The Lynx Group

The Evolution of Chemotherapy-Induced Nausea and Vomiting Management: Challenges and Opportunities

June 2017, Vol 8, No 3, Supplement 2: The Evolution of Chemotherapy-Induced Nausea and Vomiting Management: Challenges and Opportunities

Chemotherapy extends the life of many patients with cancer, but there is often a trade-off in terms of adverse effects and compromised quality of life. Up to 80% of Americans who receive chemotherapy have adverse effects that are induced by antineoplastic drugs.1 Chemotherapy-induced nausea and vomiting (CINV) are common treatment-related side effects that have a serious impact on patients’ quality of life.2,3

CINV can be categorized into 3 types—(1) acute emesis most often begins within 1 to 2 hours of chemotherapy and usually peaks within 4 to 6 hours; (2) delayed emesis occurs more than 24 hours after chemotherapy; and (3) anticipatory emesis that occurs before, during, or after the administration of a subsequent course of treatment as a conditioned response in patients who had significant nausea and vomiting during previous cycles of chemotherapy.4

The precise physiologic mechanisms that trigger an emetic response are not fully understood; however, it is clear that the central nervous system plays an important role in the pathophysiology of CINV.5,6 Researchers hypothesize that a central pattern generator in the medulla coordinates the emetic response, with indirect input from neuronal clusters in the hindbrain and the vagal afferents area of the small intestine.5,6

Chemotherapy drugs cause an emetic response through several mechanisms and pathways, including the neuro­transmitters 5-hydroxytryptamine (5-HT), substance P, and dopamine; these neurotransmitters exert their effects by binding to the 5-HT3, neurokinin 1 (NK1), and dopamine D2 receptors, respectively.5,6

The 5-HT3 receptor is thought to be the most important in mediating the acute phase of CINV. Conversely, complex interactions between the 5-HT3 and NK1 neurotransmitter pathways are thought to contribute to delayed CINV, suggesting that the concomitant use of 5-HT3 and NK1 receptor antagonists may represent a rational treatment approach for delayed CINV.6,7

Risk Assessment

The risk for CINV is typically classified in accordance with the emetogenic potential of the chemotherapy drug (Table 1).8,9 In the absence of prophylaxis, intravenous highly emetogenetic chemotherapy (HEC) regimens have a ≥90% risk for emesis, and intravenous moderately emetogenic chemotherapy (MEC) regimens have a 30% to 90% risk for emesis.8-10 Oral MEC or HEC regimens have a ≥30% risk for emesis, whereas minimally or lowly emetogenic regimens have <30% risk for emesis.8

Table 1

Other factors may also affect the emetogenic risk of chemotherapy regimens. A 2016 study by Kottschade and colleagues examined several variables and their relationship to the rates of CINV.11 The researchers found that nausea and vomiting on day 1 of chemotherapy, cisplatin therapy, and a history of motion sickness significantly predicted delayed CINV, whereas age, combination chemotherapy (ie, HEC with MEC), and treatment for breast cancer predicted CINV on day 1.11 These findings confirm previous reports that certain subgroups of patients with cancer may be more susceptible to acute or delayed CINV.11

Assessment of risk for delayed CINV is particularly problematic. Grunberg and colleagues published the results of a prospective, observational study of adult patients receiving HEC or MEC for the first time.12 Despite receiving antiemetic therapy, patients exhibited delayed nausea and vomiting far more frequently than acute nausea and vomiting, and the differences were magnified for patients who received HEC. Furthermore, although healthcare providers participating in the study accurately predicted the incidence of acute CINV, more than 75% underestimated the incidence of delayed CINV.12 Without proper identification of the problem, it is difficult to initiate appropriate treatment.

