Volume 12, Issue 3, Supplement 9 March 2014
Clinical Roundtable Monograph: New Data in Emerging Treatment Options for Chemotherapy-Induced Nausea and Vomiting
Gary R. Morrow, PhD, MS
Professor of Radiation Oncology
Professor of Psychiatry
University of Rochester Medical Center
Rochester, New York
Rudolph M. Navari, MD, PhD
Professor of Medicine
Associate Dean and Director
Indiana University School of Medicine South Bend
Clinical Director, Harper Cancer Research Institute
South Bend, Indiana
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trial Education
University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
San Francisco, California
Abstract: Chemotherapy-induced nausea and vomiting (CINV) has long been one of the most troublesome adverse effects of chemotherapy, leading to significant detriments in quality of life and functioning, increased economic costs, and, in some cases, the discontinuation of effective cancer therapy. The past 2 decades have witnessed a dramatic increase in the number of effective antiemetic agents, with the introduction of the serotonin (5-hydroxytryptamine [5-HT3]) receptor antagonists (ondansetron, granisetron, and palonosetron), the neurokinin-1 (NK1) receptor antagonists (aprepitant and fosaprepitant), and the identification of other agents that have demonstrated efficacy against CINV, including corticosteroids. These agents often provide excellent control of emesis. Nausea, however, has proven more intractable, particularly in the days after administration of chemotherapy. Newer antiemetic agents under study may provide additional CINV control, particularly against delayed nausea. New agents undergoing review by the US Food and Drug Administration for the prevention of CINV include the novel NK1 receptor antagonist rolapitant and a fixed-dose combination consisting of the novel NK1 receptor antagonist netupitant and palonosetron (NEPA). Adherence to clinical practice guidelines has been shown to significantly improve CINV control. As antiemetic therapy continues to evolve, it will be important for clinicians to stay informed of new developments and changes in guidelines.
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The Impact of Chemotherapy-Induced Nausea and Vomiting
Gary R. Morrow, PhD, MS
Professor of Radiation Oncology
Professor of Psychiatry
University of Rochester Medical Center
Rochester, New York
Since chemotherapy began to be used for the treatment of cancer, nausea and vomiting have been among the adverse events of greatest concern to patients.1,2 Before the introduction of antiemetic drugs, chemotherapy-induced nausea and vomiting (CINV) affected almost all patients, often causing symptoms severe enough to necessitate extended hospitalization. Today, virtually all chemotherapy agents are administered on an outpatient basis, largely because of the development of effective antiemetic drugs.
Multiple factors influence the incidence and severity of CINV. The primary risk factor is the chemotherapy regimen—both the type of agent and the dosage. Patient-related factors include sex and age.3,4 Women experience more chemotherapy-associated adverse events, including CINV, than men. Elderly patients report fewer side effects than younger patients.
Chemotherapy-induced nausea must be considered separately from vomiting. The development of effective antiemetic therapy has substantially reduced the incidence and severity of chemotherapy-associated vomiting. In contrast, nausea has proven more difficult to control. Patients receiving effective antiemetic regimens usually report more nausea than vomiting.5
Classification of CINV
CINV is classified as acute, delayed, or anticipatory based on its time of onset. Acute CINV typically develops within a few minutes to hours after administration of chemotherapy and resolves within 24 hours. Delayed CINV occurs more than 24 hours after chemotherapy. Delayed CINV is more common with certain agents, including cisplatin, carboplatin, cyclophosphamide, and doxorubicin.6 Anticipatory nausea and/or vomiting occurs in approximately 20% of patients receiving chemotherapy.7,8 Anticipatory CINV is a classically conditioned learned response that occurs before the administration of chemotherapy, typically in patients who experienced acute or delayed CINV in previous cycles. For some patients, seeing their doctor or nurse can trigger anticipatory CINV. Anticipatory CINV can also occur outside the medical setting; for example, a patient I know experienced anticipatory CINV while traveling along the route she usually used to visit the clinic.
Clinicians may underestimate the prevalence of CINV (Figure 1).9,10 Assessment of CINV is an essential component of care for patients receiving chemotherapy. However, this assessment is challenging, particularly in the case of nausea, which is a subjective experience and therefore difficult to quantify. Like pain or fatigue, nausea lacks an external frame of reference and is dependent upon patients’ perceptions, which vary widely. Therefore, it is important to ask patients about nausea as well as vomiting.
