Avoidable Acute Care Use Associated with Nausea and Vomiting Among Patients Receiving Highly Emetogenic Chemotherapy or Oxaliplatin

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.

Introduction

Reducing avoidable acute care services can improve cancer care and reduce cost. Acute care, such as emergency department (ED) visits and inpatient (IP) admissions, represents one of the largest components of cancer expenditures in the U.S. [1–3]. Evidence collected by the U.S. Centers for Medicare and Medicaid Services (CMS) led them to conclude “… improved hospital management of these potentially preventable symptoms—including anemia, dehydration, diarrhea, emesis, fever, nausea, neutropenia, pain, pneumonia, or sepsis—can reduce admissions and ED visits for these conditions. Measuring potentially avoidable ED visits and IP admissions for patients with cancer receiving outpatient chemotherapy will provide hospitals with an incentive to improve the quality of care for these patients by taking steps to prevent and better manage side effects and complications from treatment.” [4]. To address this gap in care quality, CMS instituted a new oncology outcome measure (OP‐35) [5] to track 30‐day postchemotherapy acute care involving any of the above‐mentioned 10 toxicities selected by an expert panel and validated by CMS’ review of over 300,000 patients treated with chemotherapy. Starting in 2020, each institution's Medicare reimbursement of outpatient chemotherapy has been determined in part by their standing relative to national average OP‐35 institutional rates, which is publicly reported for each institution [6].

The incidence of avoidable acute care events involving nausea and vomiting (NV) from chemotherapy warrants further study because of the high costs of related acute care and the improved control of chemotherapy‐induced nausea and vomiting (CINV) when patients receive guideline‐concordant antiemetic prophylaxis. Multiple previous analyses for NV‐related hospital admissions have demonstrated that costs exceed $10,000 per event during the first 5 days after chemotherapy (adjusted to 2019 U.S. dollars) [7–10]. Leading international cancer experts have developed treatment‐specific antiemetic prophylaxis guidelines [11–13] based on strong evidence demonstrating improved prevention of CINV. Nevertheless, multiple studies [14–17] show meaningful gaps in clinician adherence to antiemetic prophylaxis guidelines for highly emetogenic chemotherapy (HEC; Table 1), including carboplatin area under the curve (AUC) ≥4, classified as HEC in 2017.

In the current study, we sought to quantify rates of postchemotherapy acute care use involving the OP‐35‐defined toxicities with a specific focus on CINV for patients treated with HEC. In addition, we assessed the magnitude of any excess risk of such acute care for patients receiving HEC or oxaliplatin, relative to risks faced by patients treated with other chemotherapies. We also assessed overall clinician adherence to CINV prophylactic guidelines for HEC.

Materials and Methods

Study Design and Data

We completed a retrospective cohort study using the IBM Watson Health Explorys database of deidentified patient electronic health records (October 2012 to March 2018). The IBM Explorys data are sourced from large U.S. Integrated Delivery Networks, concentrated in the Midwest, and cover approximately 55 million patient lives. Of note, institution‐specific data in the data set (e.g., academic versus community) were not available.

Study Population

This study focused on adult (≥18 years) patients with cancer receiving cisplatin, anthracycline with cyclophosphamide (AC), carboplatin (AUC ≥4), or oxaliplatin. For each patient who received chemotherapy, we defined a distinct chemotherapy “course” as an initial administration followed by periodic subsequent administrations (multiple cycles) that continued until a ≥ 90‐day treatment gap occurred (maximum of 180 days). A 90‐day chemotherapy‐free period was required before the initial administration. To exclude multiday chemotherapy HEC courses, we excluded chemotherapy courses having ≤7 days between administrations (and < 14 days for carboplatin as a proxy for AUC <4).

Study Measures

In accordance with the CMS‐defined OP‐35 measure, we used CMS‐determined International Classification of Diseases (ICD)‐9 and ICD‐10 diagnosis codes to evaluate the following 10 specific toxicities: anemia, dehydration, diarrhea, fever, nausea, vomiting, neutropenia, pain, pneumonia, and sepsis. Additionally, consistent with the OP‐35 measure, we defined acute care use as an ED visit or IP admission within 30 days after receiving chemotherapy [18]. Following CMS rules, acute care was considered to involve the OP‐35 toxicities when the relevant diagnosis codes were included within acute care records for events occurring within 30 days following receipt of chemotherapy. An acute care event could involve greater than one OP‐35 toxicity. The OP‐35 measure is specific to chemotherapy administered in the outpatient setting to patients without leukemia, and the 30‐day acute care and toxicity analyses were completed on this subset of chemotherapy courses.

