Navari, Rudolph M.

Abstract Purpose A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. Materials and Methods A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 ­olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. Results A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. Conclusion This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

AbstractBackgroundThe relationship between CINV duration and recurrence in subsequent cycles is largely unstudied. Our objective was to determine if patients experiencing CINV in their first cycle of chemotherapy (C1) would face increased risk of CINV in later cycles and whether the duration of the CINV would predict increased risk of recurrence.Patients and MethodsUsing data from a previously reported phase III trial, we assessed patients’ recurrence of breakthrough CINV after antiemetic prophylaxis for anthracycline+cyclophosphamide (AC) for breast cancer, comparing C1 short CINV vs. extended CINV as a secondary analysis. Complete response (CR) and CINV duration were primary and secondary endpoints, respectively. CR was considered prophylaxis success; lack of CR was considered treatment failure (TF).ResultsAmong 402 female patients, 99 (24.6%) had TF in C1 (TF1). The remaining 303 patients (CR1) had ≥93% CR rates in each subsequent cycle, while the 99 patients with TF1 had TF rates of 49.8% for cycles 2-4 (P < .001). The 51 patients with extended TF (≥3 days) in C1 had recurrent TF in 73/105 later cycles (69.5%, P < .001), while the 48 patients with short TF (1-2 days) in C1 had recurrent TF in 33/108 later cycles (30.6%). The relative risk of recurrence after C1 extended TF was 2.28 (CI 1.67-3.11; P < .001) compared to short TF.ConclusionsProphylaxis success in C1 led to >90% repeat success across cycles of AC-based chemotherapy. For patients with breakthrough CINV, extended duration strongly predicted recurrent CINV. The duration of CINV should be closely monitored, and augmenting antiemetic prophylaxis considered for future cycles when extended CINV occurs.

12107 Background: Chemotherapy-induced nausea and vomiting (CINV), a major adverse effect of cancer treatment, can attenuate life quality. Multiple international antiemetic guidelines have recommended a 4-drug regimen (corticosteroid, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and the antipsychotic medication olanzapine) for decreasing highly emetogenic CINV. This raised a question regarding whether antiemetic therapy regimens for highly emetogenic chemotherapy could be de-intensified, decreasing cost and side effects from anti-emetogenic agents. Methods: Study A221602 was developed to compare two olanzapine-containing antiemetic regimens, one with the use of an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Patients (pts) received intravenous highly emetogenic chemotherapy as either 1) cisplatin, given on one day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s) or 2) doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) on one day. Pts in both arms received 1) a 5-HT3 receptor antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO,) on day one, 2) dexamethasone (12 mg PO, day one followed by 8 mg PO, days 2-4), and 3) olanzapine (10 mg/day PO, days 1 to 4). On Day 1, all agents were given prior to chemotherapy, with the exception that olanzapine could be taken prior to chemotherapy or at bedtime. Additionally, pts were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV; 346 pts) or a matching placebo (344 pts). The primary objective was to compare the proportion of patients with no nausea for 5 days following receipt of their chemotherapy between the two study arms. Results: While there was no suggestion of outcome differences on day 1 between the two study arms, fewer pts (7.4%; upper limit of the 95% confidence interval was 13.5%) without NK-1 receptor antagonists were without nausea for the complete 5-day study period. Conclusions: Per the study design, created to exclude a 10% benefit for NK-1 receptor antagonists, the results did not provide sufficient evidence to reject the hypothesis that the 4-drug regimen was superior to the protocol 3-drug regimen (p=0.24). Support: UG1CA189823; Clinical trial information: NCT03578081.

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.