Consequences of CINV
CINV can have significant negative effects on quality of life and can lead to reduced adherence to therapy or an unwillingness to continue with effective therapy. Other potential effects of nausea and vomiting include electrolyte imbalances, impaired self-care and functional ability, reductions in energy, and strains on relationships. Caregivers can be strongly affected when a loved one is experiencing nausea and vomiting.
There are substantial economic costs associated with CINV. In a study of working-aged adults receiving highly or moderately emetogenic chemotherapy, uncontrolled CINV was associated with higher monthly costs of $1300 for medical issues (eg, need for hospitalization; Table 1) and $433 for indirect costs (eg, lost work time).11
Given the numerous potential negative effects of CINV, proper control through the use of effective antiemetic therapy is an essential part of the planning for chemotherapy. Management of CINV should begin at the start of treatment.
Dr Morrow has no real or apparent conflicts of interest to report.
1. Coates A, Abraham S, Kaye SB, et al. On the receiving end—patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol. 1983;19(2):203-208.
2. Dubey S, Brown RL, Esmond SL, Bowers BJ, Healy JM, Schiller JH. Patient preferences in choosing chemotherapy regimens for advanced non-small cell lung cancer. J Support Oncol. 2005;3(2):149-154.
3. Osoba D, Zee B, Pater J, Warr D, Latreille J, Kaizer L; Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Determinants of postchemotherapy nausea and vomiting in patients with cancer. J Clin Oncol. 1997;15(1):116-123.
4. Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer. 1989;64(5):1117-1122.
5. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100(10):2261-2268.
6. Gralla RJ, Osoba D, Kris MG, et al; American Society of Clinical Oncology. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol. 1999;17(9):2971-2994.
7. Moher D, Arthur AZ, Pater JL. Anticipatory nausea and/or vomiting. Cancer Treat Rev. 1984;11(3):257-264.
8. Jacobsen PB, Redd WH. The development and management of chemotherapy-related anticipatory nausea and vomiting. Cancer Invest. 1988;6(3):329-336.
9. Young A, Dielenseger P, Fernandez Ortega P, et al. Helping patients discuss CINV management: development of a Patient Charter. Ecancermedicalscience. 2013;7:296. doi: 10.3332/ecancer.2013.296. Print 2013.
10. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100(10):2261-2268.
11. Tina Shih YC, Xu Y, Elting LS. Costs of uncontrolled chemotherapy-induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer. 2007;110(3):678-685.
Clinical Trial Data in Chemotherapy-Induced Nausea and Vomiting
Rudolph M. Navari, MD, PhD
Professor of Medicine
Associate Dean and Director
Indiana University School of
Medicine South Bend
Harper Cancer Research Institute
South Bend, Indiana
Antiemetic therapy has undergone a substantial evolution in the past few decades. In the early 1990s, therapeutic options included prochlorperazine and metoclopramide. In the current era, there are several new agents targeting different physiologic pathways. Table 2 lists the mechanisms of action of the various commonly used antiemetics. By combining agents with multiple mechanisms of action, greater antiemetic efficacy can be achieved. The development of antiemetic agents has been based on the identification of the main neurotransmitters involved in CINV: dopamine, serotonin, and substance P (Figure 2). These neurotransmitters are detectable in both the periphery and the central nervous system, to varying degrees.
Serotonin (5-HT3) Receptor Antagonists
The first generation of serotonin (5-hydroxytryptamine [5-HT3]) receptor antagonists—ondansetron, grani-setron, and dolasetron—were developed in the 1990s and represented a significant advance in the control of CINV. In numerous clinical trials, these 5-HT3 antagonists demonstrated a significant improvement over previous therapies for CINV, controlling approximately half of patients’ emesis over the first 24 hours and the subsequent days after administration of chemotherapy.1,2 In the late 1990s, multicenter, double-blind, randomized trials demonstrated comparable outcomes among the 3 first-generation 5-HT3 receptor antagonists. Intravenous dolasetron was equivalent to ondansetron,3 and oral granisetron was equivalent to intravenous ondansetron.4 Thereafter, these agents were selected based primarily on economic factors.
The use of first-generation 5-HT3 receptor antagonists has changed throughout the years. Table 3 shows the recommended doses for the commonly used agents. In 2010, the US Food and Drug Administration (FDA) issued a warning about dolasetron and QTc prolongations, particularly in patients with ischemic heart disease or arrhythmias.5 As a result of this warning, dolasetron is rarely used or available. In 2012, the FDA issued a safety warning about ondansetron, noting that the intravenous dose should not exceed 16 mg owing to the risk of QTc prolongation, which could potentially precipitate a serious arrhythmia6 (although clinical reports are rare).
