Consultations. Perspectives on Improving the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (CINV)

Transcription

1 Oncology Consultations Perspectives on Improving the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (CINV) Developing Clinically and Economically Efficient Antiemetic Regimens A CME-Certified Activity Featuring Consultations With Mohammad Jahanzeb, MD Medical Oncologist Professor of Clinical Medicine, Hematology-Oncology Medical Director, Deerfield Beach Campus University of Miami Sylvester Comprehensive Cancer Center Deerfield Beach, FL Beverly Bell, MD Medical Director, Comprehensive Hematology Oncology Care Management inventiv Medical Management Augusta, GA Medical Writer: Elizabeth Cameron, PhD To participate in this activity online, go to

2 Oncology Consultations: Improving Outcomes in Chemotherapy-Induced Nausea and Vomiting (CINV) Developing Clinically and Economically Efficient Antiemetic Regimens Initial release date: March 25, 2013 Expiration date: March 25, 2014 Media Used: Print monograph with online posttest, evaluation, and request for credit Estimated time to complete this CME activity: 1 hour Copyright: Physicians Education Resource, LLC. Statement of Need Chemotherapy-induced nausea and vomiting (CINV) is a major side effect of many common chemotherapy regimens, and is often undertreated. CINV can adversely affect patients quality of life and may impair adherence to prescribed treatment regimens or even lead to withdrawal from potentially curative therapy. Expert guidelines on the prevention and management of CINV have recently been updated based on several new studies, and it is important for clinicians to remain current on the latest standards in order to further improve outcomes for their patients. Learning Objectives Review the recently updated clinical practice guidelines for CINV Identify the contributing factors that predispose patients to developing CINV Examine the managed care aspects of CINV Evaluate clinical data regarding the efficacy and safety of available agents and combination strategies for the prevention and/ or treatment of CINV Target Audience This educational activity is directed toward hematologists, medical oncologists, fellows, and other health care professionals involved in the treatment and management of patients with cancer. Accreditation and Designation of Credit Statements Physicians Education Resource, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physicians Education Resource, LLC, designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Commercial Support Acknowledgment This activity is supported by an educational grant from Eisai Inc. Faculty Mohammad Jahanzeb, MD Medical Oncologist Professor of Clinical Medicine, Hematology-Oncology Medical Director University of Miami Sylvester Comprehensive Cancer Center Deerfield Beach, FL Beverly Bell, MD Medical Director, Comprehensive Hematology Oncology Care Management inventiv Medical Management Augusta, GA The following individuals have no relevant financial relationships with commercial interests to disclose: Beverly Bell, MD; Elizabeth Cameron, PhD; Mohammad Jahanzeb, MD; and the PER Planning Staff (Alexis Mascitti, MD, and Emily Valko). Off-Label/Investigational Use Disclosure and Disclaimer This CME activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. For additional information about approved uses, including approved indications, contraindications, and warnings, participants are advised to consult prescribing information and appropriate resources for all products/devices discussed or consult the Physicians Desk Reference. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians Education Resource, LLC, or the company that provided commercial support for this CME activity. Method of Participation/How to Receive Credit 1. Read the monograph in its entirety. 2. Go to 3. Complete and submit the posttest, evaluation form, and request for credit. 4. Print your Certificate of Credit. This activity is provided free of charge to participants. Educational Partner Contact Information: For questions about this CME activity, please contact: Physicians Education Resource, LLC 666 Plainsboro Road, Ste 356 Plainsboro, NJ Phone: (888)

3 Oncology Consultations Improving Outcomes in Chemotherapy- Induced Nausea and Vomiting (CINV) Developing Clinically and Economically Efficient Antiemetic Regimens INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) are among the most common and debilitating side effects of cancer treatment. The significant improvement in CINV prevention with the approval of new agents has helped reduce its severity and incidence, such that the modern clinician may not recognize the importance or predict the potential difficulties of successful prophylactic treatment of symptoms. Despite advances, CINV can still pose a significant clinical challenge. Without effective prevention and control, CINV can result in metabolic imbalances, dehydration, esophageal tears/rupture, and nutritional deficiencies. 1,2 In addition, uncontrolled side effects interfere with the delivery of potentially life-saving treatment by causing dose reductions or delays in administration. 1 Controlling chemotherapy-induced emesis also facilitates decreasing the direct and indirect costs of managing cancer, 3 including the costs for the patient both psychologically and financially of not being capable of returning to work. Successful prevention and control of chemotherapy-induced emesis can also contribute to the overall quality of a patient s treatment experience, in turn supporting compliance and adherence, preventing premature withdrawal from or cessation of treatment, and preventing side effects that decrease cancer patients functional performance status and quality of life. 1,3 Question: In your experience, what are the challenges facing clinicians in effectively preventing and treating CINV? Dr. Mohammad Jahanzeb: Many factors can make effective treatment difficult. First and foremost are patient-based factors: those who are on highly emetogenic chemotherapy and/or very young patients. These can be challenging patients, especially