We evaluated two long‐established HEC regimens (containing cisplatin or AC), as well as regimens including carboplatin AUC ≥4 (recategorized as HEC in 2017). Additionally, for context, we evaluated oxaliplatin, a moderately emetogenic chemotherapy (MEC) often viewed as considerably emetogenic and the only commonly used platinum chemotherapy not categorized as HEC, as well as other intravenous (IV) non‐HEC and oral chemotherapy classified as HEC/MEC. We assessed clinician adherence to CINV prophylactic guidelines defined as receiving triple prophylaxis (a combination of a neurokinin 1 [NK1] receptor antagonist [RA], 5‐hydroxytryptamine type 3 [5HT3] RA, and dexamethasone) at initiation of the first cycle of chemotherapy. Subsequent antiemetic use was not evaluated. We did not include the prophylactic use of olanzapine [19] within the definition of guideline adherence. 5HT3 receptor antagonists plus dexamethasone significantly reduce CINV in the first 24 hours postchemotherapy. The addition of NK‐1 RA has reduced delayed CINV in days 2 to 5 postchemotherapy [11].

Statistical Analysis

We analyzed patient characteristics, HEC courses, and clinician practice patterns using descriptive statistics. Odds ratios were used to evaluate the excess risk of acute care related to OP‐35 and specifically related to CINV, relative to other chemotherapies. The χ² statistics were used for significance testing of rates between HEC and other chemotherapies. All study analyses were conducted using SAS 9.4 and Microsoft Excel.

Results

We identified 17,609 HEC courses between October 2012 and March 2018, including 4,794 cisplatin, 2,576 AC, and 10,239 carboplatin (AUC ≥4) courses. Non‐HEC courses included 4,231 oxaliplatin, 52,393 other IV non‐HEC, and 1,776 oral HEC/MEC courses (supplemental online Fig. 1). Mean ages of patients were 60, 55, 64, and 61 for cisplatin, AC, carboplatin, and oxaliplatin, respectively (Table 2).

We found that the 30‐day postchemotherapy acute care event rates for any cause were 32% for cisplatin, 21% for AC, 31% for carboplatin, and 29% for oxaliplatin courses. Rates for other intravenous non‐HEC and oral HEC/MEC courses were 19% and 14%, respectively (p < .00001 for each vs. HEC; Fig. 1A). For HEC, 76% of the acute care involved one or more of the 10 OP‐35 toxicities, most often anemia (42%), pain (41%), dehydration (24%), and NV (24%). The odds ratio (OR) of OP‐35–related acute care in HEC relative to non‐HEC IV was 1.83 (95% confidence interval [CI], 1.76–1.91; p < .0001). Relative to oral HEC/MEC, the OR was 3.00 (CI, 2.59–3.48; p < .0001). Among OP‐35–related acute care events, NV was involved in 37% of cisplatin, 32% AC, 28% carboplatin, and 34% oxaliplatin (Fig. 1B). The odds for acute care specifically related to CINV for patients treated with HEC relative to non‐HEC IV was 2.29 (CI, 2.11–2.49; p < .0001).

We investigated clinician adherence to CINV guidelines for HEC (i.e., use of triple antiemetic prophylaxis: NK1 RA plus 5HT3 RA plus dexamethasone) and found that clinician adherence at chemotherapy initiation was 66% for cisplatin courses and 76% for AC courses. Omission of an NK1‐RA was the principal cause of nonadherence to CINV prophylactic guidelines, occurring in 10,935 of 11,051 nonadherent HEC courses (99.0%). As previously reported [17], triple prophylaxis was used upfront in 14% of carboplatin courses and did not show any meaningful improvement following the 2016–2017 reclassification as HEC; 11% of oxaliplatin courses received upfront triple prophylaxis (Fig. 2).