Clinical trials of antiemetic therapy in the 1990s also focused on the role of dexamethasone, which was found to be an effective antiemetic agent. The combination of dexamethasone and a 5-HT3 receptor antagonist protected up to 60% of patients from delayed emesis.7 The optimal dose of dexamethasone has been a topic of investigation. Data from the Italian Group for Antiemetic Research suggest that the most appropriate dexamethasone dosages are 20 mg administered 1 day before administration of highly emetogenic chemotherapy (eg, regimens with cisplatin or an anthracycline) and 8 mg administered 1 day prior to the administration of moderately emetogenic chemotherapy.8
Palonosetron is a second-generation 5-HT3 antagonist approved by the FDA for the treatment of acute and delayed CINV. Palonosetron has demonstrated superior efficacy over first-generation 5-HT3 antagonists in multiple clinical trials. It has shown greater efficacy compared with dolasetron in patients receiving moderately emetogenic chemotherapy,9 and greater efficacy compared with ondansetron in patients receiving moderately emetogenic10 or highly emetogenic11 chemotherapy. In a combined analysis of 2 trials, palonosetron was more effective than either ondansetron or dolasetron.12 Palonosetron plus dexamethasone demonstrated significantly greater efficacy vs granisetron plus dexamethasone in patients receiving highly emetogenic chemotherapy.13 In this study, the superiority of palonosetron was observed in the acute phase (the first 24 hours), the delayed phase (days 2-5 postchemotherapy), and the overall combined 120-hour period after chemotherapy administration.
The structure of palonosetron differs from that of the first-generation 5-HT3 receptor antagonists. Laboratory studies suggest that the enhanced efficacy of palonosetron may relate to its unique ability to not only block the 5-HT3 receptor, but also to change the receptor, triggering 5-HT3 receptor internalization and inhibiting receptor function.14 Evidence from the past 10 to 15 years confirms that administering a first- or second-generation 5-HT3 receptor antagonist plus dexamethasone before chemotherapy controls emesis. Even with these effective agents for emesis, however, nausea has remained poorly controlled.
NK1 Receptor Antagonists
Neurokinin-1 (NK1) receptor antagonists selectively block binding of substance P to the NK1 receptor, primarily in the central nervous system. The primary effect of blocking the NK1 receptor appears to be in controlling delayed emesis. The first NK1 receptor antagonist to receive FDA approval was aprepitant. In 2 randomized, double-blind, placebo-controlled trials in patients receiving highly emetogenic chemotherapy, the addition of aprepitant to standard antiemetic therapy (a 5-HT3 antagonist and dexamethasone) was associated with substantial reductions in delayed emesis and some reduction in acute emesis.15,16
Aprepitant also demonstrated efficacy in preventing CINV when added to ondansetron and dexamethasone in patients with breast cancer receiving moderately emetogenic chemotherapy.17 In the study, the addition of aprepitant was associated with a small improvement over the control regimen in acute CINV, no improvement in delayed CINV, and a small improvement overall in CINV. There was no improvement specifically in nausea throughout the entire 120 hours after administration of chemotherapy. Overall, the role of aprepitant for patients receiving moderately emetogenic chemotherapy is still under study, and the agent is not routinely used in this setting.
A clinical issue with aprepitant had been its formulation, which was limited to an oral form that is administered on days 1, 2, and 3. Access to oral medications has been a challenge for some patients, perhaps owing to insurance and co-pay issues. Subsequently, an intravenous formulation of aprepitant, known as fosaprepitant, was developed. It showed noninferiority to the 3-day oral dosing of aprepitant.18 The ability to administer CINV medications intravenously before highly emetogenic chemotherapy has had a substantial benefit on CINV management in clinical practice.
Additional NK1 receptor antagonists have been studied in recent years. Rolapitant has completed phase 3 trials in patients receiving moderately and highly emetogenic chemotherapy.19 Specific detailed data from these trials are not yet available, but it is assumed that the results of the rolapitant clinical trials will be submitted to the FDA for approval in the near future.