if a clinician is not familiar with the available guidelines. Treating physicians also need to be cognizant of non-chemotherapy-related potential causes of nausea and vomiting in a patient such as brain metastases, an electrolyte imbalance, concomitant medications such as opiates, anticipatory CINV, etc. Dr. Beverly Bell: When I started my fellowship more than 30 years ago, there were not very many effective antiemetics, and the hematologyoncology clinics and hospitals were just miserable. When serotonin inhibitors became available, it was like a night and day shift; the introduction of effective antiemetics changed the sociology of the hematology-oncology clinics. Patients could now speak to and interact with each other, the fear factor decreased, and new support systems formed. However, challenges remain, such as the delayed vomiting that occurs with platinum agents. CLASSES OF ANTIEMETIC AGENTS Routine CINV prophylaxis generally involves 5-hydroxytryptamine type 3 ( ) receptor antagonists, NK1 receptor antagonists (Table 1), and/or the corticosteroid dexamethasone used as single agents or in combination. Dopamine agonists such as metoclopramide or prochlorperazine are also used, especially for breakthrough emesis. 1,4 Antiemetic medications are supportive agents, but they also have their own adverse-event potential, cautions, and contraindications. For example, the NK1 receptor antagonists, receptor antagonists, and dexamethasone all are inducers of and/or metabolized by cytochrome p450 enzymes, 5 so indirect drug-drug interactions with antineoplastics and other concomitant medications need to be considered. 1,5-8 Receptor Antagonists The receptor antagonists are selective inhibitors of a particular type of serotonin receptor known to be involved in the mechanism of nausea and vomiting. Serotonin acts through at least 15 different receptors located in the central nervous system and throughout the body. 9 Approximately 95% of serotonin in the human body is located in the gastrointestinal tract, involved in intestinal physical mobility and secretions, among other functions. 10 The first available receptor antagonists were dolasetron, granisetron, and ondansetron, and these agents are now available in multiple formulations: intravenous (IV), oral tablets, oral solution, and ondansetron is available as an oral rapidly disintegrating tablet, with granisetron available as a transdermal patch (Table 1). Oral formulations have been shown to be as effective as intravenous formulations, 1,11 but may differ in cost (Table 1). 4 These agents are generally considered equally effective at preventing CINV, particularly acute emesis, 1,11 but IV dolasetron is no longer recommended by National Comprehensive Cancer Network (NCCN) due to an association of IV (but not oral) dolasetron with an increased risk for cardiac arrhythmias. 1 The efficacy of receptor antagonists has a plateau in therapeutic efficacy (further dose escalations do not improve efficacy), but the efficacy of these agents is significantly improved when combined with glucocorticoids. 11 A second-generation receptor antagonist became available in 2003: palonosetron for intravenous use. 12 It has a higher affinity for the receptor than the first-generation agents, and has a significantly longer half-life 13,14 (Table 2). Similar to the first-generation receptor antagonists, palonosetron also has increased efficacy when administered with dexamethasone. 1 All receptor antagonists are metabolized by the cytochrome P450 system of enzymes (Table 2), and have reported electrocardiogram interval changes (QT prolongation). 1,12,15-18 The receptor antagonists are recommended by several agencies guidelines for the prophylactic treatment of acute and delayed CINV for chemotherapy with high emetogenic potential (HEC), including anthracyclines and cyclophosphamide (AC) combinations, and moderate emetogenic potential chemotherapy (MEC) 1,4,19 (see the Developing Guidelines section below). These agents are generally well tolerated, with constipation and headache the most common adverse events. 20 An additional formulation of granisetron, APF530, may be available in the near future. It uses a unique drug delivery technology that allows efficacy for 5 days after a single subcutaneous injection. 21 The drug company has resubmitted a New Drug Application to the FDA Oncology Consultations 3

4 Table 1. and NK1 Receptor Antagonists Class Drug Generic Company Brand Name Brand Company Cost per dose 4,a Total cost per HEC 3-day treatment cycle 4,b Serotonin ( ) antagonists Granisetron Oral Injection Transdermal Several Several Kytril c Kytril c Sancuso (Discontinued) (Discontinued) Prostrakan Inc Ondansetron ODT Oral solution Inj and with dextrose Several Several Several Zofran ODT Zofran Zofran GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Dolasetron Oral Injection d Anzemet Anzemet sanofi-aventis sanofi-aventis Palonosetron Injection Teva Pharma and Dr Reddys Labs c,e Aloxi Eisai Neurokinin 1 (NK1) receptor antagonists Aprepitant 125 mg oral 80 mg oral Sandoz Pharma c Emend Merck Fosaprepitant Powder for IV Emend Merck Inj=injection; =not available; ODT=oral disintegrating tablet; (x)=no longer available under this brand. a Drug prices determined by clear (non-shaded) boxes if both brand and generic available. Drug prices based on reimbursement rates from the Centers for Medicare & Medicaid Services as of the first quarter of 2011, computed at the manufacturer s average sales price plus 6%. Other treatment-related direct and indirect costs were not considered. Actual treatment costs and reimbursement will most likely vary considerably across regions, payers, institutions, and practices, as well as over time, and the reader should consult current local cost information specific to the specific environment. b Per ASCO guidelines. c Not available as of publication. d Intravenous dolasetron not included in NCCN guidelines due to an association with an increased risk for cardiac arrhythmias. 1 e Tentative approval by FDA. for review, and a Prescription Drug User Fee Act (PDUFA) action date of March 27, 2013 has been announced. 