Richard J. Gralla, MD Medical Director Quality of Life Research Associates New York, NY

Oncology Consultations Improving the Management of Chemotherapy-Induced Nausea and Vomiting (CINV) A CE-Certified Activity Featuring Consultations With Supported by an educational grant from Eisai. Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hours. RNs outside California must verify with their licensing agency for approval of this course. Richard J. Gralla, MD Medical Director Quality of Life Research Associates New York, NY Rebecca A. Clark-Snow, RN, BSN, OCN Oncology Clinical Nurse Coordinator University of Kansas Cancer Center Westwood, KS Medical Writer: Susan R. Peck, PhD A supplement to To participate in this activity online, go to www.cancerlearning.com/per/cinv12.

Oncology Consultations: Improving the Management of Chemotherapy- Induced Nausea and Vomiting (CINV) Initial release date: June 25, 2012 Expiration date: June 25, 2013 Media used: Print monograph with online posttest, evaluation, and request for credit Estimated time to complete this CME activity: 1 hour Copyright: 2012. 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 chemotherapy-induced nausea and vomiting (CINV) Discuss the contributing factors that predispose patients to developing CINV: personal risk factors, chemotherapy emetogenicity category 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 advanced practice nurses and registered nurses involved in the management of patients with cancer. Oncologists, hematologists, physician assistants, nurse practitioners, and other healthcare providers involved in the treatment of patients undergoing chemotherapy may also benefit from this activity. Accreditation and Designation of Credit Statements Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hours. RNs outside of California must verify with their licensing agency for approval of this activity. Commercial Support Acknowledgment This activity is supported by an educational grant from Eisai Inc. Faculty Richard J. Gralla, MD Medical Director Quality of Life Research Associates New York, NY Rebecca A. Clark-Snow, RN, BSN, OCN Oncology Clinical Nurse Coordinator University of Kansas Cancer Center Westwood, KS Disclosure of Relevant Financial Relationships The following individuals have relevant financial relationships with commercial interests to disclose: Richard J. Gralla, MD is a consultant for Merck & Co., Inc. and Helsinn Group. The following individuals have no relevant financial relationships with commercial interests to disclose: Rebecca Clark-Snow, RN, BSN, OCN; Emily Valko (PER staff); Susan R. Peck, PhD (medical writer); Erin Fletcher (Dannemiller staff). Off-Label/Investigational Use Disclosure This enduring activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the enduring activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Further, attendees/ participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this program. Method of Participation/How to Receive Credit 1. Read the monograph in its entirety. 2. Go to www.cancerlearning.com/per/cinv12 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 CE activity, please contact: Dannemiller 5711 Northwest Parkway San Antonio, TX 78249 Toll-Free: 800-328-2308 Fax: 210-641-8329

