Experts Discuss Ways to Remove Barriers to Optimal Management of CINV

Lee S. Schwartzberg, MD, FACP

Although many targeted anticancer therapies have become available over the past several decades, chemotherapy remains the cornerstone of treatment for many types of cancer. Despite the widespread availability of antiemetic regimens, between 30% and 50% of patients receiving chemotherapy experience treatment-related nausea and/or vomiting.¹ Poorly controlled chemotherapy-induced nausea and vomiting (CINV) increases the risk of treatment delays, treatment discontinuation, and hospitalization.^2,3 It is also one of patients’ biggest concerns during chemotherapy and significantly affects their quality of life.³

Antiemetic Guidelines and Barriers to Care

On behalf of OncLive^®, Lee S. Schwartzberg, MD, FACP, moderated a Peer Exchange panel on the management of CINV. All the panelists have substantial knowledge of and experience with CINV; Schwartzberg, Dawn Dolan, PharmD, BCOP, and Eric Roeland, MD, were members of the National Comprehensive Cancer Network (NCCN) panel that updated the NCCN antiemesis guidelines in March 2017. The panelists discussed how to ensure that more patients undergoing chemotherapy receive optimal antiemetic regimens, their own approaches to managing CINV, and some of the more recently approved antiemetics.The American Society of Clinical Oncology (ASCO), NCCN, and the Multinational Association of Supportive Care in Cancer/European Society of Medical Oncology have all published evidencebased antiemetic guidelines, which they routinely update (Table). “We have great guidelines now,” said Schwartzberg, who noted that they are all similar. The guidelines identify which drugs are highly emetogenic chemotherapy (HEC) or moderately emetogenic (MEC). “HEC is typically considered to induce nausea in more than 90% of the population if you were not to give any prophylactic antiemetics...MEC induces emesis in 30% to 90% if you were not to give antiemetics,” Dolan said. She praised the reclassification of carboplatin and cisplatin from MEC to HEC in the guidelines.

Table. Emetic Risk Levels for Antineoplastic Agents

“I have a little bit of a problem with the way the categories are laid out; 90% or more is highly emetogenic but 89% is not,” said panelist Howard Levine, PharmD. The risk of emetogenicity is used to guide choice of prophylaxis. The panel agreed that since many antiemetics are available, the goal should be to prevent CINV in all patients by using the most effective agent first—even if the chemotherapy agent has a low risk of emesis.

Roeland pointed out that the guidelines stratify chemotherapy solely by risk of vomiting, whereas nausea is more prevalent. Supporting Roeland’s point, a survey of 386 patients about their most recent cycle of chemotherapy found that 60% experienced nausea only and 18% experienced vomiting with or without nausea.³ He emphasized the need to consider patient factors that increase the risk of nausea with chemotherapy, which in women includes younger than 50 years, a history of motion sickness or pregnancy-induced nausea and vomiting, and low alcohol intake. The greatest risk factor for all patients is CINV with a previous cycle of chemotherapy. “If you had CINV in your first cycle, you were 4 to 5 times more likely to have CINV in subsequent cycles,” Roeland said. Beth Eaby-Sandy, CRNP, OCN, said the guidelines help but that it remains difficult to predict who will experience CINV. “Know your patient, do a thorough review of systems and history and understand what is causing their nausea besides the drug that you’re giving them, and then tailor your approach to managing it based on the patient,” she recommended.

Nonadherence to the guidelines remains a barrier to optimal management of CINV, which can be broken down into acute phase, delayed phase, breakthrough, and anticipatory. “Acute CINV is defined as the first 24 hours after the treatment... from 2 days out after treatment, it becomes the delayed phase,” Levine explained. He described breakthrough as nausea or vomiting that occurs despite appropriate use of antiemetic therapy, which he said can occur any time from day 1 through day 5. Anticipatory CINV occurs before treatment is administered. Levine said it might be triggered by a smell or sight or, in many cases, by the expectation that chemotherapy causes nausea. “We actually do a pretty good job of controlling acute nausea and vomiting...but the delayed phase is really where the challenge has been,” he said.