Abstract Background: Although many studies have demonstrated consistent levels of effectiveness of CINV prophylaxis for the entire study population across multiple chemotherapy cycles, rarely have studies reported how each patient’s risk of subsequent CINV differs based on prior cycle breakthrough CINV with the same prophylaxis. We lack data on whether prophylaxis continues to fail in the same group of patients each cycle, or whether failure is random with each subsequent cycle. We sought to evaluate individual patients’ risk of repeat CINV in each subsequent chemotherapy cycle. Methods: In a prospective, 4-cycle CINV prophylaxis trial of oral or intravenous combination netupitant/palonosetron (NEPA) + dexamethasone (day 1) for patients with breast cancer receiving anthracycline + cyclophosphamide (AC), we defined CINV as vomiting or use of rescue medication during days 1-5 after chemotherapy. Patients without CINV were classified as complete response (CR); the rest as treatment failure (TF). We analyzed patients’ sequences of CR and TF, and compared CR or TF for cycles 2-4 based on cycle 1 outcomes, using chi-square statistics. To provide context, we performed a post-hoc similar analysis of results reported by Herrstedt et al [2005] from a clinical trial of ondansetron + aprepitant (APR) for patients with breast cancer receiving 4 cycles of AC. Results: The 402 female patients in the NEPA trial received a total of 1,299 cycles. In cycle 1, 99 (24.6%) patients experienced TF (TF1); over all 4 cycles, TF occurred 253 times (19.5%). Patients with CR in cycle 1 (CR1) had a ≥92% rate of CR in cycle 2; their rates of repeat CR were similar in each subsequent cycle. Patients with TF1 had nearly equal risk of CR or TF in cycle 2 (45:55); thereafter 85% of this TF1 subgroup repeated their cycle 2 outcome (CR or TF) in cycles 3 and 4. Over all cycles of NEPA, patients with CR1 subsequently had CR in >90% of cycles 2-4; those with TF1 subsequently had TF in 49.8% of cycles 2-4 (p<0.0001) (see Table). We separately examined Herrstedt’s evaluation of 433 patients across 1537 cycles with APR. In cycle 1, TF was seen 213 times (49.2%), with TF reported in 46.7% of cycles 1-4. We found that patients with CR1 had an 80.5% rate of CR in cycle 2 and repeat CR rates were higher in subsequent cycles. Patients with TF1 had TF in cycle 2 (TF2) at a rate of 78.4%, with 76.6% TF3 and 72.7% TF4. For APR, CR1 resulted in subsequent CR in 78.6% of cycles 2-4 while patients with TF1 again had TF in 74.8% of cycles 2-4 (p<0.0001). Patients with TF1 were more likely to later drop from the study (see Table). Notably, among those with CR1 after APR, the few patients who later had TF in any cycle, had a subsequent repeat failure rate similar to those with TF1. Conclusions: When patients receiving guideline-recommended triple antiemetic prophylaxis successfully avoided CINV in their first cycle of HEC, they had 80-95% likelihood of repeating that success in later cycles. After NEPA, those whose prophylaxis failed in cycle 1 did not face a similar high risk of repeat failure in cycle 2. The pattern of repeat failure after aprepitant was different, with a high repeat failure risk starting in cycle 2. These findings strongly suggest that consistent population average CR rates reported across cycles may mask a higher repeat failure rate for individual patients that experience cycle 1 CINV, particularly for aprepitant. Further study of this phenomenon is needed for other HEC regimens, and to confirm the lack of high repeat failure seen in cycle 2 for NEPA. Repeat CINV in Later Cycles, Based on Cycle 1 ResultsNEPAAprepitant + OndansetronInitial Cycle Result (n/total initial cycles)CR1 (303/402)TF1 (99/402)CR1 vs TF1 (P value)CR1 (220/433)TF1 (213/433)CR1 vs TF1 (P value)Subsequent CR cycles (n, % of total subseq. cycles)636 (93.0%)107 (50.2%)<0.0001464 (78.6%)124 (25.2%)<0.0001Subsequent TF cycles (n, % of total subseq. cycles)48 (7.0%)106 (49.8%)126 (21.4%)370 (74.8%)Total subsequent cycles (n, % of total subseq. cycles)684 (100%)213 (100%)590 (100%)494 (100%)Dropped vs ITT* (n, % ITT cycles)225 (24.8%)84 (28.3%)0.226370 (10.6%)145 (22.7%)<0.0001* The NEPA trial was closed when the last patient completed the first cycle, resulting in an artificially high proportion of patients that did not complete 4 cycles. Citation Format: Rudolph M Navari, Gary Binder, Alexander Molassiotis, Eric Roeland, Kathryn J. Ruddy, Thomas W. LeBlanc, Dwight D. Kloth, Silvia Sebastiani, Lina Y. Dimberg, Luke M. Schmerold, Xing Liu, Lee Schwartzberg. Chemotherapy-induced nausea and vomiting (CINV) risk after prior breakthrough CINV: Unmasking the false average [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 PS13-09.