Netupitant is another NK1 receptor antagonist that has been formulated in a fixed-dose combination with palonosetron known as NEPA. Two phase 3 trials presented at the 2013 Annual Meeting of the American Society of Clinical Oncology evaluated the efficacy and safety of NEPA. One study compared NEPA vs palonosetron alone for the prevention of CINV in patients receiving moderately emetogenic chemotherapy.20 The combination of NEPA was associated with higher complete response rates than palonosetron alone in the acute phase (88.4% vs 85.0%; P=.047), the delayed phase (76.9% vs 69.5%; P=.001), and the full 120 hours (74.3% vs 66.6%; P=.001). In a companion study examining 3 different dosages of NEPA plus dexamethasone, all dosages were associated with greater efficacy vs palonosetron plus dexamethasone in patients receiving highly emetogenic chemotherapy (Figure 3).21 The fixed-dose combination of netupitant and palonosetron was submitted to the FDA for approval in December 2013.
The NK1 receptor antagonists have not been directly compared, and any differences in the efficacy and safety are unknown. However, the newer agents will likely have at least similar efficacy and a similar toxicity profile to aprepitant.
Other Antiemetic Combinations
Other combinations of antiemetic drugs may have some applicability in the future. Olanzapine was originally developed as an antipsychotic agent and found to have significant effects on preventing emesis and nausea in patients taking it for other indications, leading to off-label use as an antiemetic agent to prevent CINV. A phase 2 trial demonstrated the efficacy of olanzapine, dexamethasone, and palonosetron for the prevention of acute and delayed CINV in patients receiving both moderately and highly emetogenic chemotherapy.22 The regimen effectively controlled emesis and reduced nausea in many cases. In another study, a combination of olanzapine, the 5-HT3 receptor agonist azasetron (used in East Asia), and dexamethasone demonstrated significantly greater efficacy than azasetron plus dexamethasone in patients receiving moderately or highly emetogenic chemotherapy.23 The results with the olanzapine-containing regimen were striking, yielding a complete response rate of 70% to 80% and a high degree of nausea control in patients receiving highly emetogenic chemotherapy. Among patients receiving moderately emetogenic chemotherapy, the regimen was associated with a complete response rate of 89% throughout the 120-hour period after administration of chemotherapy.
A subsequent randomized phase 3 trial compared olanzapine vs aprepitant, each with dexamethasone and palonosetron, in patients receiving highly emetogenic chemotherapy.24 Overall complete response rates were similar (77% with olanzapine and 73% with aprepitant). Olanzapine was associated with better nausea control, with 69% of patients reporting no nausea for the overall period, compared with 38% for aprepitant. The olanzapine regimen has recently been added to the National Comprehensive Cancer Network (NCCN) guidelines as an alternative first-line preventative therapy for patients receiving highly emetogenic chemotherapy.25
Dr Navari has no real or apparent conflicts of interest to report.
1. Chevallier B, Cappelaere P, Splinter T, et al. A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy. Support Care Cancer. 1997;5(1):22-30.
2. Audhuy B, Cappelaere P, Martin M, et al. A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer. 1996;32A(5):807-813.
3. Hesketh P, Navari R, Grote T, et al; Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol. 1996;14(8):2242-2249.
4. Perez EA, Hesketh P, Sandbach J, et al. Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. J Clin Oncol. 1998;16(2):754-760.
5. Anzemet (dolasetron mesylate): drug safety communication—reports of abnormal heart rhythms. US Food and Drug Administration. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm237341.htm. Posted December 17, 2010. Accessed February 1, 2014.
6. Ondansetron (Zofran) IV: drug safety communication—QT prolongation. US Food and Drug Administration. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm. Posted June 29, 2012. Accessed February 1, 2014.
7. Kaizer L, Warr D, Hoskins P, et al. Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: a phase III trial by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12(5):1050-1057.
8. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342(21):1554-1559.
9. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98(11):2473-2482.
10. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14(10):1570-1577.
11. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17(9):1441-1449.
12. Rubenstein EB, Gralla RJ, Eisenberg P, et al. Palonosetron (PALO) compared with ondansetron (OND) or dolasetron (DOL) for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV): combined results of two phase III trials. Proc Am Soc Clin Oncol. 2003;22:729. A2932.
13. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10(2):115-124.
14. Rojas C, Thomas AG, Alt J, et al. Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol. 2010;626(2-3):193-199.
15. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21(22):4112-4119.
16. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97(12):3090-3098.
17. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23(12):2822-2830.
18. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol. 2011;29:1495-1501.