Barriers to CINV Prophylaxis

A survey of more than 500 US oncology nurses in 2015 found that although most nurses expressed familiarity with NCCN or ASCO antiemetic guidelines, adherence was inconsistent.² While high proportions of respondents felt the antiemetics used in their practices were adherent to guidelines for acute and delayed CINV phases in the MEC setting (85% and 91%, respectively), adherence rates for prescribing patterns were much lower in the HEC setting in both phases (73% and 25%, respectively).²

Levine said another obstacle is that physicians are more interested in treating the cancer than addressing CINV. Accordingly, his practice has shifted much of the responsibility for managing CINV from the physicians to physicians’ assistants, nurses, and pharmacists, and Levine said the change improved management of CINV dramatically. Roeland said part of the problem is that physicians have difficulty keeping up with the pace of change in the oncology field. “Having a team-based approach is the way to go,” Roeland said.

Eaby-Sandy said her facility, like many others, has a multidisciplinary team to maintain specific order sets in the electronic medical record that pair the appropriate antiemetics with each chemotherapy regimen. “I think that fosters adherence with the guidelines because if they’re prebuilt, then you’re building them as part of the guidelines,” she said.

Dolan questioned whether using prebuilt order sets might make clinicians too complacent. “We fired off the order, everything is kind of already in there, and so it doesn’t lend itself to having to think about the more individualized approach,” she said. The panel also talked about the importance of patient education in CINV management. Roeland said it was important to inform patients and caregivers “that they’re not to expect nausea.” He said movies and the media may have fostered the popular perception that nausea means your chemotherapy is working but that is not the case. “We have tools available for patients,” he said. Dolan said it is also important to encourage patients to inform their provider when they feel nausea with chemotherapy. “I always tell patients there are no points for bravery,” she said.

New Antiemetic Agents

Schwartzberg said oncologists need to remind patients “to tell us everything” because there are ways to deal with nausea without compromising the chemotherapy regimen. Dolan recommended the NCCN patient guide, which now includes a mobile app. She said the guide “provides a lot of good information for patients [and] is easy to read.” Dolan also recommended that someone from the healthcare team call patients after chemotherapy to ask them how they are feeling.Guidelines agree that preventing CINV is easier than treating it, and they recommend starting with the most effective regimen first. “Unfortunately, some payers use something called step therapy, which basically mandates that patients should get sick before they get the optimal regimen. I don’t think that’s an appropriate approach,” Schwartzberg said. Controlling CINV in the delayed phase is the greatest unmet need, and many of the newer antiemetic agents have longer half-lives to prolong their efficacy.

Most of the antiemetic regimens recommended for HEC combine a neurokinin 1 (NK1) receptor agonist (RA) with a 5-HT3 RA and dexamethasone. Dolan said first-generation 5-HT3 RAs include ondansetron, dolasetron (Anzemet), and oral granisetron. Palonosetron and subcutaneous (SC) granisetron are second-generation 5-HT3 RAs. “Early first-generation 5-HT3 RAs typically have a shorter half-life; they’re pretty good for preventing acute nausea but not so great in the delayed phase,” she said. In comparison, Dolan said palonosetron and granisetron SC have much longer half-lives and greater binding affinity for the 5-HT3 receptor. “They definitely have higher efficacy rates compared with the first-generation 5-HT3 antagonists,” she said. Adding dexamethasone improves the efficacy of 5-HT3 RAs. Dolan said oral and intravenous 5-HT3 RAs are equally effective.

The NK1 RAs were introduced after 5-HT3 RAs. Eaby-Sandy said that combining an NK1 RA with a 5-HT3 RA “dramatically improved control [of CINV] in the delayed setting” because of how long NK1 RAs bind to substance P, a neurotransmitter that stimulates vomiting pathways in the brain. Newer NK1 RAs such as rolapitant (Varubi) and netupitant bind longer to substance P than first-generation NK1 RAs such as aprepitant and fosaprepitant (an intravenous [IV] form of aprepitant).

“Rolapitant has a much longer half-life, so that can be dosed on day 1 and have coverage up to 7 days or even longer,” she said. The FDA approved an oral formulation of rolapitant in September 2015. In October, the agency granted approval for its use in combination with other antiemetic agents to treat delayed CINV in adults.

