The efficacy of standard-dose versus reduced-dose everolimus in patients with advanced neuroendocrine tumors: A multicenter retrospective cohort study.
Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose-escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real-world progression-free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time-varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log-rank p = .02). However, after multivariable adjustment (N = 124 G1-G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31-1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log-rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56-1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any-grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard-dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment-related toxicity who may not tolerate SD.
Authors
Sahwan Sahwan, Mohamed Mohamed, Jamal Jamal, Alsulaiman Alsulaiman, Bauernfeind Bauernfeind, Myers Myers, McGarrah McGarrah, Hobday Hobday, Starr Starr, Halfdanarson Halfdanarson, Sonbol Sonbol
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