21 NK1 Receptor Antagonists Currently, only one NK1 receptor antagonist is available in the US, but it is available in two formulations: aprepitant and fosaprepitant, approved for use in the US in 2003 and ,8 Fosaprepitant is a parenteral water-soluble prodrug of the oral aprepitant, 7 and it is effective as a one-day treatment. 22 NK1 receptor antagonists are most effective when combined with a receptor antagonist and dexamethasone. 11 When a pooled analysis of patients on aprepitant with ondansetron and dexamethasone was compared with the same regimen without aprepitant, consistent efficacy was observed with the addition of aprepitant among various tumor types and HEC or MEC chemotherapies. 23 Di Maio et al 24 determined that approximately 20% of patients on HEC therapy are spared from emesis with the use of aprepitant, after comparing trials where it was reported that 48% to 57% of patients experienced vomiting or required rescue therapy in regimens without aprepitant compared with the 27% to 37% of patients reported when aprepitant was included. Similarly, the authors also determined that about 10% of patients on MEC therapy are spared from emesis and possible rescue therapy with the use of aprepitant, after comparing the 44% to 58% of patients reported with vomiting or requiring rescue therapy without aprepitant to the 31% to 49% of patients reported with aprepitant. 24 Aprepitant is a moderate CYP3A4 inhibitor, and its use requires a 50% dose reduction in dexamethasone dosages, and also affects the metabolism of warfarin and oral contraceptives, but does not clinically affect the dosages of antagonists. 5,7,8 Aprepitant and/or fosaprepitant are recommended by available guidelines for HEC and AC combinations, and some, but not all, guidelines include NK1 receptor antagonists as an option in patients on MEC 1,4,19 (see the Developing Guidelines section below). These agents are generally well tolerated, with fatigue or asthenia, hiccups, and dyspepsia the most common adverse events. 20 Two new oral NK1 receptor antagonists are in development, netupitant (in a fixed-dose combination with palonosetron) and rolapitant. 25 Netupitant-palonosetron capsules recently completed two phase III clinical trials, 26,27 and has a potential market launch in Rolapitant has also several phase III trials ongoing with an oral formulation, and results are expected in the second half of 2013, 32 with a potential market launch of this product in An intravenous formulation of rolapitant is also in clinical trials. 32 Another novel NK1 receptor antagonist, casopitant, was in development, and completed phase III clinical trials, but the pharmaceutical company withdrew the application for FDA approval after the FDA requested additional safety data that required further clinical trials. 19,33 Dopamine Agonists Dopamine agonists were historically the drugs of choice for CINV, but these agents have a lower therapeutic index than the receptor antagonists, NK1 receptor antagonists, and glucocorticoids for HEC or MEC. 11 They are currently generally recommended for use in patients intolerant or refractory to these agents in patients on HEC or MEC, or on an as-needed basis for patients with minimally emetogenic chemotherapy (MinEC). 1,4 Metoclopramide, a 5HT receptor at high doses, can be co-administered with diphenhydramine to prevent the development of extrapyramidal symptoms such as dystonic movements, irritability, agitation, or somnolence. 34 Metoclopramide comes in multiple dosage forms and has rapid onset of action (1-3 minutes after intravenous administration or minutes after oral administration 34 ). 35 Prochlorperazine is an antipsychotic which has multiple effects on neurotransmitter systems, and as such, has some contraindications, including patients with severe liver or renal dysfunction, Parkinson s disease, or hypothyroidism. It comes in oral, intravenous, and suppository formulations, and may cause drowsiness or lead to a mild leukopenia in patients if on a prolonged high dosage. 36 Antipsychotics Olanzapine, an antipsychotic with numerous mechanisms of action, including blocking dopamine, serotonin, catecholamines, acetylcholine, and histamine receptors, 37 has evidence of efficacy against em- 4 Oncology Consultations

5 esis similar to other agents, but has a potentially superior response to nausea Olanzapine is included in the current guidelines as an option for refractory and/or breakthrough CINV. 1,4,19 DEVELOPING GUIDELINES Question: Are guidelines useful and applicable to real-life practice? What are the roadblocks to following these guidelines encountered by clinicians? Dr. Jahanzeb: Guidelines are useful, but gaps exist. They can be challenging because the guidelines are more permissive than restrictive, with several options at every step. It is good in that we have all the options to work with, but the practitioner has no guidance on which option may be the best. In my experience, you see both extremes: low-risk chemotherapies accompanying big gun antiemetic regimens, and some high-risk chemotherapy regimens being undertreated. Systems or pathways may bundle chemotherapies with antiemetics, but the patient may not get the right match due to a lack of leeway (or incentive) in prescribing practices to tailor to the individual patient. In some institutions, the doctors only choose the chemotherapy regimen, and a nurse or pharmacist will add the antiemetics. It s difficult to quantify the occurrence of these issues at a population level, and part of the overall challenge is variation in practice. Dr. Bell: Guidelines are generalities. Though they are put together by some of the best authorities, they offer many options and are not specific. For practitioners not accustomed to using antiemetics, they are helpful. Medical institutions may have their own pathways, algorithms of antiemetic supportive care, and/or have prewritten/computerized orders based on the chemotherapies ordered. My role is to be an extension of the whole team: the patients, the providers, and the payers. Payers look at what chemotherapy the patient is receiving. From an audit perspective it s not always easy to evaluate the antiemetics, because, again, the guidelines are helpful but not very specific. Still, we have to ensure adequate supportive care, because once a patient starts vomiting, it is so difficult to stop. Evidence shows that with the proper use of antiemetics, emesis can be prevented in the majority of patients. Several organizations have guidelines for the management of CINV, including the NCCN, 1 the American Society of Clinical Oncology (ASCO), 4 and the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) joint guidelines 19,44 (Table 3), yet management of CINV continues to be a problem, and implementation of these guidelines is suboptimal. 