Rolapitant

Schwartzberg, who was involved in the pivotal phase III multicenter trials of oral rolapitant, said it performed well in adults with cancer who received HEC or MEC.^4,5 In 2 of the trials, patients scheduled to undergo their first cycle of highly emetogenic cisplatin-based chemotherapy were randomly assigned to prophylaxis with oral rolapitant or placebo; patients in both cohorts also received granisetron SC and dexamethasone.⁴

The trial defined complete response (CR), which was the primary endpoint, as no emesis or need for rescue medication more than 24 to 120 hours after cycle 1. In a pooled analysis, significantly more patients in the rolapitant group than in the placebo group achieved a CR (71% vs 60%, respectively; P = .0001).⁴

In a randomized phase III trial of patients receiving MEC containing an anthracycline plus cyclophosphamide, patients were randomly assigned to oral rolapitant or placebo, as well as oral granisetron and dexamethasone.⁵ The primary endpoint was again CR in the delayed phase. The CR rate was 71% in the rolapitant arm versus 62% in the placebo arm (P = .0002).⁵ Rolapitant was well tolerated, and none of the studies reported any serious treatment-emergent adverse events or deaths.^4,5

The approval for the IV formulation was based on a bioequivalence trial that showed the comparability of the IV and oral formulations. The bioequivalence study randomized healthy volunteers to a single dose of 166.5 mg of IV rolapitant administered over 30 minutes (n = 61) or 180 mg of oral rolapitant (n = 62). Bioequivalence was defined by estimating whether the 90% confidence intervals for the ratio of the area under the curves of the 2 formulations were entirely included within the acceptance range of 80% to 125%, according to Tesaro, the company developing the drug.

NEPA

In 2014, the FDA approved NEPA (Akynzeo), which is an oral fixed-dose combination of the NK1 RA netupitant (300 mg) plus palonosetron. Approval was based on results of clinical trials in chemotherapy-naïve patients scheduled for HEC or MEC.^6,7

In a dose-finding trial, patients received NEPA or palonosetron monotherapy; all patients received dexamethasone. The study defined CR as no emesis or rescue medication for up to 120 hours after administration of cisplatin-based chemotherapy.6 The CR rate in the NEPA 300-mg arm was 90% compared with 77% in the palonosetron-only arm (P <.050).⁶ NEPA was also superior to palonosetron at controlling nausea during the acute phase.⁶

In a phase III trial of NEPA, patients scheduled to receive MEC were randomly assigned to prophylaxis with NEPA 300 mg or a single dose of palonosetron; both arms received dexamethasone.⁷ In this trial, CR was defined as no emesis or rescue medication for 25 to 120 hours after chemotherapy administration. Patients in the NEPA arm were significantly more likely to achieve CR than patients in the placebo arm (74% vs 67%; P = .001).⁷

NEPA was well tolerated in both trials.^6,7 “In general, we’re seeing that the NK1 RAs really don’t add an incremental increase in toxicity,” Dolan said.

Eaby-Sandy shared the story of a patient whose insurance company would not authorize NEPA unless the patient first failed aprepitant or fosaprepitant and ondansetron. She referred the insurer to the NCCN guidelines but “they did not budge.”

Schwartzberg criticized the insurer’s decision as arbitrary and said it did not make sense. The panel discussed how in the United States it is far more difficult to get approval for oral antiemetics than IV ones even though, as Roeland pointed out, the efficacy is equal.

Olanzapine

Another antiemetic regimen recommended as equal to the others in the NCCN guidelines combines olanzapine (Zyprexa), palonosetron, and dexamethasone.8

Roeland said, “Olanzapine has been used in the treatment of schizophrenia and bipolar disorder at high doses over chronic periods of time.” Olanzapine, an antipsychotic, has several targets, including multiple serotonin and dopamine receptors, said Roeland.

In a randomized phase III trial, olanzapine was compared with placebo; both regimens included dexamethasone, aprepitant, or fosaprepitant, and a 5-HT3 RA.⁹ Investigators “chose a primary endpoint of no nausea, which I think all of us would agree is probably the most clinically meaningful endpoint as we move forward,” Roeland said. In the first 24 hours after chemotherapy, 74% of patients in the olanzapine arm had no nausea compared with 45% in the placebo arm (P = .002).⁹

Olanzapine also controlled nausea significantly better than placebo in the delayed phase (P = .002). The most common adverse effect was sedation, which peaked on day 2.9 Olanzapine is typically administered the night before chemotherapy, and Levine expressed concern that some patients might forget to take it.