19. ClinicalTrials.gov. Phase 3 safety and efficacy study of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving highly emetogenic chemotherapy (HEC). http://clinicaltrials.gov/show/NCT01499849. Identifier: NCT01499849. Accessed February 6, 2014.
20. Aapro MS, Rossi G, Rizzi G, et al. Phase III study of NEPA, a fixed-dose combination of netupitant (NETU) and palonosetron (PALO), versus PALO for prevention of chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC) [ASCO abstract LBA9514]. J Clin Oncol. 2013;31(15 suppl).
21. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC) [ASCO abstract 9512]. J Clin Oncol. 2013;31(suppl).
22. Navari RM, Einhorn LH, Loehrer PJ Sr, et al. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer. 2007;15(11):1285-1291.
23. Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res. 2009;28:131.
24. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 2011;9(5):188-195.
25. NCCN Guidelines: antiemesis. Version 1.2014. National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Updated August 19, 2013. Accessed February 3, 2014.
Management of Chemotherapy-Induced Nausea and Vomiting in Clinical Practice
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trial Education
University of California San Francisco
Helen Diller Family Comprehensive
San Francisco, California
The primary goal of antiemetic therapy in patients receiving chemotherapy is to attain the best possible control of CINV with the best quality of life. Control of CINV must take into account multiple factors, including the chemotherapy agents being used, the dose and schedule of the agents, and patient characteristics.
Highly emetogenic therapies (eg, anthracycline and platinum-based combinations, higher-dose cisplatin) induce emesis in more than 90% of patients; this incidence decreases to approximately 30% with the use of appropriate antiemetic agents.1 Therapies with a moderate emetic risk (eg, bendamustine, carboplatin, and irinotecan) induce emesis in 30% to 90% of patients. Agents with a low emetic risk (eg, fluorouracil, paclitaxel, docetaxel, and pemetrexed) are associated with emesis in 10% to 30% of patients. Agents in the fourth category, minimal emetic risk, induce emesis in less than 10%.
There are some limitations to this classification system. First, the use of combination chemotherapy may alter the emetogenic classification; single agents with a moderate emetogenic risk may become highly emetogenic when administered in combination with other chemotherapies. Second, individual risk factors (eg, age, sex, and alcohol use) affect the likelihood of CINV. Third, pharmacogenomics, although not well understood, may also influence CINV risk, resulting in unusual responses to specific chemotherapy agents in individual patients.
A prospective observational study from Europe evaluated the significance of various patient-related and treatment-related risk factors for CINV in nearly 1000 patients receiving highly and moderately emetogenic chemotherapy.2 Patients completed daily diaries for 6 days per chemotherapy cycle to report on episodes of nausea/vomiting, expectations of nausea, prechemotherapy anxiety, and prechemotherapy nausea. The investigators found that different variables contributed to the acute, delayed, and overall phases of CINV. Notably, a key predictive factor associated with CINV was the use of antiemetic therapy in ways that were inconsistent with international guidelines. Other independent predictive variables included younger age, prechemotherapy nausea, and history of CINV in prior cycles. Factors that were important predictors in some phases of CINV included anxiety, history of nausea/vomiting, and expectations of nausea.
These findings highlight the importance of following evidence-based guidelines for preventing CINV, but data suggest that these guidelines are not adequately followed in clinical practice. In a prospective observational study of 1295 chemotherapy-naive patients in the Southeastern United States receiving single-day highly or moderately emetogenic chemotherapy, only 57% of patients received CINV prophylaxis that was consistent with guideline recommendations.3 Treatment that adhered to the guidelines significantly decreased the proportion of patients with CINV throughout the 5-day postchemotherapy period (44% vs 53%; P<.001; Table 4). A study from the Pan European Emesis Registry also showed that rates of CINV were lower among patients treated according to guidelines (Figure 4).4,5
General Principles of CINV Management
In general, CINV control is best achieved with the appropriate use of available prophylactic medications and through patient education on how to treat breakthrough CINV. Adjustments may need to be made throughout the duration of treatment based on how patients tolerate chemotherapy and CINV prophylaxis. It is important to be flexible with each cycle of treatment.
A critical aspect of CINV management is to listen to patients. By listening to a patient’s description of his or her situation, clinicians may better understand the causes of symptoms and provide more appropriate management. For example, gastric distress may arise as a result of chemotherapy, steroids, and other treatments, as well as from lifestyle factors. For these patients, an H2 blocker or proton pump inhibitor may help control gastrointestinal symptoms associated with the treatment. Given the demonstrated role of anxiety in contributing to CINV risk, anxiety-reducing strategies, including counseling services and medication, may reduce CINV. These interventions should be discussed with patients upfront and during the treatment period.
