP3 Ca2+ Ca2+ Endoplasmic reticulum IP3-R Ca2+ CAMKs ERK/MAPK pathway Other pathways Transcription factors Ca2+ DNA Nucleus Sigma -1 ligand mu opioid receptor Ca2+ σ1R Ca2+ Opioid agonist Plasma membrane σ1R NR1 Sigma -1 receptor Gß? Ga Trial Objectives This is a proof-of-concept study to evaluate the efficacy and safety of E-52862 for the treatment of OXL-induced neuropathy. Short- and long-term evaluation of effects to establish E-52862 suitability to treat Acute and Chronic OXL-induced Neuropathy. Comprehensive evaluation will include quantitative sensory testing and nerve conduction studies. GENETICS SUB-STUDY Collection and storage of frozen blood samples from patients as a source of reference DNA for the post-hoc search for biomarkers of chemotherapy-induced peripheral neuropathy severity Genes encoding for: 1. drug transporters (ABCC1, ABCG1) 2. detoxification enzymes (MPO, GSTA1, GSTM1/3, GSTP1 y GSTT1) 3. genes involved in DNA repair mechanisms (ERCC2, XPA, XRCC1 y ERCC1). TREATMENT DULOXETINE • Based on primary results (n=220) Duloxetine 60mg daily: Diminishes CIPN pain in the majority Improves function & QOL One of the few drugs recommended that has data to support its use for painful CIPN TAKE HOME MESSAGES INVALIDATING AE, HIGH INCIDENCE NO PREVENTIVE THERAPIES NO CURATIVE THERAPIES (duloxetine) FINDING TRUE RELIABLE MEASURE NEED RIGOROUS PRECLINICAL MODEL