Discussion

Avoidable acute care represents a significant opportunity to improve the quality and cost of cancer treatment, evidenced by CMS’ decision to track and link hospital cancer reimbursement to these OP‐35 acute care event rates, within their sole medical oncology outcome measure. We hypothesize that HEC represents a rich area for intervention, because of the limited proportion of patients that HEC represents among all patients with cancer and the high potential for evidence‐based prevention of 2 of the 10 OP‐35 potentially avoidable toxicities: nausea and vomiting. In this study, we evaluated retrospective data to assess the relative levels of avoidable acute care following HEC or oxaliplatin versus non‐HEC chemotherapy and, specifically, the proportion of acute care events involving NV.

We found that a 50%–100% higher proportion of patients receiving HEC required postchemotherapy acute care, compared with patients receiving less emetogenic chemotherapy (except for oxaliplatin, for which acute care use was similar to HEC despite its categorization as MEC). Roughly three‐quarters of these acute care events involved 1 or more of the 10 toxicities included in the OP‐35 measure. Patients receiving HEC or oxaliplatin had an 83% higher risk of this subset of acute care use involving the OP‐35–defined “avoidable” toxicities compared with patients receiving other intravenous non‐HEC chemotherapy (occurring in 23% of patients vs. 13%). This higher rate of OP‐35–related acute care, combined with the excess risk of CINV from receiving HEC (by definition), resulted in over double the risk (OR, 2.29) of CINV‐related acute care for HEC relative to other IV chemotherapies.

This excess rate of avoidable acute care among patients receiving HEC may be explained by data shown here and in prior studies documenting considerable nonadherence to use of guidelines recommending upfront triple prophylaxis in this setting [13–16]. This adherence gap, and apparent acute care consequence, highlights the need for efforts to optimize adherence to the antiemetic guidelines for patients receiving HEC. CINV prophylaxis represents an actionable strategy for institutions and clinicians to reduce the frequency of avoidable acute care for patients with cancer and, thus, to improve their reported ratings by CMS. Given the >$10,000 event cost of a single CINV hospitalization [6–9], and the prevalence of HEC, sizable opportunities exist for cost and quality improvement as a result of reducing CINV‐related avoidable acute care. In fact, the American Society of Clinical Oncology (ASCO) has included Measure 30 as an indicator of quality of cancer care (i.e., Appropriate Antiemetic Therapy for HEC and MEC within the Quality Oncology Practice Initiative certification criteria effective Round 2 2020) [20].

Causes for suboptimal antiemetic guideline adherence remain poorly understood. Potential reasons may include clinician lack of knowledge of updated antiemetic guidelines, poor integration of guideline updates into chemotherapy electronic prescribing order sets, and under‐reporting of and nonsystematic clinician responsiveness to NV symptoms. Notably, prior research suggests wide variation among individual physicians’ adherence with antiemetic guidelines in HEC [21]. Each oncologist should consider assessing their own adherence and/or amending those of their institution if not supportive of guidelines. Specifically, to reduce avoidable acute care use in patients with cancer, we should consider the following: (a) pursue oncologist and pharmacist involvement in development and approval of antiemetic order sets in medical records; (b) assign a “champion” to regularly review antiemetic guideline updates for the clinic, update order sets accordingly, and remind oncologists who are <90% adherent [20]; (c) use triple prophylaxis upfront in HEC rather than trying a “watch and wait” approach, which is associated with worse subsequent control of CINV [22]; (d) consider additional prophylaxis for patients with personal emetic risk factors who receive oxaliplatin and/or develop breakthrough CINV [23–25]; (e) ensure NK‐1 agents are not omitted due to pharmacy cost concerns and focus on total cost of care and quality outcomes rather than short‐term drug costs; and (f) monitor and address patient‐reported outcomes (i.e., symptoms and quality of life) between office visits, ideally accompanied with an integrated clinician response to poorly controlled symptoms [26, 27].

Strengths of this study include the large sample size and use of an updated, current data source. Additionally, we investigated an outcome quality measure for potentially avoidable acute care (OP‐35) that has been adopted by the world's largest payer of cancer claims (CMS). Notable limitations of the study include the potential underestimation of acute care rates due to the possibility that some acute care events, such as ED visits, may occur at institutions outside the IBM Watson Explorys data source. Furthermore, there may be under‐reporting of toxicities in the electronic medical record relative to those observed in clinical trials. Additionally, we lack patient‐reported outcomes and relied on medical record data to determine rates of toxicities, including NV as captured by ICD‐9 and ICD‐10 codes. As such, these data likely underrepresent the true burden of CINV in our analysis cohort.

