A Pragmatic Cluster-Randomized Trial of a Standing Order Entry Intervention for Colony-Stimulating Factor Use Among Patients at Intermediate Risk for Febrile Neutropenia.

PURPOSE: Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens. METHODS: TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to SOE of automated PP-CSF orders for high FN risk regimens and alerts against PP-CSF use for low-risk regimens versus usual care. A secondary 1:1 randomization assigned 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for intermediate-risk regimens. Clinicians were allowed to over-ride the SOE. Patients with breast, colorectal, or non-small-cell lung cancer were enrolled. Mixed-effect logistic regression models were used to test differences between randomized sites. RESULTS: Between January 2016 and April 2020, 846 eligible patients receiving intermediate-risk regimens were registered to either SOE to prescribe (12 sites: n = 542) or an alert to not prescribe PP-CSF (12 sites: n = 304). Rates of PP-CSF use were higher among sites randomized to SOE (37.1% v 9.9%, odds ratio, 5.91; 95% CI, 1.77 to 19.70; P = .0038). Rates of FN were low and identical between arms (3.7% v 3.7%). CONCLUSION: Although implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving first-line intermediate-risk regimens, FN rates were low and did not differ between arms. Although this guideline-informed SOE influenced prescribing, the results suggest that neither SOE nor PP-CSF provides sufficient benefit to justify their use for all patients receiving first-line intermediate-risk regimens.

Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing: A Cluster Randomized Clinical Trial.

Importance: Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines. Objective: To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia. Design, Setting, and Participants: This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021. Interventions: Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. Main Outcomes and Measures: The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic. Results: A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups. Conclusions and Relevance: In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing. Trial Registration: ClinicalTrials.gov Identifier: NCT02728596.

Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy: North Central Cancer Treatment Group trial N08C1.

BACKGROUND: Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P-APS and eventual peripheral neuropathy symptoms. METHODS: Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose, and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Chemotherapy-Induced Peripheral Neuropathy 20-item instruments were completed weekly. RESULTS: The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1 to 4, 5 or 6, or 7 to 10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0 to 4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5 to 10 (P = 0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy than was pain. CONCLUSIONS: Patients with worse P-APS severities appear to have more eventual chemotherapy-induced peripheral neuropathy. This provides support for the concept that P-APS is a form of nerve pathology.

Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1.

PURPOSE: The characteristics and natural history of the paclitaxel-acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. METHODS: Patients receiving weekly paclitaxel (70 to 90 mg/m(2)) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) -20 instruments during the entire course of therapy. RESULTS: P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. CONCLUSION: These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.

Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention.

OBJECTIVE: To compare the combination of a nicotine inhaler and bupropion to either treatment alone for initiating smoking abstinence and relapse prevention. METHODS: Smokers were randomized to receive a nicotine inhaler, bupropion, or both for 3 months. At 3 months, smoking-abstinent study participants were randomized to their initial medications or placebo. Participants who were smoking at 3 months were randomized to an alternative treatment regimen or placebo. This study was conducted from July 2001 to January 2003. RESULTS: A total of 1700 smokers were randomized to treatment (phase 1) for 3 months. Among the 941 study participants eligible for randomization to the phase 2 trial, 837 continued in the study. For the phase 2 trial, 405 smoking-abstinent participants were randomized to relapse prevention for 9 additional months, and 432 smokers were randomized to re-treatment for an additional 3 months. At the end of the initial 3 months of treatment (phase 1), 82 (14%) of 566, 145 (26%) of 567, and 194 (34%) of 567 study participants receiving a nicotine inhaler, bupropion, or both, respectively, were abstinent from smoking. Of the 405 smoking-abstinent participants at the end of 3 months, the bupropion group had more smokers than the placebo group (mean No. of smokers, 1.5 vs 1.1; P < .001), and the nicotine inhaler group had higher smoking abstinence rates at 12 months than the placebo group. Those receiving combination therapy had reduced rates of relapse to smoking for the first 3 months of relapse prevention, but this difference disappeared after the initial 3 months. Of the 432 study participants who were smoking at the end of 3 months and who received an alternative treatment regimen, the 223 smokers initially assigned to a nicotine inhaler were more likely to stop smoking at 6 months if they were re-treated with bupropion instead of placebo (8 [7%] of 111 vs 0 [0%] of 112; P = .003), and the 209 smokers initially treated with bupropion and re-treated with a nicotine inhaler did not have significantly higher smoking abstinence rates (6 [6%] of 104 vs 3 [3%] of 105; P = -.50). CONCLUSION: Combined therapy with a nicotine inhaler and bupropion increased smoking abstinence rates. Continuation of the initial combination therapy does not appear to prevent relapse to smoking. Timing of re-treatment and alternative approaches to relapse prevention should be further examined.