Another component of managing CINV involves informing patients about eating habits and other lifestyle measures that may reduce nausea and vomiting, including eating small, frequent meals; selecting foods less likely to induce nausea or vomiting; and eating food at room temperature. Although these strategies have not been studied in the same rigorous way as pharmacologic therapies, they may help patients feel more comfortable during therapy.
Overview of CINV Guidelines
Multiple guidelines are available for the prevention and treatment of CINV, including the NCCN guidelines,1 which are updated annually; the American Society of Clinical Oncology guidelines,6 last updated in 2011; and guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)7 and the European Society of Medical Oncology, last updated in 2010. Tools are also available to assist in CINV prevention and treatment, including the validated MASCC Antiemesis Tool.8
Highly Emetogenic Chemotherapy
The NCCN guidelines recommend a combination of agents for CINV prophylaxis regimens for highly emetogenic chemotherapy. The regimen should consist of a 5-HT3 antagonist (palonosetron is preferred, but other options are dolasetron, granisetron, and ondansetron), a steroid (dexamethasone [with aprepitant or fosaprepitant]), and an NK1 antagonist (aprepitant or fosaprepitant), lorazepam, or an H2 blocker or proton pump inhibitor. The NCCN guidelines also list several olanzapine-containing regimens for primary prophylaxis, but this approach tends to be used in countries without access to NK1 antagonists.1 In the breast cancer setting, olanzapine seems to be associated with more neuropsychiatric adverse events than the other NK1 antagonists and is a less preferred and less commonly used agent. Some patients cannot tolerate 5-HT3 receptor antagonists, and it will be interesting to see whether NEPA, by combining the 5-HT3 antagonist and the NK1 antagonist, will be easier for patients to tolerate than current therapies. If NEPA does provide better control of CINV, it will change management moving forward.
Many patients receiving highly emetogenic chemotherapy require additional breakthrough medication. The choice of agent may depend on the patient’s tolerance for different classes of agents. Lorazepam and prochlorperazine are commonly used; other agents recommended by the NCCN include olanzapine, cannabinoids, 5-HT3 antagonists, dexamethasone, promethazine, haloperidol, metoclopramide, or the scopolamine transdermal patch.
Moderately Emetogenic Chemotherapy
In general, the difference between the approaches for moderately emetogenic regimens and highly emetogenic regimens lies in the use of the NK1 antagonist. For moderately emetogenic regimens, an NK1 antagonist is used prophylactically in selected patients, such as those at a higher risk for CINV.1 In those patients, it may be preferable to start with a more aggressive antiemetic regimen that includes an NK1 antagonist and then reduce the intensity of treatment if good CINV control is attained.
It is important to maintain the dosage and intensity of chemotherapy, particularly in early-stage disease. When significant nausea and vomiting are not decreased by guideline recommendations for moderately emetogenic chemotherapy, the recommendations for highly emetogenic chemotherapy should be followed.
Low Emetogenic-Risk Chemotherapy
Occasionally, patients will develop significant CINV from agents that are considered to have low or minimal emetic risk. In these situations, it is essential to consider other potential causes of nausea. For example, a small number of patients develop significant nausea and vomiting from capecitabine, which is considered to have minimal to low emetic risk. These patients may have reduced metabolism of capecitabine (5-fluorouracil), with the potential to develop life-threatening toxicities from this drug.
Other Causes of Nausea and Vomiting
For patients without good CINV control despite adherence to guidelines and use of all available medications, other potential causes of emesis must be considered. Alternative causes of nausea and vomiting vary based on individual circumstances but can be found in both early-stage and advanced disease. Potential contributing factors include direct effects of chemotherapy on the gastrointestinal tract (eg, gastroparesis); coexisting conditions, such as diabetes or gastrointestinal disorders; nausea from other drugs, such as opioids; and direct effects of the disease (eg, bowel obstruction or vestibular dysfunction caused by brain metastases).