45,46 It is generally recommended that the aggressiveness of treatment should correspond with the emetogenicity of chemotherapy agents used. This has resulted in the development of a grading system, with categories based on associated rates of CINV incidence. An agent is considered to be 1,47,48 : Table 2. Receptor Antagonists Receptor Antagonist T 1/2, h Cytochrome P450 Metabolism Dolasetron CYP2D6, CYP3A4 15 Granisetron CYP3A4, 18 CYP1A1 109 Ondansetron ,17 CYP1A2, CYP2D6, CYP3A4 16,17 Palonosetron ~40 12 CYP2D6 12 CYP=cytochrome P450; h=hours; T 1/2 =half-life. HEC if the incidence of CINV occurs in more than 90% of patients MEC if CINV is reported in 30% to 90% of patients Low emetogenic chemotherapy (LEC) if CINV is reported in 10% to 30% of patients MinEC if less than 10% of patients get CINV from the agent or regimen For example, cisplatin is an antineoplastic drug classically associated with acute and delayed emesis potential, and the current NCCN guidelines list all doses of cisplatin as HEC, 1 though previous versions divided the emetogenicity by the dose administered. 49 In the case of combination chemotherapy, the recommended treatment is based on the most emetogenic agent. 1,4 For example, the most appropriate antiemetics for patients on AC therapy are along the lines of the HEC (Table 3), even though each agent alone may be considered moderate risk. 4,19,49 Chemotherapeutic agents in combination may potentiate each other s emetogenicity 50 and are not always recognized by the current grading systems. 51,52 Furthermore, because of the design of the trials used to create the grading system, these categories describe acute emetogenicity that occurs within 24 hours of a single dose of the chemotherapy, 52 and therefore may be unable to accurately account for an agent s potential to cause nausea or delayed emetogenicity. Even the best guidelines can only help if patients are receiving care based on them. The reported adherence to antiemetic guidelines is low, with a meaningful amount of both overtreatment and undertreatment, compared with guideline recommendations reported. 45,46 The ASCO Quality Oncology Practice Initiative Programs of Excellence, which in 2012 performed institutional chart review of 12,621 charts at 289 institutions desiring to be recognized as a Program of Excellence, found that less than 70% of patients were receiving aprepitant with HEC. 53 Another study of US outpatient hospital facilities reported that aprepitant was used in approximately 5.1% of patients receiving HEC (n = 3069) and 0.9% of patients receiving MEC (n = 16,070) between 2003 and Current guidelines recommend NK1 receptor antagonists for 100% of patients on HEC and AC, 1,4,19 and ASCO and NCCN guidelines include aprepitant or fosaprepitant as an option for patients on MEC. 1,4 The reason for the underutilization of aprepitant may include unfamiliarity with the agent (first approved by the FDA on March 26, 2003) or the cost (especially considering it is an adjunct and not an alternative to antagonists). A generic version of aprepitant has been approved in the US, 55 and exclusivity for brand-name aprepitant expires on March 19, However, the pricing of the generic versus the branded formulation remains to be seen. According to reports evaluating the rate of guideline adherence for members of their respective institutions, prophylaxis of acute CINV was nonadherent to guidelines in 39% to 45% of patients. 45,46 For delayed CINV, treatment was nonadherent to guidelines in 54% to 89% of patients, 45,46 with a significant overuse of antagonists reported for prophylaxis of delayed CINV. 46 The odds for complete response, defined as no emesis and no use of rescue therapy, for both acute and delayed phases, were improved in the group following the guidelines. 45 The rates for health care visits were lower in the guideline-following cohort, with statistically more patients in the guideline-inconsistent group requiring additional emergency department (ED) and specialist visits in the 5 days after initiation of cycle 1 chemotherapy, but the number of hospital days was not statistically different between guideline-consistent and guidelineinconsistent cohorts. 45 Although guidelines are valuable tools, they generalize treatment options, and CINV may demand a patient-tailored management approach. 25,57 Guidelines are what work best for most patients. They are not necessarily the best for all patients undergoing all regimens, and a percentage of patients do not respond to established antiemetics/ antiemetic combinations despite consistency with guidelines. 51 Practitioners and institutions need effective strategies to further reduce CINV, especially in the delayed phase, to reduce health care Oncology Consultations 5