Clinical and Financial Burden

For patients with CINV, performing activities of daily living is often challenging, resulting in a reduced quality of life.3 One prospective study showed that 37.2% of all patients who received HEC or MEC regimens reported reduced daily functioning, and of those with poorly managed CINV, approximately 90% reported a significant impact on daily functioning.3

Uncontrolled CINV may also impede patients’ ability to work.13 A medical claims–based analysis showed that uncontrolled CINV was associated with increased absenteeism.13 Patients with cancer who were receiving chemotherapy and had uncontrolled CINV averaged 6.23 lost work days monthly, whereas patients with cancer with controlled CINV lost an average of 3.61 days monthly.13

In addition, uncontrolled CINV is associated with several medical complications, including poor nutrition, dehydration, electrolyte imbalances, and physical and/or mental deterioration.14

Furthermore, uncontrolled CINV can affect patients’ adherence to chemotherapy, and may be detrimental to health outcomes.3,14 In some cases, patients may refuse to continue potentially beneficial or curative treatment regimens because of CINV.3,14 Alternatively, healthcare providers may choose to curtail or discontinue therapy when patients cannot tolerate CINV.15 In a 2014 survey of 2388 healthcare providers, 32% reported delaying or discontinuing a patient’s chemotherapy regimen because of CINV.15

In addition to the clinical burden of CINV, poorly controlled CINV requires the use of rescue medications and is associated with incremental healthcare utilization, which increases the overall cost of care.16,17 In a 2014 retrospective cohort study, a health plan’s total expenditures for CINV-related emergency department visits and hospitalizations was $3.6 million during a 2-year period.16

In another retrospective observational study of hospital service claims that evaluated hospital inpatient, outpatient, emergency department visits, and pharmacy costs for more than 11,000 patients, the average all-cause cost of CINV events was $1850 daily.17

These data indicate that the clinical burden of poorly controlled CINV has important cost implications for payers, and suggest that current antiemetic treatments are limited in their ability to mitigate CINV-related medical expenses.

Overall, these data underscore why CINV prophylaxis has been identified as a clinical consideration, particularly for patients who receive HEC or MEC regimens. Previous research findings further illustrate an unmet need for more effective antiemetic therapies and therapeutic options to manage the risk for CINV, especially in the delayed phase.3

Approach to Treatment

The past 25 years have brought significant advancements in CINV research and have revolutionized the prevention and management of CINV. In the early 1990s, dexamethasone was the standard of care for CINV.18 Later in the decade, the development of the 5-HT3 receptor antagonists granisetron, dolasetron, and ondansetron represented an important clinical advancement in the treatment of CINV.18,19

Subsequently, the discovery of the NK1 receptor antagonists aprepitant, fosaprepitant, netupitant, rolapitant, and the second-generation 5-HT3 inhibitor palonosetron led to significant developments in the management of CINV.18,19

More recently, olanzapine, a second-generation antipsychotic drug, combined with a 5-HT3 receptor antagonist and dexamethasone, demonstrated effectiveness in controlling CINV after a HEC or a MEC regimen.18,19

Today, the objective of antiemetic therapy is to prevent CINV, which should be feasible in the majority of patients who receive chemotherapy, even in those who receive HEC regimens.8 For most patients who receive HEC regimens, the current standard of care for treating CINV is a 3-drug combination regimen that includes an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone.8,20

Even with the emergence of newer CINV drugs, some patients continue to struggle with delayed CINV, particularly those who receive HEC regimens.21 Before the introduction of 5-HT3 receptor antagonists, the incidence of acute CINV and delayed CINV after treatment with cisplatin-based regimens was approximately 40% and 93%, respectively.11 Today, treatment with dexamethasone, 5-HT3 receptor antagonists, and NK1 receptor antagonists is associated with delayed nausea rates near 50%, and delayed emesis rates ranging from 30% to 50%.11

Updated National Comprehensive Cancer Network Guidelines for CINV

The US treatment guidelines recommend the prophylactic use of multidrug antiemetic regimens in patients at risk for CINV.8,20,22 Antiemetic drugs are most effective when used to prevent nausea and vomiting, because emesis in progress is much more difficult to suppress and increases the risk for anticipatory nausea or vomiting in future treatment cycles.8 Therefore, maximally effective antiemetic drugs are recommended as first-line therapy rather than withholding more effective antiemetic drugs for use at the time of antiemetic failure.8

