Turini, Marco

Abstract Background: CINV remains a challenging chemotherapy toxicity, particularly for anthracyclines + cyclophosphamide (AC) for breast cancer. Complete response (CR), defined as no vomiting or use of rescue medication over 5 days after chemotherapy, has been the standard endpoint for successful antiemetic prophylaxis, yet duration of prophylaxis treatment failure (i.e., breakthrough CINV) is rarely assessed. Previous work demonstrated that initial cycle breakthrough CINV is associated with at least one subsequent cycle with CINV (Schwartzberg 2011), and that longer duration CINV is associated with more lost work time and impaired activity (Schwartzberg ASCO 2020). We sought to evaluate the duration of breakthrough CINV in cycle one and its association with individual patients’ repeat breakthrough CINV in subsequent cycles. Methods: Days of CINV was a prespecified endpoint in a prospective, 4-cycle CINV prophylaxis trial of combination netupitant/palonosetron (NEPA) + dexamethasone (Dex) for patients with breast cancer receiving AC; the primary endpoint was CR. Patients without CR were classified as prophylaxis treatment failure (TF) and categorized as short TF (sTF, 1-2 days) or extended TF (xTF, ≥3 days), consistent with work by Ballatori [2006] and Roeland [2019]. We analyzed patients’ sequences of CR, sTF, and xTF for cycles 1-4 and assessed likelihood of CR for cycles 2-4 based on cycle 1 TF duration, using chi-square statistics. Results: Of 402 patients in cycle 1, 303 had CR and 99 (24.6%) had TF. Duration of TF in cycle 1 was sTF for 48 patients while 51 patients had xTF. Patients with sTF in cycle 1 often experienced CR in cycle 2 (32/46 remaining patients; 69.6%) while patients with xTF in cycle 1 often had TF in cycle 2 (38/49; 77.6%). Patients had >84% likelihood of repeating their cycle 2 outcome (CR or TF) in cycles 3 and 4. Over all cycles, those with sTF in cycle 1 had CR in 75/108 later cycles (69.4%) while xTF in cycle 1 led to CR in 32/105 later cycles (29.0%), p<0.001) (see Table). Duration of later-cycle TF was typically consistent with initial cycle TF duration (p=0.046). As a predictor of later cycle TF, xTF had a positive predictive value of 0.695, with sensitivity of 0.689 and specificity of 0.701. Those with xTF in cycle 1 had 2.28 times the relative risk of later TF (CI 1.67-3.11; p<0.001) vs those with sTF. The absolute increase in risk from xTF was 40.4%. Conclusions: Although the majority of patients receiving NEPA + Dex as prophylaxis for AC in breast cancer successfully avoided breakthrough CINV, for patients with prophylaxis treatment failure, CINV duration in cycle 1 strongly predicted their future likelihood of CINV. Patients with extended (≥3 days) breakthrough CINV in cycle 1 had CINV again in over 2/3 of later cycles; conversely those with short breakthrough CINV in cycle 1 avoided CINV entirely in over 2/3 of later cycles. The markedly higher risk faced by patients with initial-cycle extended CINV is both statistically significant and clinically meaningful, due not only to its longer duration and risk-prediction but also to previously demonstrated worsening of work loss and impaired activity. Clinicians should monitor breakthrough CINV duration, seek to avoid extended CINV, and consider changing antiemetic prophylaxis when extended CINV does occur. Further study is needed to confirm this finding in other chemotherapy regimens and with other triple prophylaxis regimens. Impact of Extended CINV in Cycle 1 on CINV in Later CyclesTF1P valueInitial Cycle Result (n/total initial cycles)Total TF1 (99/402)Short TF1 (48/99)Extended TF1 (51/99)Short vs Extended TF1Later CR cycles (n, % of total later cycles)107 (50.2%)75 (69.4%)32 (29.0%)<0.0001Later TF (n, % of total later cycles)106 (49.8%)33 (30.6%)73 (71.0%)Duration of Later TF (n, % of all later TF)Later sTFLater xTFLater sTFLater xTF0.04620 (60.6%)13 (39.4%)29 (39.7%)44 (60.3%)Total later cycles (n, %)213 (100%)108 (100%)105 (100%)TF: prophylaxis Treatment Failure; TF1: TF in cycle 1; CR: Complete Response (0 days TF); CR1: CR in cycle 1; sTF: Short (1-2 days) TF; xTF: Extended (≥3 days) TF Citation Format: Rudolph M. Navari, Gary Binder, Eric J. Roeland, Alexander Molassiotis, Kathryn J. Ruddy, Thomas W. LeBlanc, Dwight D. Kloth, Silvia Sebastiani, Marco Turini, Luke M. Schmerold, Xing Liu, Lee Schwartzberg. Duration of chemotherapy-induced nausea and vomiting (CINV) as a predictor of later-cycle CINV [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-27.

e24133 Background: The impact of chemotherapy-induced nausea and vomiting (CINV) on work loss and activity impairment is important to patients yet not well described in literature. We sought to evaluate CINV-related work loss and activity impairment and their associations with CINV duration. Methods: In a prospective CINV prophylaxis trial of oral or intravenous netupitant/palonestron (NEPA) + dexamethasone (DEX) (12mg day 1 only) for patients with breast cancer receiving anthracycline + cyclophosphamide (AC), we defined CINV as vomiting or use of rescue medication during days 1-5 after AC. Pre-specified endpoints included CINV duration (0-5 days), patient reported CINV-associated work loss (Work Productivity and Activity Impairment survey), and CINV-related impaired activity [0 (none) - (worst) Likert scale] for chemotherapy cycles 1 and 2. CINV-related work loss and activity impairment could involve nausea with or without vomiting or rescue medication use. We categorized CINV duration as 1-2 days (d) or ≥3 d, and compared results using the chi-squared test. We report here on the first 2 cycles. Results: Survey data was captured for 792 cycles in 402 female patients including 132 (32.8%) employed patients. Mean age was 55.4. CINV was observed in 173 (21.8%) of total cycles. CINV-related work loss was reported in 26 (3.3% of all cycles, 15.0% of cycles with CINV, 38.2% of employed patient cycles with CINV) while 142 had related activity impairment. When we categorized cycles by CINV duration, CINV-related work loss was seen in 25.9% of 81 cycles with ≥3 d CINV duration vs. 5.4% for 92 cycles of 1-2 d of CINV (p < 0.001); mean scores of CINV-related impaired activity were 5.0 for ≥3 d CINV vs 3.0 for 1-2 d CINV (p < 0.001). Conclusions: Despite guideline recommended prophylaxis, CINV occurred in > 20% of AC cycles. In cycles with CINV, CINV-related work loss occurred in 38.2% for employed patients while activity impairment occurred in 82.1% for all patient cycles. The majority of CINV lasted 1-2 d. Notably, ≥3 d of CINV was associated with considerably higher levels of work loss and activity impairment suggesting that duration may be a meaningful measure of CINV impact. Clinical trial information: NCT03403712 . [Table: see text]