Abstract Purpose Chemotherapy-induced nausea and vomiting (CINV) contributes to avoidable acute care, a metric now tracked in Medicare's oncology outcome measure. CINV is preventable, yet guidelines are often not followed. We sought to quantify acute care involving CINV and other avoidable toxicities after highly emetogenic chemotherapy (HEC) to identify excess risk and assess clinician adherence to antiemesis guidelines for HEC. Materials and Methods We retrospectively evaluated U.S. electronic health records (2012-2018) using Medicare's OP-35 outcome measure to identify avoidable acute care involving any of 10 toxicities, including CINV, after HEC regimens relative to non-HEC. Antiemetic guideline adherence was defined as use ofneurokinin-1 (NKl) receptor antagonists Q5 (RAs) plus 5-hydroxytryptamine type 3 RA+ dexamethasone at HEC initiation. Results Among 17,609 patients receiving HEC, acute care rates associated with HEC chemotherapy included 32% cisplatin, 31% carboplatin, and 21% anthracycline/cyclosphospharnide (AC), with 76% meeting the criteria as avoidable events. Oxaliplatin rates were 29%. Avoidable acute care occurred 1.83 times (95% confidence interval, 1.76-1.91, p < .0001) as often after HEC versus non-HEC excluding oxaliplatin; CINV-related acute care occurred 2.29 times as often. Nonadherence to antiemesis guidelines occurred in 34% and 24% of cisplatin and AC courses, respectively, because of omission of a NKl RA. Conclusions Patients treated with HEC regimens experienced high avoidable acute care use, 1.8 times the risk seen for other chemotherapy. Nonadherence to guideline-directed antiemetic prophylaxis highlights the need to ensure adherence to antiemetic guidelines, including the use of NKl RA in HEC. Implications for Practice After survival, perhaps the most important goal in oncology is limiting avoidable acute care, a goal now used by Medicare to impact cancer reimbursement. This study found that patients treated with highly emetogenic chemotherapy (HEC) regimens had high rates of avoidable acute care use, 1.8 times the risk seen for other chemotherapy. A substantial proportion of the avoidable acute care involved chemotherapy-induced nausea and vomiting. Results showed that incomplete adherence to national antiemetic guidelines for HEC regimens primarily driven by omission of upfront neurokinin-1 receptor antagonist use, suggesting that improved adherence can meaningfully resolve this gap in quality and cost of care.

Background: Clinician adherence to antiemetic guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC) remains poorly characterized. The primary aim of this study was to evaluate individual clinician adherence to HEC antiemetic guidelines. Patients and Methods: A retrospective analysis of patients receiving HEC was conducted using the IBM Watson Explorys Electronic Health Record Database (2012–2018). HEC antiemetic guideline adherence was defined as prescription of triple prophylaxis (neurokinin-1 receptor antagonist [NK1 RA], serotonin type-3 receptor antagonist, dexamethasone) at initiation of cisplatin or anthracycline + cyclophosphamide (AC). Clinicians who prescribed ≥5 HEC courses were included and individual guideline adherence was assessed, noting the number of prescribing clinicians with >90% adherence. Results: A total of 217 clinicians were identified who prescribed 2,543 cisplatin and 1,490 AC courses. Patients (N=4,033) were primarily women (63.3%) and chemotherapy-naïve (92%) with a mean age of 58.6 years. Breast (36%) and thoracic (19%) cancers were the most common tumor types. Guideline adherence rates of >90% were achieved by 35% and 58% of clinicians using cisplatin or AC, respectively. Omission of an NK1 RA was the most common practice of nonadherence. Variation in prophylaxis guideline adherence was considerable for cisplatin (mean, 71%; SD, 29%; coefficient of variation [CV], 0.40) and AC (mean, 84%; SD, 26%; CV, 0.31). Conclusions: Findings showed substantial gaps in clinician adherence to HEC CINV guidelines, including a high variability across clinicians. Clinicians should review their individual clinical practices and ensure adherence to evidence-based CINV guidelines to optimize patient care.

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]