Nonpharmacologic interventions can be used to help alleviate CINV symptoms.8 For example, changes in eating habits can help to mitigate nausea; patients should drink small amounts of clear liquids and eat frequent, small meals. In addition, desensitization behavioral therapy or acupuncture may be beneficial for the prevention of anticipatory nausea and/or vomiting.8

Prophylactic Treatment

For prophylactic treatment of HEC-induced nausea and vomiting, the recently updated National Comprehensive Cancer Network (NCCN) guidelines recommend triple-drug therapy with a 5-HT3 receptor antagonist (dolasetron, granisetron, ondansetron, or palonosetron), an NK1 receptor antagonist (aprepitant, fosaprepitant, or rolapitant), and dexamethasone; with olanzapine plus palonosetron and dexamethasone; or with netupitant plus palonosetron and dexamethasone.8

Granisetron extended-release injection, in combination with an NK1 receptor antagonist and dexamethasone, was added as a Category 1 treatment option in the updated NCCN guidelines for patients who receive HEC regimens.8

For patients who receive MEC regimens, a 2-drug antiemetic regimen that includes a 5-HT3 receptor antagonist plus dexamethasone is recommended for the prevention of CINV.8 Granisetron extended-release injection and palonosetron are listed as the preferred 5-HT3 drugs in this 2-drug regimen. Alternative antiemetic treatment options for patients receiving MEC regimens include a 3-drug regimen comprising a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone; or olanzapine, palonosetron, and dexamethasone; or netupitant plus palonosetron and dexamethasone.8

Furthermore, dexamethasone, metoclopramide, pro­chlorperazine, or 5-HT3 receptor antagonists, are recommended as single agents for lowly emetogenic chemotherapy.8 Routine prophylaxis is not recommended in patients who receive minimally emetogenic chemotherapy.8

Breakthrough Emesis

When an antiemetic regimen does not prevent CINV, patients are considered to have refractory CINV, which can lead to breakthrough symptoms. When breakthrough emesis occurs, an additional agent should be added, as needed, from a different class of drugs.8 In this case, several rescue options can be added to antiemetic regimens, including prochlorpromazine, promethazine, metoclopramide, or olanzapine.

Lorazepam and alprazolam may be used as adjunctive drugs with the preferred antiemetic regimens for patients who require breakthrough treatment for HEC and/or MEC regimens; these drugs are not recommended for use as monotherapy.

Adhering to Antiemetic Guidelines

Adhering to CINV treatment guidelines leads to improved CINV control.23,24 In a US-based observational study, the incidence of CINV was 56% in the patient population that received guideline-inconsistent antiemetic prophylaxis compared with 47% in patients who received guideline-consistent care (P .037).23

Similarly, a large European observational study showed that patients who received guideline-consistent antiemetic prophylaxis had significantly better CINV control than those who did not receive guideline-consistent antiemetic prophylaxis.24

Although these studies demonstrate a clear association between guideline-consistent antiemetic prophylaxis and enhanced CINV control, they also show that the utilization of guidelines for CINV control is unacceptably low.24,25 In the European study, the overall adherence to guidelines was 29% across emetic risk categories.24 Similar results were reported in a 2015 Brazilian study.25 These data suggest a need to redouble education and awareness-raising efforts regarding well-established CINV treatment guidelines.