Multiple effective antiemetic agents are available for the prevention and treatment of CINV. In clinical practice, the primary goal with antiemetic therapy is to prevent CINV and effectively manage any symptoms that arise. Treatment should be individualized based on risk factors such as the chemotherapy in use and the patient’s physiology. The antiemetic regimen should be modified if needed to optimize tolerability. Importantly, adherence to guidelines has been shown to markedly improve control of emesis and moderately control the risk of postchemotherapy nausea. Clinicians should become aware of new guidelines as they are released.
Eisai Inc. has provided research funding to Dr Rugo’s institution, the University of California, San Francisco.
1. NCCN Guidelines: antiemesis. Version 1.2014. National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Updated August 19, 2013. Accessed February 3, 2014.
2. Molassiotis A, Aapro M, Dicato M, et al. Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study. J Pain Symptom Manage. 2013 Sep 24. pii: S0885-3924(13)00397-7. [Epub ahead of print]
3. Gilmore JW, Peacock NW, Gu A, et al. Antiemetic Guideline Consistency and Incidence of Chemotherapy-Induced Nausea and Vomiting in US Community Oncology Practice: INSPIRE Study. J Oncol Pract. 2014;10(1):68-74.
4. Young A, Dielenseger P, Fernandez Ortega P, et al. Helping patients discuss CINV management: development of a Patient Charter. Ecancermedicalscience. 2013;7:296. doi: 10.3332/ecancer.2013.296. Print 2013.
5. Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol. 2012;23(8):1986-1992.
6. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. 2011;29(31):4189-4198.
7. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243.
8. Molassiotis A, Coventry PA, Stricker CT, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom Manage. 2007;34(2):148-159.
New Data in Emerging Treatment Options for Chemotherapy-Induced Nausea and Vomiting in Clinical Practice: General Discussion
Hope S. Rugo, MD: What is your experience in using olanzapine or other rescue medications?
Rudolph M. Navari, MD, PhD: I have done a lot of work with olanzapine. In a recent study, olanzapine (10 mg/day for 3 days) was compared with metoclopramide (10 mg 3 times/day for 3 days) for breakthrough CINV in patients receiving highly emetogenic chemotherapy; all patients received prophylactic aprepitant, palonosetron, and dexamethasone.1 For patients who developed breakthrough CINV, olanzapine was substantially more effective than metoclopramide. NCCN guidelines now recommend olanzapine as a first-line therapy in breakthrough CINV.2
Hope S. Rugo, MD: So your use of olanzapine is primarily for breakthrough CINV?
Rudolph M. Navari, MD, PhD: We have also included olanzapine in CINV prophylaxis for highly emetogenic chemotherapy, particularly in patients who may have done poorly on an aprepitant regimen. For these patients, switching to prophylactic olanzapine plus palonosetron and dexamethasone is quite effective in controlling nausea.
Hope S. Rugo, MD: We often see patients who cannot tolerate 5-HT3 antagonists because of headaches. For these patients, we tend to rely more on steroids, aprepitant, and other antiemetics. Might olanzapine have a role for those patients?
Rudolph M. Navari, MD, PhD: Our preventive studies have always used olanzapine in combination with a 5-HT3 antagonist. However, I have used olanzapine as a single agent for the treatment of chronic nausea with some success.
Hope S. Rugo, MD: It is important to mention that olanzapine is associated with sleepiness and other adverse effects to the central nervous system.
Rudolph M. Navari, MD, PhD: I agree that mentioning olanzapine-induced sedation is important. In most trials, olanzapine has been administered at 10 mg/day for 4 days in combination with dexamethasone. Olanzapine at 10 mg administered alone without dexamethasone may be associated with significant sedation; reducing the dose to 5 mg or 2.5 mg may be preferable.
Hope S. Rugo, MD: Why aren’t clinicians following CINV guidelines? In my practice, I have seen patients who are receiving fairly emetogenic regimens but are not receiving proper CINV support. I am uncertain of the reason; perhaps clinicians are hesitant to consult the guidelines for each regimen, they have a diverse patient population, or they use many different chemotherapy regimens.
Rudolph M. Navari, MD, PhD: I agree that the guidelines for prevention of emesis and nausea are not followed as much as we would like. I am unsure why; perhaps oncologists are focused on the disease and the chemotherapy, and they leave the antiemetics to their support staff, who may or may not follow the guidelines. Or they may work in an institution in which antiemetics are preprescribed based, at least partially, on cost. Each institution should evaluate the available guidelines and select which set they will follow, to ensure consistency in CINV prevention and management.