Another limitation of the study is the categorization of groups of chemotherapies. Carboplatin was recategorized as HEC by ASCO and National Comprehensive Cancer Network in 2017, an event that occurred during the period under study. Consequently, we chose to report carboplatin separately. Similarly, we also chose to separately evaluate the remaining platinum‐based chemotherapy agent, oxaliplatin, because of prior evidence suggesting it may result in considerable NV [16] and our objective to provide context for the HEC results. Last, we lacked institution‐specific data, resulting in the inability to determine whether clinician nonadherence was associated with the institution or was more suggestive of individual clinician choice.

Conclusion

In this large retrospective cohort study, we found that patients treated with HEC experienced high rates of avoidable acute care use, having more than 1.8 times the risk compared with individuals receiving less emetogenic chemotherapy. Notably, a substantial proportion of the avoidable acute care involved CINV, for which related acute care risk was more than double that for patients receiving non‐HEC. We also identified relatively high rates of nonadherence to guideline‐directed antiemetic prophylaxis for HEC, underscoring the need for action to ensure individual and institutional adherence to antiemetic guidelines, including the use of upfront NK1 receptor antagonists in HEC. Heightened oncologist and institutional attention to these outcomes is necessary as focus builds on avoiding acute care use measured by CMS’ publicly reported OP‐35 oncology quality metric and its impact on reimbursement.

Acknowledgments

This study was funded by Helsinn Therapeutics (U.S.), Inc.

Author Contributions

Conception/design: Rudolph M. Navari, Gary Binder, Luke M. Schmerold, Eric J. Roeland

Provision of study material or patients: Rudolph M. Navari, Gary Binder

Collection and/or assembly of data: Ravi Potluri, Luke M. Schmerold, Eros Papademetriou

Data analysis and interpretation: Rudolph M. Navari, Kathryn J. Ruddy, Thomas W. LeBlanc, Ryan Nipp, Rebecca Clark‐Snow, Lee Schwartzberg, Gary Binder, Ravi Potluri, Luke M. Schmerold, Eros Papademetriou, Eric J. Roeland

Manuscript writing: Rudolph M. Navari, Kathryn J. Ruddy, Thomas. LeBlanc, Ryan Nipp, Gary Binder, William L. Bailey, Luke M. Schmerold, Eric J. Roeland

Final approval of manuscript: Rudolph M. Navari, Kathryn J. Ruddy, Thomas W. LeBlanc, Ryan Nipp, Rebecca Clark‐Snow, Lee Schwartzberg, Gary Binder, William L. Bailey, Ravi Potluri, Luke M. Schmerold, Eros Papademetriou, Eric J. Roeland

Disclosures

Thomas W. LeBlanc: Jazz Pharmaceuticals, Seattle Genetics (RF), AbbVie, Agios, Amgen, Daiichi‐Sankyo, Heron Therapeutics, Medtronic, Otsuka (Other [Scientific advisor]), Agios, AstraZeneca, CareVive, Flatiron, Helsinn Therapeutics, Otsuka, Pfizer, Seattle Genetics, Welvie (C/A); Lee Schwartzberg: Amgen, Pfizer, Helsinn Therapeutics, Genentech/Roche, Genomic Health, Bristol‐Myers Squibb, Myriad, AstraZeneca, Bayer, Spectrum, Napo (C/A); Gary Binder: Helsinn Therapeutics (E, OI); William L. Bailey: Helsinn Therapeutics (E, OI); Ravi Potluri: Helsinn Therapeutics (C/A); Luke M. Schmerold: Helsinn Therapeutics (C/A); Eros Papademetriou: Helsinn Therapeutics (C/A); Eric J. Roeland: Asahi Kasei Pharmaceuticals, DRG Consulting, American Imaging Management, Napo Pharmaceuticals, Immuneering Corporation, Prime Oncology (C/A), Heron Pharmaceuticals, Vector Oncology, Oragenics, Inc., Galera Pharmaceuticals, Enzychem Lifesciences Pharmaceutical Company (Other [Scientific advisor]). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

References

Author notes