Granisetron Extended-Release Injection

Granisetron hydrochloride was first US Food and Drug Administration (FDA) approved in November 1993 for the treatment of patients with CINV, and was marketed under the brand name Kytril.26

In 2008, the FDA approved a transdermal patch formulation of granisetron (Sancuso).27 In 2016, the FDA approved an extended-release formulation of granisetron (Sustol).28,29

Granisetron extended-release injection (10 mg/0.4 mL), a potent 5-HT3 receptor antagonist, is indicated, in combination with other antiemetic drugs, for the prevention of acute and delayed CINV associated with initial and repeated courses of MEC or anthracycline and cyclophosphamide combination chemotherapy regimens in adults.28

Granisetron extended-release injection is administered subcutaneously as a single dose at least 30 minutes before chemotherapy.28 For some patients, this single subcutaneous dose may be preferable to oral regimens that require pharmacy pickup and self-administration before chemotherapy.

In addition, patients who receive oral drugs for CINV may encounter dosing-specific challenges to treatment adherence.30 A study that compared patient adherence to oral antiemetic regimens and providers’ perceptions of patient adherence to oral regimens showed that only 38% of patients were fully adherent when self-administering antiemetic drugs.30 The most common reasons for patient nonadherence were the increasing pill burden and the fear that swallowing would induce nausea or vomiting.30

The granisetron extended-release delivery system is formulated using the unique, proprietary Biochronomer technology.28,31 Granisetron extended-release injection contains 10 mg of granisetron incorporated into the Biochronomer polymer. Once injected, granisetron is slowly released as the polymer erodes at a controlled rate, maintaining therapeutic levels of granisetron for ≥5 days with a single subcutaneous injection. Subsequently, the polymer fragments are rapidly cleared from the body.28,31

Pivotal Clinical Trials

The approval of granisetron extended-release injection was based on the safety and efficacy data from 2 large phase 3 clinical trials.28,29,32-35

Noninferiority Study

In the first phase 3, randomized, double-blind, multinational clinical trial, granisetron extended-release injection was compared with palonosetron in preventing acute and delayed CINV after MEC or HEC regimens during cycle 1 of chemotherapy.32 In addition, the study evaluated the efficacy of granisetron extended-release injection over multiple cycles of chemotherapy.34,35

The primary objectives of the study were to establish the noninferiority of granisetron extended-release injection to palonosetron in preventing acute CINV after MEC or HEC and delayed CINV after MEC, and to determine whether granisetron extended-release injection is superior to palonosetron in preventing delayed CINV after HEC. The primary end point was complete response.32

Overall, 1395 patients were stratified according to the emetogenicity of their chemotherapy regimen (ie, MEC or HEC) and were randomized to receive subcutaneous granisetron 10 mg plus placebo or intravenous palonosetron 0.25 mg plus placebo, before chemotherapy. All patients also received dexamethasone as part of their antiemetic treatment.32

Granisetron extended-release injection was noninferior to palonosetron in preventing acute and delayed CINV in patients who received MEC or HEC and in preventing acute CINV after HEC, as measured by complete response to treatment (Table 2).32,36 Although granisetron extended-release injection did not meet the primary objective of superiority to palonosetron for delayed HEC, a difference of 15% was required to demonstrate superiority.32

Table 2

After completion of this study, emetogenicity criteria were revised by the American Society of Clinical Oncology, and anthracycline plus cyclophosphamide regimens were reclassified from MEC to HEC, and carboplatins were changed from HEC to MEC.

In the reanalysis of the study, the proportion of patients receiving anthracycline plus cyclophosphamide regimens in the granisetron and palonosetron groups was similar (51.1% vs 50.5%).37

The efficacy results were similar between the subset of patients who received anthracycline plus cyclophosphamide regimens and those in the overall study population (Figure).37


In addition, the response rates for granisetron extended-release injection were sustained and similar across multiple cycles of chemotherapy.35 There was no significant difference in the rates of complete response in any cycle, and the majority of patients who had a complete response in cycle 1 continued to have a complete response in subsequent cycles, regardless of the study drug received in cycle 1.35

Adverse events, including injection-site reactions, were generally mild and occurred at similar rates across all the treatment groups.32 There were no significant differences between treatment groups in the severity of treatment-related adverse events or in the percentage of patients who discontinued therapy because of a treatment-related adverse event.32