6 Table 3. Summary of Recommended Antiemetic Guidelines Emetogenic class and emetic potential NCCN 1 ASCO 4 MASCC/ESMO (international) 19,44 Acute CINV High Palo a + Dex + NK1 (±Lorazepam) + Dex + NK1 + Dex + Apr (±H 2 blocker or PPI) AC Palo a + Dex + NK1 (±Lorazepam) + Dex + NK1 + Dex + Apr c (±H 2 blocker or PPI) Moderate (no AC) Palo a + Dex (±NK1) Palo a + Dex (±NK1 b ) Palo + Dex (±Lorazepam PRN) (±H 2 blocker or PPI) High to moderate oral Granisetron or Ondansetron (±Lorazepam PRN) (±H 2 blocker or Classification not used, oral included with IV in High or Classification not used, oral included with IV in High or Moderate PPI) Moderate Low Dex or Metoclopramide or Dex Dex or or DRA Prochlorperazine (±Lorazepam PRN) (±H 2 blocker or PPI) Minimal No routine prophylaxis No routine prophylaxis No routine prophylaxis Low to minimal oral Delayed CINV High AC Moderate (no AC) High to moderate oral PRN Metoclopramide or PRN Prochlorperazine or PRN Haloperidol (±Lorazepam PRN) (±H 2 blocker or PPI) ( for consideration if Palo not used d1) + Dex + (Apr if Fos not used d1) (±Lorazepam) (±H 2 blocker or PPI) ( for consideration if Palo not used d1) + Dex + (Apr if Fos not used d1) (±Lorazepam) (±H 2 blocker or PPI) ( if Palo not used d1) or Dex or Apr ± Dex (if Apr used d1) (±Lorazepam PRN) (±H 2 blocker or PPI) Not reported after stop chemotherapy Classification not used, oral included with IV in Low or Minimal Dex + (Apr if Fos not used d1) Dex + (Apr if Fos not used d1) Dex Classification not used, oral included with IV in High or Moderate Classification not used, oral included with IV in Low or Minimal Dex + Apr Apr Dex Classification not used, oral included with IV in High or Moderate Low Metoclopramide or Prochlorperazine No routine prophylaxis No routine prophylaxis PRN Minimal No routine prophylaxis No routine prophylaxis No routine prophylaxis Low to minimal oral Granisetron or Ondansetron Classification not used, oral included with IV in Low or Minimal Classification not used, oral included with IV in Low or Minimal =serotonin receptor antagonists ( setrons ); AC= anthracycline and cyclophosphamide; Apr=aprepitant; Dex=dexamethasone; DRA=dopamine receptor antagonist; Fos=fosaprepitant; NK1=NK1 receptor antagonists (aprepitant or fosaprepitant); Palo=palonosetron; PPI=proton pump inhibitor; PRN=as needed. a If palonosetron is not available, use first-generation, though NCCN does not recommend IV dolasetron due to association with increased risk of cardiac arrhythmias. 1 b If use NK1 receptor antagonist, any is allowed. c If NK1 receptor antagonist is not available, palonosetron is preferred receptor antagonist. utilization and costs. 54 Any developed plans for effective CINV supportive care need frequent reevaluation, including careful consideration of agent efficacy and cost-effectiveness to limit the under- and overtreatment of patients in a practice setting, which can include the development of evidence-based pathways that are in line with established CINV guidelines. COST CONSIDERATIONS Dr. Jahanzeb: Many institutions also have their own pathways for clinicians to adhere to, which use evidence-based guidelines as a starting point, and then take pharmacoeconomics into consideration. Dr. Bell: We have to provide adequate supportive care because readmission for delayed vomiting can become very expensive and troublesome for all concerned. In managed care, we tend to be more concerned with whether the chemotherapy is appropriate, but we re now seeing more questions regarding antiemetics. With the next-generation antiemetics, which are very effective and more expensive, we may begin to question the shotgun approach of dexamethasone, palonosetron, aprepitant, ondansetron, and whether it would be more cost-effective to stratify the way the NCCN guidelines try to do. Most companies will pay for antiemetics. They generally cost less than chemotherapy, although 6 Oncology Consultations

7 the antiemetics can be expensive. The conundrum is how liberal or tightly should we control the antiemetic options? Again, once a patient starts vomiting, it is difficult to stop. We should be reviewing the whole treatment package more consistently, keeping an eye on the cost-effectiveness of this type of symptom control. We can also do claims reviews, we know what the patients are getting upfront, and be sure they are getting antiemetics. Finally, compliance and adherence need to be looked at, risks of recurrence and resistance should be evaluated, and we need to look at the appropriateness of treatment as regards both cost and effectiveness. Engaging the patient in understanding the value of emotional, clinical, and financial investment in antiemetics is critical to effectiveness. Ultimately, if the patient does not recognize and feel a benefit from any therapy, it is difficult to overcome nonadherence. An additional issue is that clinical trials are needed to further improve care, but individuals may be limited in enrollment due to costs and managed care stipulations. We have to do the trials to get the new agents to treat the diseases that are out there. We cannot and should not let patients suffer from CINV. CINV results in a high amount of health care resource utilization. The direct costs of CINV include the costs of the antiemetic regimens, as well as administration devices, time from nurses and physicians for additional care, and potentially extended hospitalization or readmission. 24 Indirect costs of CINV can include reduced productivity at work and/or workdays lost for both patients and caregivers. 24 The most frequently used health care resources for patients with uncontrolled CINV in one study were rescue medication, additional office visits, or outpatient hospital visits. 58 A report from Italy determined there was an 85% increase in overall costs when CINV is not well controlled, 59 and another from Australia found that 45% of unplanned presentations to the hospital for patients who had received chemotherapy in the previous 6 months were due to nausea and/or vomiting. 60 A recent US report found that 13.8% of patients who had received HEC or MEC required a CINVassociated hospital visit; 0.2% were due to acute CINV, and 13.7% were delayed CINV. 54 The hospital admissions associated with CINV were 64% inpatient (with a mean cost of over $7400), 26% outpatient (with a mean cost of just under $1500), and 10% ED visits (with a mean cost of over $900), with an overall mean hospital-reported cost of $5299 for a patient with CINV. 54 Another recent US report determined that CINV events in a hospital setting cost approximately $1850 per day. 61 Using data from before the nonclinical trial use of aprepitant and palonosetron, the cost of uncontrolled CINV was approximately $1300 higher per patient of working age than that of a patient of working age with controlled CINV, with this report having 28% of patients defined as uncontrolled. 