Hope S. Rugo, MD: I agree. The introduction of electronic health record systems that include electronic chemotherapy orders will likely help improve adherence to guidelines. Electronic orders will likely include guideline-oriented antiemetic regimens that can be selected by checking a box.
The new agents, such as aprepitant and palonosetron, have made a huge impact on patients with breast cancer receiving anthracycline-based regimens. How will newer drugs fit into CINV management?
Rudolph M. Navari, MD, PhD: I am not sure whether the new NK1 receptor antagonists rolapitant and netupitant will be any more efficacious than current approaches. Their toxicity profiles will likely be similar to existing agents. I predict that there will be 3 drugs in the NK1 receptor antagonist class, which will compete primarily on the basis of cost. When speaking with oncologists throughout the country about guidelines and individual antiemetic agents, I get the impression that decisions about antiemetic agents at their institution, whether a hospital or clinical practice, are highly influenced by cost. Therefore, pharmacy committees and formulary committees probably have substantial influence on which antiemetic agents are used.
Hope S. Rugo, MD: Yes, I agree. In order to be used in practice, newer antiemetic agents must have greater efficacy and an affordable price. There is also significant work trying to minimize the emetogenic potential of the regimens we are using. Our ability to control emesis so well has been a great improvement. Our ongoing task now is to control the lingering delayed nausea that can develop.
Eisai Inc. has provided research funding to Dr Rugo’s institution, the University of California, San Francisco. Dr Navari has no real or apparent conflicts of interest to report.
1. Navari RM, Nagy, CK, Gray SE. The use of olanzapine versus metoclopramide for the
treatment of breakthrough chemotherapy induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013; 21(6):1655-1663.
2. NCCN Guidelines: antiemesis. Version 1.2014. National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Updated August 19, 2013. Accessed February 3, 2014.
This activity has been designed for all oncologists, hematologists, and oncology nurses who treat cancer patients who receive chemotherapy.
Statement of Need/Program Overview
Most patients who receive chemotherapy will experience chemotherapy-induced nausea and vomiting (CINV). CINV can have an enormous impact on the course of cancer management and quality of life. Control of CINV must take into account multiple factors, including the chemotherapy agents being used, the dose and schedule of the agents, and patient characteristics. CINV prevention is the primary principle of emesis control, as outlined by the major antiemetic guidelines. These guidelines characterize chemotherapies according to emetogenic risk and adjust management approaches accordingly. Adherence to guidelines has been shown to improve control of emesis and nausea. Multiple effective antiemetic agents are available, such as the second-generation 5-hydroxytryptamine (5-HT3) antagonists ondansetron, granisetron, and palonosetron and the neurokinin-1 (NK1) receptor antagonists aprepitant and fosaprepitant. Nausea and vomiting should be considered distinct events. Newer antiemetic agents under study, such as the fixed-dose combination consisting of the novel NK1 antagonist netupitant and palonosetron (known as NEPA), show promise in clinical trials.
After completing this activity, the participant should be better able to:
• Identify patient-related and/or treatment-related factors that heighten the risk of developing CINV
• Manage the impact of CINV on general patient functioning
• Implement evidence-based treatment strategies to incorporate antiemetic agents as CINV prophylaxis for patients with cancer in clinical practice
• Discuss with patients and colleagues the efficacy and safety data of novel and emerging antiemetic agents to improve CINV outcomes for patients with cancer
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Millennium Medical Publishing, Inc. PIM is accredited by the ACCME to provide continuing medical education for physicians.
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure of Conflicts of Interest
PIM assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of continuing medical education (CME) activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest or a commercial interest.
The contributing speakers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Gary R. Morrow, PhD, MS—No real or apparent conflicts of interest to report.
Rudolph M. Navari, MD, PhD—No real or apparent conflicts of interest to report.
Hope S. Rugo—Eisai Inc. has provided research funding to the University of California, San Francisco.
The following PIM planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, RN, MSN, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Jacquelyn Matos: No real or apparent conflicts of interest to report. Mindy Tanzola, PhD: No real or apparent conflicts of interest to report.
Method of Participation
There are no fees for participating in and receiving CME credit for this activity. During the period March 2014 through March 31, 2015, participants must 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. You may also complete the post-test online at www.cmeuniversity. com. On the navigation menu, click on “Find Post-tests by Course” and search by project ID 9607. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.
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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM, Millennium Medical Publishing, Inc., and Eisai Inc., do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Millennium Medical Publishing, Inc., and Eisai Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.