Lustberg, Maryam

AbstractPlatinum‐induced peripheral neurotoxicity (PIPN) is a common side effect of platinum‐based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non‐length‐dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs. Chronic sensory axonal neuropathy manifesting as stocking‐and‐glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum‐based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.

AbstractVinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy‐induced peripheral neurotoxicity (CIPN) emerged as their main non‐hematological and among dose‐limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length‐dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre‐existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.

Abstract Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a potentially dose‐limiting side effect of several commonly used cytotoxic chemotherapy agents. The main pharmacological classes that may cause CIPN include classical anticancer drugs, as well as the recently introduced immune checkpoint inhibitors and antibody drug conjugates. The absence of a complete knowledge of CIPN pathophysiology is only one of the several unsolved issues related to CIPN. Among some of the most relevant aspects of CIPN deserving further attention include the real number of patients exposed to the risk of CIPN, the long‐term impact on cancer survivors' quality of life due to incomplete recovery from CIPN, the economic burden related to acute and chronic CIPN, and the different perspective and education of the healthcare specialists in charge of managing patients with CIPN. Overall, CIPN remains a very challenging area of research as there are still several unresolved issues to be addressed in the future. In this special issue, the multifaceted profile of CIPN will be presented, with particular emphasis on bolstering the need to develop more optimized outcome measures than the existing ones to accurately evaluate the extent of CIPN, but also to ascertain the differences in the incidence, risk factors, clinical phenotype, and management of CIPN, according to the most commonly used neurotoxic chemotherapy classes. Perspectives for future research to pursue in order to cover the gaps in knowledge in the CIPN field will also be discussed.

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity, negatively affecting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.

Abstract Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Individuals diagnosed with chemotherapy-induced peripheral neuropathy (CIPN) demonstrate impaired balance and carry an increased risk of falling. However, prior investigations of postural instability have only compared these individuals against healthy controls, limiting the understanding of impairments associated with CIPN. Therefore, the purpose of this study was to better isolate postural control impairments that are associated with CIPN. Twenty cancer survivors previously diagnosed with breast or colorectal cancer participated. Participants were separated into 3 groups: no prior chemotherapy exposure (CON, n = 6), and recent treatment with taxane- or oxaliplatin-based chemotherapy with no/mild symptoms of CIPN (−CIPN, n = 8) or moderate/severe symptoms of CIPN (+CIPN, n = 6). Postural control was assessed by measuring center of pressure during standing balance conditions that systematically interfered with somatosensory, visual, and/or vestibular information. The presence of CIPN sensory symptoms was associated with impaired postural control, particularly during eyes-closed balance conditions ( P < .05). Additionally, medial-lateral postural instability was more pronounced in the +CIPN group compared with the −CIPN group and CON participants ( P < .05). Greater postural instability during eyes-closed balance in individuals with CIPN is consistent with impaired peripheral sensation. Balance impairments in cancer survivors with CIPN demonstrate the unique challenges in this population and motivate the need for targeted efforts to mitigate postural control deficits that have previously been associated with fall risk.