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PURPOSE To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update. RECOMMENDATIONS The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-L-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited.

Preclinical data demonstrated that combining an anti-programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti-PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.

Introduction: KEYNOTE-155 (NCT02684617) evaluated the antitumor activity of pembrolizumab (pembro) plus dinaciclib in patients (pts) with relapsed/refractory (rr) CLL, MM, and DLBCL. Here we present data from an interim analysis of safety and efficacy in pts with rrDLBCL. Method(s): In this phase 1b, two-part, non-randomized, open-label study, pts with rrDLBCL who received >=2 prior therapies were enrolled into a dose-evaluation phase (two 21-day [d] cycles of pembro 200 mg [d1] and dinaciclib 7 mg/m2 [d1], 10 mg/m2 [d8] in cycle 1 and 14 mg/m2 [d1, d8] from cycle 2 onwards). The DLBCL expansion cohort was opened for the signal-detection phase (>=30 patients) if <=4 pts had dose-limiting toxicities (DLTs) during dose-evaluation. Treatment continued up to 35 cycles or until progression (PD) or unacceptable toxicity. Response was assessed every 3 cycles for DLBCL (Revised Response Criteria for Malignant Lymphoma 2007). Pts who discontinued before PD were followed Q12W until PD, new anticancer treatment, or death. The primary endpoint was safety and tolerability. Secondary endpoints included ORR by investigator, DOR, PFS, and OS. Efficacy and safety were assessed in all pts who received >=1 dose of pembrolizumab or dinaciclib. Result(s): As of Apr 25, 2018, 38 pts with rrDLBCL were enrolled and treated. Median age was 64.5 years (range, 39-85), 22 (58%) pts had ECOG PS 1, and 22 (58%) had >=3 prior therapies. After median follow-up of 2.79 mo (range, 1.5-6.8), 36 (95%) pts discontinued treatment: 21 (55%) PD, 12 (32%) by physician decision (10 [26%] clinical progression, 1[3%] logistics, 1 [3%] new therapy), 2 (5%) pt decision, and 1 (3%) AE. Median time on treatment was 51d (range, 1-471). Among 12 pts in all disease cohorts enrolled in the dose-evaluation phase, DLTs occurred in 1 of 6 (17%) evaluable pts (grade 4 thrombocytopenia) with rrDLBCL. Of 38 pts with rrDLBCL, 24 (63%) had a treatment-related AE. Common treatment-related AEs were decreased platelets (21%), l

Introduction: KEYNOTE-155 (NCT02684617) evaluated the antitumor activity of pembrolizumab (pembro) plus dinaciclib in patients (pts) with relapsed/refractory (rr) CLL, MM, and DLBCL. Here we present data from an interim analysis of safety and efficacy in pts with rrDLBCL. Method(s): In this phase 1b, two-part, non-randomized, open-label study, pts with rrDLBCL who received >=2 prior therapies were enrolled into a dose-evaluation phase (two 21-day [d] cycles of pembro 200 mg [d1] and dinaciclib 7 mg/m2 [d1], 10 mg/m2 [d8] in cycle 1 and 14 mg/m2 [d1, d8] from cycle 2 onwards). The DLBCL expansion cohort was opened for the signal-detection phase (>=30 patients) if <=4 pts had dose-limiting toxicities (DLTs) during dose-evaluation. Treatment continued up to 35 cycles or until progression (PD) or unacceptable toxicity. Response was assessed every 3 cycles for DLBCL (Revised Response Criteria for Malignant Lymphoma 2007). Pts who discontinued before PD were followed Q12W until PD, new anticancer treatment, or death. The primary endpoint was safety and tolerability. Secondary endpoints included ORR by investigator, DOR, PFS, and OS. Efficacy and safety were assessed in all pts who received >=1 dose of pembrolizumab or dinaciclib. Result(s): As of Apr 25, 2018, 38 pts with rrDLBCL were enrolled and treated. Median age was 64.5 years (range, 39-85), 22 (58%) pts had ECOG PS 1, and 22 (58%) had >=3 prior therapies. After median follow-up of 2.79 mo (range, 1.5-6.8), 36 (95%) pts discontinued treatment: 21 (55%) PD, 12 (32%) by physician decision (10 [26%] clinical progression, 1[3%] logistics, 1 [3%] new therapy), 2 (5%) pt decision, and 1 (3%) AE. Median time on treatment was 51d (range, 1-471). Among 12 pts in all disease cohorts enrolled in the dose-evaluation phase, DLTs occurred in 1 of 6 (17%) evaluable pts (grade 4 thrombocytopenia) with rrDLBCL. Of 38 pts with rrDLBCL, 24 (63%) had a treatment-related AE. Common treatment-related AEs were decreased platelets (21%), l

Purpose: Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. Methods: Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. Results: Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. Conclusions: Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.

Purpose: Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. Methods: Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. Results: Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. Conclusions: Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.

© Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. OBJECTIVE To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. DESIGN, SETTING, AND PARTICIPANTS Thiswas a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, toMay 2, 2013. All analyses were performed using an intent-to-treat approach. INTERVENTIONS Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. MAIN OUTCOMES AND MEASURES Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. RESULTS A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90%CI,-3.5%to 10.5%; P =.36) and did not meet the n

© Copyright 2015 American Medical Association. All rights reserved. IMPORTANCE For patients with limited prognosis, some medication risks may outweigh the benefits, particularly when benefits take years to accrue; statins are one example. Data are lacking regarding the risks and benefits of discontinuing statin therapy for patients with limited life expectancy. OBJECTIVE To evaluate the safety, clinical, and cost impact of discontinuing statin medications for patients in the palliative care setting. DESIGN, SETTING, AND PARTICIPANTS Thiswas a multicenter, parallel-group, unblinded, pragmatic clinical trial. Eligibility included adults with an estimated life expectancy of between 1 month and 1 year, statin therapy for 3 months or more for primary or secondary prevention of cardiovascular disease, recent deterioration in functional status, and no recent active cardiovascular disease. Participants were randomized to either discontinue or continue statin therapy and were monitored monthly for up to 1 year. The study was conducted from June 3, 2011, toMay 2, 2013. All analyses were performed using an intent-to-treat approach. INTERVENTIONS Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group. Patients in the continuation group continued to receive statins. MAIN OUTCOMES AND MEASURES Outcomes included death within 60 days (primary outcome), survival, cardiovascular events, performance status, quality of life (QOL), symptoms, number of nonstatin medications, and cost savings. RESULTS A total of 381 patients were enrolled; 189 of these were randomized to discontinue statins, and 192 were randomized to continue therapy. Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90%CI,-3.5%to 10.5%; P =.36) and did not meet the n

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

Background Dysregulation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway signaling has been implicated in the pathogenesis of lymphoma. SAR245409 is a potent inhibitor of class I PI3K isoforms (alpha, beta, gamma and delta) and also inhibits mTORC1 and TORC2. In the phase 1 dose-expansion cohort of study TED11440 (NCT00485719), SAR245409 showed promise in several lymphoma subtypes: 1 complete response (CR) in a transformed lymphoma and 2 partial response (PR) [1 diffuse large B cell lymphoma (DLBCL) and 1 mantle cell lymphoma (MCL) and 3 patients with stable disease (SD) longer than 3 months [1 follicular lymphoma (FL), 1 MCL and 1 Hodgkin Lymphoma (Papadopoulos et al. ASH 2011). The Sanofi sponsored study ARD12130 (NCT01403636) is an ongoing multicenter, multinational, open-label, phase 2 study of SAR245409 in patients with lymphoproliferative malignancies enrolling on 4-arms: FL, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL and DLBCL. Preliminary Stage 1 results from FL patients (pts) are reported. Methods Eligible pts for the FL arm had relapsed or refractory FL (Grade 1, 2, or 3a) with no clinical suspicion of transformation to an aggressive subtype and who had received >=2 but <= 6 prior chemotherapy regimens. Pts were treated with SAR245409 at 50 mg twice daily orally until disease progression or withdrawal for other reasons including toxicity. Tumor response was based on modified International Working Group response criteria. A Simon 2-stage design was used to evaluate the primary efficacy endpoint of objective response rate (ORR) in the FL arm; if at least 6 of the first 24 evaluable patients in Stage 1 achieved an objective response (OR), the study would continue to Stage 2 with a total of 45 evaluable patients. If 14 or greater total patients among the 45 total evaluable achieved OR, the null hypothesis would be rejected. Results Twenty-eight FL patients were enrolled to stage 1. Median age was

Background Dysregulation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway signaling has been implicated in the pathogenesis of lymphoma. SAR245409 is a potent inhibitor of class I PI3K isoforms (alpha, beta, gamma and delta) and also inhibits mTORC1 and TORC2. In the phase 1 dose-expansion cohort of study TED11440 (NCT00485719), SAR245409 showed promise in several lymphoma subtypes: 1 complete response (CR) in a transformed lymphoma and 2 partial response (PR) [1 diffuse large B cell lymphoma (DLBCL) and 1 mantle cell lymphoma (MCL) and 3 patients with stable disease (SD) longer than 3 months [1 follicular lymphoma (FL), 1 MCL and 1 Hodgkin Lymphoma (Papadopoulos et al. ASH 2011). The Sanofi sponsored study ARD12130 (NCT01403636) is an ongoing multicenter, multinational, open-label, phase 2 study of SAR245409 in patients with lymphoproliferative malignancies enrolling on 4-arms: FL, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL and DLBCL. Preliminary Stage 1 results from FL patients (pts) are reported. Methods Eligible pts for the FL arm had relapsed or refractory FL (Grade 1, 2, or 3a) with no clinical suspicion of transformation to an aggressive subtype and who had received >=2 but <= 6 prior chemotherapy regimens. Pts were treated with SAR245409 at 50 mg twice daily orally until disease progression or withdrawal for other reasons including toxicity. Tumor response was based on modified International Working Group response criteria. A Simon 2-stage design was used to evaluate the primary efficacy endpoint of objective response rate (ORR) in the FL arm; if at least 6 of the first 24 evaluable patients in Stage 1 achieved an objective response (OR), the study would continue to Stage 2 with a total of 45 evaluable patients. If 14 or greater total patients among the 45 total evaluable achieved OR, the null hypothesis would be rejected. Results Twenty-eight FL patients were enrolled to stage 1. Median age was