The 2-drug versus 2-drug study design was consistent with the NCCN guidelines at the time of this clinical trial; however, the NCCN guidelines have since been revised to recommend a 3-drug regimen for patients who receive HEC regimens.8

MAGIC Clinical Trial

The MAGIC (Modified Absorption of Granisetron in the Prevention of Chemotherapy-Induced Nausea and Vomiting) clinical trial, a prospective, randomized, double-blind, multicenter US study, included 902 patients who received HEC regimens.33

MAGIC is the first phase 3, registrational, 3-drug versus 3-drug study that was designed in accordance with the updated NCCN guidelines for the prevention of CINV in patients receiving HEC.33

Of the patients 450 included in the granisetron extended-release injection group, 64.7% received anthracycline plus cyclophosphamide chemotherapy regimens, 27.8% received cisplatin-based therapy, and 7.7% received other HEC regimens.33 However, the study was only powered to evaluate granisetron extended-release injection in the overall HEC population and not in the different patient subsets.33

The primary end point was complete response in the delayed phase of CINV, defined as no vomiting or retching and no use of rescue medication, after a single dose of granisetron extended-release injection or ondansetron, when either drug was combined in a 3-drug regimen with fosaprepitant and dexamethasone.33 The ondansetron group received Biochronomer polymer subcutaneous injections as a placebo control for granisetron extended-release injection.33

In the modified intent-to-treat population, significantly more patients in the granisetron extended-release injection group (64.7%) achieved complete response in the delayed phase of CINV than patients in the ondansetron group (56.6%; P .014; Table 3).33,36 Response rates were similar between the groups in the acute phase of CINV.33

Table 3

Patient-reported satisfaction with nausea and vomiting control was significantly better in the granisetron extended-release injection group than in the ondansetron group (P .040): more than twice as many patients in the ondansetron group were dissatisfied or very dissatisfied with nausea and vomiting control than patients in the granisetron extended-release injection group.33

Overall, the frequency of treatment-emergent adverse events was similar between the treatment groups, and the majority of the events were grade 1 or grade 2. Serious adverse events (injection-site infection and atrial fibrillation) were reported in 2 patients in the granisetron extended-release injection group and in 1 patient (dehydration) in the ondansetron group.33


More than 25 years ago, nausea and vomiting were inevitable side effects of chemotherapy and forced up to 20% of patients to delay or refuse treatment.38 The introduction of 5-HT3 inhibitors revolutionized the management of CINV and has made substantial progress in reducing the debilitating impact of CINV.

Over time, the standard of care has evolved to include multidrug regimens, typically comprising a combination of a 5-HT3 receptor inhibitor, an NK1 receptor inhibitor, and dexamethasone. Clinical advancements in antiemetic care have resulted in improved adherence to anticancer treatment, as well as an improvement in patients’ quality of life.18

Nevertheless, a significant proportion of patients with cancer continue to suffer from the effects of CINV, particularly in the delayed phase. Guideline-based treatment of CINV can prevent nausea and vomiting in the majority of patients, but not in all patients.23-25 Therefore, antiemetic research continues, with the goal of optimizing CINV control for all patients.

Granisetron is an FDA-approved 5-HT3 receptor antagonist that has a well-established record of safety and efficacy since its initial approval in 1993. The approval of granisetron extended-release injection in 2016 introduced an important treatment option for patients with CINV, especially for those with delayed-phase CINV after HEC regimens. Utilizing an extended-release drug delivery technology, granisetron extended-release injection is a novel, long-acting formulation of granisetron that is conveniently administered in a single, subcutaneous dose by a healthcare provider, and is the only 5-HT3 receptor antagonist that is approved for the prevention of delayed CINV associated with HEC.28,39,40 Given the burden of delayed CINV, this treatment option represents an important advance in meeting the therapeutic needs of patients, particularly those at risk for delayed CINV associated with HEC treatment.


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