62 As for the cost of antiemetics themselves, a recent market analysis estimated that the global CINV market for 2013 would be over 1.5 billion USD. 28 An Italian group compared the cost of antiemetics with the cost of commonly used chemotherapy in Italy from The authors determined that maximal guideline-following antiemetics for prophylaxis cost 2.3% to 13.2% of frequently used chemotherapy regimens docetaxel, doxorubicin, cyclophosphamide (TAC), cisplatin with pemetrexed, cisplatin with gemcitabine and bevacizumab, or cisplatin with capecitabine and bevacizumab; however, with older regimens such as fluorouracil with epirubicin and cyclophosphamide, the antiemetics were 42.5% to 82.8% the cost of the chemotherapy. 24 Other studies evaluated the cost-effectiveness of particular agents. antagonists were found to be cost-effective in studies published in the late 1990s from both the United States 63 and Canada. 64 An analysis of the cost-effectiveness of aprepitant performed in Belgium found the drug costs to be worth the improvement in quality of life and improvement in CINV treatment-associated costs. 65 Cost-effectiveness reports raise a number of vital questions 24 : How much is the health care system willing to pay to achieve a reduction in a distressing but time-limited side effect like CINV? How can we properly quantify the impact that CINV has on the physical and mental status of patients? What is the impact of these adverse events on the daily quality of life? How can all of the indirect costs (for the patient, the caregivers, the family, and society) deriving from the failure of antiemetics prophylaxis be adequately assessed and incorporated into a pharmacoeconomic model? PERSOLIZING TREATMENT Question: How can clinicians best personalize treatment for CINV? Dr. Jahanzeb: What I have found most productive for delayed CINV, which I see a fair amount of because I prescribe a lot of cisplatin and doxorubicin-based therapies, is to tailor and individualize the antiemetics to the patient; one size does not fit all. Dr. Bell: I do not know how well algorithms and guidelines work for this problem when these are being used in practice. They are so impersonal when the clinician may need individualized treatment options. This is a problem. We want to be efficient yet get treatment that works. Still, it requires some art to customize the regimen to prevent breakthrough or anticipatory CINV. Patients must be assured that this intolerable side effect of cancer and treatment will be controlled. Once CINV begins, it is generally more difficult to control; therefore, it is much easier to prevent nausea and/or vomiting than to treat it. 1 Although some health care practitioners and patients may believe that CINV is an indication that the chemotherapy is working, 66 this relationship has never been demonstrated, 52 and CINV should be prophylactically managed, if at all possible. Different factors may limit optimal antiemetic control regardless of the antiemetics the clinician prescribes. The 2011 ASCO guidelines suggest that it might be prudent for a clinician and patient to have a discussion about cost and its impact on treatment compliance and patient finances 4 to improve patient anxiety and treatment compliance. Clinicians may also need options for treatment choices if there is variability in renal or liver function, or if the patent has comorbidities (eg, preexisting arrhythmias or electrocardiogram abnormalities), in addition to financial and insurance considerations. 67 If patient compliance is believed to be a problem, switching to a single dose of fosaprepitant and palonosetron administered on the day of chemotherapy or use of the granisetron patch and/or the patient has a history of CINV (causing an inability to effectively administer oral medications) may help minimize CINV risk on multi-day aprepitant and/or a first-generation antagonist. Risk factors for CINV include patient characteristics such as age, gender, alcohol use, history of motion sickness and/or morning sickness, and behavioral characteristics that may be influenced by previous emesis with chemotherapy, anxiety, and expectations of chemoand antiemetic therapies. 68 An individual s genetic and molecular characteristics, such as cytochrome P450 expression levels or presence of a receptor mutation, have also been identified as risk factors for CINV, making an individual more or less likely to experience these symptoms. 51,68,69 Genetic polymorphisms have been reported for the cytochrome P450 metabolizing enzyme CYP2D6 that may be responsible for variation in responses to particular receptor antagonists between individual patients. Depending on their genotype, individuals can be characterized as extensive CYP2D6 metabolizers (the majority of the population), or poor, intermediate, or ultrarapid CYP2D6 metabolizers. 70,71 Ultrarapid metabolizers given ondansetron or tropisetron had a significantly greater number of acute and delayed emesis episodes than Oncology Consultations 7

8 non-ultrarapid metabolizers. 71 Some of these risks can be eliminated with newer agents. Studies seem to suggest that gender does not affect CINV incidence once aprepitant is added to a patient s regimen, 72 and palonosetron has minimal variation in metabolism between poor and extensive CYP2D6 metabolizers. 12 Even with the best antiemetics and following guidelines, 33% to 64% of patients still experience nausea. 42,73-75 The precise role of NK1 antagonists in nausea prevention is still unclear. One study presented in 2008 shows an improvement in nausea when aprepitant is in the prophylaxis regimen, 76 but there is still a significant amount of nausea despite aprepitant 3-drug regimens. 42 Part of the issue may be due to differences between what patients experience and what clinicians believe is occurring, both in incidence and severity, 77 a difference not nearly as vast with emesis. 78 This is probably due in part to the subjective nature of nausea and/or different reporting tools used to assess nausea, as well as a disconnect between the definition of nausea in different cultures. 79,80 Clinicians ruling out other things patients may interpret as nausea (eg, dyspepsia) is encouraged. 1,79 Although CINV is generally treated with antiemetics, nausea may be caused by different pathophysiologic mechanisms 1 that may not respond to antiemetic therapy, or one antiemetic may be more effective than another depending on the nausea s root cause. 68 ATOMY AND PATHOPHYSIOLOGY Dr. Bell: Right now we are treating symptoms, but there is still so much we do not understand about the process and the factors that influence nausea, so additional work can still be done. There has to be an objective approach to what we are doing with these agents in an area with so much subjectivity. Understanding the pathophysiology of emesis has helped develop effective antiemetic agents that have revolutionized CINV management. However, the mechanisms behind CINV are varied and complex, involving more than two dozen neurotransmitter and receptor sets involved in initiating symptoms and chronic persistence of CINV. 81 Vomiting was historically been postulated to be caused by a distinct location ( vomiting center ) in the medulla, 82 but is now believed to not be a center per se, but multiple connected neuronal areas in the medulla. 20,83 This area is stimulated by nerves from a chemoreceptor trigger zone (area postrema in the medulla), the pharynx and gastrointestinal tract, and cerebral cortex (sensory input, anxiety and memory). 1,83,84 These afferent pathways use particular neurotransmitters, and efferent pathways going to the nerves in end organs causing the vomiting utilize some similar and some distinct neurotransmitters from those used in the afferent pathways. The pathways include interactions involving serotonin and its receptor 5HT and substance P and its receptor neurokinin 1 (NK1) (Table 4). 83 Emesis is believed to involve 85 : 3 The brainstem vomiting center in the medulla which predominantly consists of substance P and NK1 receptors Gastrointestinal vagal afferent nerve fibers that have a predominance of serotonin and receptors, but also contain substance P and NK1 receptors The roles of these neurotransmitters have helped researchers better understand and target the mechanisms that underlie the different types of CINV. For example, serotonin seems to play the largest role during the initiation of symptoms and in the acute symptoms, while the role of substance P is thought to be a major factor in delayed CINV. 20,24,85-87 The biphasic curve of CINV (acute and delayed) is a relative description, and exactly where acute - dominant phase ends and delayed substance P-dominant phase begins remains unclear. 87 CINV CLASSIFICATIONS CINV is classified by the length of time it takes to occur after the administration of chemotherapy 1 : Acute nausea and/or vomiting occurs within minutes up to 24 hours, and generally peaks 5 to 6 hours after chemotherapy. Delayed nausea and/or vomiting occurs after 24 hours, and can persist for 5 to 7 days after chemotherapy. Anticipatory nausea and/or vomiting occurs before the administration of the chemotherapy and is thought to be a conditioned response occurring because of prior poor control of CINV. Breakthrough nausea and/or vomiting refers to nausea and vomiting that occurs despite antiemetic prophylaxis and requires rescue medication. Refractory nausea and/or vomiting is the term used when patients have had failure of antiemetic prophylaxis and/or required rescue medications in previous chemotherapy cycles, and have nausea and/or vomiting in subsequent cycles. Question: How does your approach to delayed-onset CINV differ from acute-onset symptoms? Dr. Jahanzeb: Of all the areas we have discussed, delayed-onset CINV is where more research would be the most beneficial. Additional research areas should include the effect of chronic oral therapy with respect to CINV, controlling nausea induced by opiates, and radiation-induced nausea. Clinicians can use NK1 receptor antagonists such as 3 days of aprepitant, or fosaprepitant on day 1 only for prevention of delayed CINV. Clinicians sometimes leave patients on 5HT3 receptor antagonists for several days, or use dexamethasone, which can lead to blood sugar fluctuations in diabetics or to other side effects like thrush. If the patient is left on dexamethasone for longer than a few days, it can cause other adverse events and patients will need to be tapered off. A granisetron patch has been introduced, but patients may remove it for various reasons. We still do not have the ideal solution that works for all patients. Dr. Bell: The NCCN Guidelines cite a Canadian meta-analysis that a 5HT3 antagonist (ie, ondansetron) on days 2 to 4 was not cost-effective for delayed emesis. However, when ondansetron was used alone, it did protect against delayed emesis in this meta-analysis. Delayed nausea and vomiting is difficult to stop. It also has social implications. Older patients in the hospital may not want to stay for extra days to receive the desired hydration required to flush out the platinums, even with ondansetron. Apart from experience with the patient and their chemotherapy, it is hard to predict who will have difficulty. The vomiting center and the individual patient response to chemotherapy or the antiemetics remains an enigma in many ways. Delayed CINV may go underappreciated because it occurs after patients leave observation of medical personnel. 52,53 The administration of prophylaxis for single-day chemotherapy occurs under medical supervision on day 1, but not on subsequent days when the patients are taking the prophylaxis at home. 53 One study from Singapore showed that 42.1% of patients were not adherent to delayed (day 2-4) antiemetic regimens. 88 Palonosetron has been shown to be more effective for delayed CINV than first-generation antagonists, potentially due to a long half-life, so it may be an option for a clinician when platinums and other agents known to cause delayed CINV are utilized, or alternatively, a granisetron patch (applied hours prior to chemotherapy, can be worn up to 7 days total). 93 Additional follow-up measures of a CINV check of a nausea and vomiting diary to share with the physician at the next visit, a phone call a few days after chemotherapy, or use of a reporting tool after the first dose of chemotherapy may provide a way to assess a need for changes for future delayed CINV prophylaxis. 52 A review of patientreporting CINV tools was published in The authors believe that none of the evaluated tools were optimal for clinical use, but 8 Oncology Consultations

9 Table 4. Neurotransmitters Involved in CINV a Neurotransmitter 81 Receptor known to be involved in CINV 83 Drug Class Agents Dopamine D 2 Dopamine receptor antagonists (phenothiazines, butyrophenones, dopamine 2 antagonists) propose the development of a new tool combining several of the aspects of existing tools. 94 CINV quantitation outside of the hospital or clinician s office could be a potential role for case management nurses, if one is available for a particular practice or institution. Another review for utilization of patient-reporting tools for nurses noted that different providers in specific clinical settings may find different tools to provide optimal care. 95 An observation from a clinician s own patients seems to be more effective than literature or expert lectures at changing practices and improving guideline adherence. 68,96 Question: Is there a specific population for whom effective prevention/treatment is particularly elusive? Dr. Jahanzeb: Younger patients can pose a challenge because they are more prone to anticipatory nausea and vomiting; in general, they can have more nausea, and they may be more sensitive to particular drugs. Another would be patients that are receiving highly emetogenic therapy, as they get delayed nausea and vomiting that can be tricky to manage. Dr. Bell: There are patients that are difficult to control and areas difficult to treat, including patients that are easily nauseated and/or people who vomit easily, idiosyncratic nausea or vomiting. Adolescents tend to vomit more. From personal experience, it is an elusive target. Poorly nourished and debilitated patients did worse, in my experience, but that is anecdotal. Patients with brain metastases, especially if having concomitant radiation therapy, tend to experience more CINV. Breakthrough CINV occurs when a patient experiences clinically significant CINV despite prophylaxis with an antiemetic(s). The NCCN guidelines recommend using agents for breakthrough CINV Metoclopramide b Prochlorperazine c Haloperidol Chlorpromazine Promethazine g-aminobutyric acid (GABA) GABA b Benzodiazepines Lorazepam Midazolam Serotonin (5HT) Serotonin ( ) receptor antagonists Granisetron Ondansetron Tropisetron Dolasetron Palonosetron Histamine H 1 Antihistamine Diphenhydramine d Meclizine Buclizine Dimenhydrinate Acetylcholine Muscarinic Anticholinergics Scopolamine Norepinephrine, epinephrine a 2 adrenergic Phenothiazines Prochlorperazine c Substance P Neurokinin 1 (NK1) NK1 receptor antagonists Aprepitant Fosaprepitant Unknown CB1, CB2 Cannabinoids Dronabinol Nabilone Unknown Unknown Corticosteroids Dexamethasone a List is not all-inclusive. b Metoclopramide is also a 5HT receptor antagonist at higher doses. c Phenothiazines are adrenergic and dopamine receptor antagonists with weak antihistamine and anticholinergic properties. d Not antiemetic, but often taken with metoclopramide for prevention of extrapyramidal symptoms. from a different drug class than that used for prophylaxis. 1 Due to CINV, the oral route may not be feasible, so nasal sprays, rectal preparations, or intravenous therapy can be used. 1 Dopamine agonists, benzodiazepines, cannabinoids, lorazepam, corticosteroids, olanzapine, and other agents can all be used to treat breakthrough CINV. 1,19,45,46,97,98 Question: How have newer classes of agents affected your practice? Dr. Jahanzeb: The 5HT3 receptor antagonists were a tremendous leap forward in antiemetic treatment, and then NK1 receptor antagonists were another huge leap forward. Newer chemotherapy and targeted agents and a shift to maintenance therapies may cause both more and less CINV. There are more oral therapies available so practitioners will shy away from highly emetogenic chemotherapy in metastatic disease, but in early stages we are still using agents like cisplatin for adjuvant therapy of lung cancer and anthracyclines for adjuvant therapy of breast cancer. There is not much research on oral agents for chronic use and the likelihood of CINV, but patients will report nausea on some of these agents. Dr. Bell: I hope that newer chemotherapy like the targeted chemotherapy agents will be less emetogenic, and many targeted agents are currently listed in the NCCN guidelines (eg, most included in the minimal to low category for oral targeted agents, and low or minimal for intravenous targeted agents). As far as antiemetics, I do not know yet where some of the newer agents such as NK1 antagonists are fitting in. I personally used to want to try any new drug; others will use a drug only if it has worked for them in the past, but the newer agents are starting to show some meaningful improvements over the older agents. I still don t see them widely used. One thing that is worrisome is that they are using them as complementary in the NCCN guidelines. We are not losing the old agents, just adding to them. We add more drugs to the patients already taking a lot of drugs, not replacing with more effective agents. We would prefer to cut down on the number of drugs a patient has to take, for compliance purposes, cost, and quality of life. Yet for the individual patient, we cannot quantify or put a dollar amount on adequately controlling symptoms. From an economic point of view, we are already starting to quantify cost-effectiveness. Fewer, more effective agents would be optimal for patients, clinicians, and payers. NONPHARMACOLOGIC AND ALTERTIVE TREATMENT Question: Are there any alternative therapies that you have seen be beneficial to your patients in CINV prevention/treatment besides pharmacotherapy? Oncology Consultations 9