Oncology Consultations Improving the Management of CINV Case 1 - Presentation and Treatment A 64 year-old man presents with cough and weight loss of 3 kilograms. A computed tomography (CT) scan of the chest reveals a 1.9 cm 2 left upper lobe (LUL) mass, and some enlarged mediastinal lymph nodes. The rest of his workup is entirely negative (including normal 12-channel blood chemistries and complete blood count) with the exception of a positron emission tomography (PET) scan showing increased standardized uptake value (SUV) of 12.3 involving the LUL mass and 1 lymph node area in the mediastinum; all is consistent with the CT findings and with a primary lung cancer. The patient has a long smoking history (quit 6 weeks ago) and has moderate chronic obstructive pulmonary disease (COPD). Percutaneous needle biopsy of the lung lesion reveals squamous cell carcinoma. He is staged as having IIIA squamous cell carcinoma of the left lung. Past medical history additionally includes type 2 diabetes which is well controlled on an oral hypoglycemic drug. He generally consumes about 2 alcoholic drinks per day. His Karnofsky performance status (KPS) is 90%. While several options of therapy exist, his physicians recommend surgical resection. He undergoes video-assisted thoracoscopic surgery (VATS) with left upper lobectomy and mediastinal node dissection, and has complete resection of all known cancer. Final pathology stages the cancer as T1N2M0, Stage IIIA. He is advised to undergo adjuvant chemotherapy. The recommended regimen is vinorelbine 25 mg/m 2 on days 1 and 8 plus cisplatin 75 mg/m 2 on day 1. Cycles are planned for every 3 weeks for a total of 4 cycles. The following anti-emetic regimen is planned: Fosaprepitant 150 mg IV prior to chemotherapy on day 1, plus Palonosetron 0.25 mg IV prior to chemotherapy on day 1 His physician elects not to give dexamethasone due to the history of diabetes He is given a prescription for ondansetron 8 mg for use orally BID starting on day 2, for 3 days, and then as needed Question: How important is it to take a thorough patient history prior to initiating treatment with chemotherapy and an antiemetic regimen? Richard Gralla: First of all, the most important factor in planning for antiemetics is the chemotherapy that patients will be receiving. All the guideline groups agree on that, and the starting point of planning antiemetics is always based on type of chemotherapy. There are other factors that can influence the strategy as well, including medical issues, and known emetic risk factors. (See Tables 1 and 2 for classification of chemotherapy by emetic risk, and Table 3 for patient-specific risk factors.) Rebecca Clark-Snow: I agree with Dr Gralla, and from a nursing perspective, when we see patients in a clinical situation, whether they are new patients, or patients returning for another course of chemotherapy, we always update our patient profiles. In most cases new patients are given a document where they can write down their personal information, including past medical history, medications, surgeries, etc. As oncology nurses who see patients who will be treated with chemotherapy, we ll also probably ask about a past history of alcohol intake. If our patient is a female, we may ask what their obstetrical history is, if they ve had pregnancies, and if they ve had any difficulty with nausea or vomiting associated with those pregnancies. It is important to get a thorough history to see if any background information might possibly influence how they might respond to their treatment. Richard Gralla: It may not be that their past history alters the antiemetic recommendation, but it does tell us something about how well they re likely to do with that regimen, and also where the emetic priority should be among the many teaching messages that patients receive from their treating team. Regarding risk factors, older age and male gender tell you that somebody is at less risk, and if they have a chronic alcohol intake history especially 4 or more drinks per day they re also at less risk. You want to educate the person, but you don t have to harp on it because they re at pretty low risk if you re giving them the right antiemetics. On the other hand, when you get a younger woman with a low alcohol intake history, and for whom emesis during her pregnancies was a real issue, as in Case 2, we know that this person will hopefully do well with what we have, but their chances of having real issues are high up on our list. Question: What do evidence-based guidelines recommend regarding the use of antiemetic therapy for this patient with lung cancer? Richard Gralla: There is quite a bit of consensus among the 4 major evidence-based guideline groups (Multinational Association of Supportive Care in Cancer [MASCC], American Society of Clinical Oncology [ASCO], European Society for Medical Oncology [ESMO], and National Comprehensive Cancer Network [NCCN]). They re so similar because they are all based on the same data. Three of the groups are very strongly based on evidence, while the fourth group considers evidence strongly, but bases their recommendations on consensus. If practice groups have their own local guidelines, that s fine as long as they don t disagree with the evidence-based international guidelines. If they disagree, then the evidence must be presented as to why to vary from the international and national guidelines. (See Tables 4, 5, and 6 for highlights of the expert guidelines for the prevention of acute/delayed CINV.) Now, if we take Case 1, a patient getting initial cisplatin, an NK-1 receptor antagonist, and palonosetron were advised those are indeed consistent with all the guidelines. The problem here is that since the patient has diabetes, the physician has elected to avoid corticosteroids because the physician is aware that this will increase the patient s blood sugar. However, that is not consistent with any guideline. Instead, it can be argued that the person with diabetes is at important risk if they have emesis, meaning impact on how to control their anti-diabetes medicine if they can t take food or fluids, and it becomes a real problem. So most individuals advise the same regimen for the diabetic but enhanced training about monitoring their diabetes during their chemotherapy period. Rebecca Clark-Snow: This is a scenario that we see on a daily basis. Many patients do have diabetes and need to receive the most appropriate antiemetic regimen, in addition to carefully monitoring their chemistries. Oncology Consultations 3

[NCCN 2012] Table 1. Emetic Risk of Various Intravenous Chemotherapeutic Agents According to the NCCN Guidelines Emetic Risk Agents High ( >90%) AC combination (doxorubicin or epirubicin with cyclophosphamide) Carmustine (>250 mg/m 2 ) Cisplatin 50 mg/m 2 Cyclophosphamide >1500 mg/m 2 Dacarbazine Epirubicin >90 mg/m 2 Ifosfamide 10 g/m 2 Mechlorethamine Streptozocin Moderate (30%-90%) Aldesleukin >12-15 MIU/m 2 Amifostine >300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine 250 mg/m 2 Cisplatin <50 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Cytarabine >200 mg/m 2 Dactinomycin Daunorubicin Doxorubicin 60 mg/m 2 Epirubicin 90 mg/m 2 Idarubicin Ifosfamide <10 g/m 2 Interferon alfa >10 MIU/m 2 Irinotecan Melphalan Methotrexate 250 mg/m 2 Oxaliplatin Temozolomide Low (10%-30%) Amifostine 300 mg/m 2 Aldesleukin 12 MIU/m 2 Cabazitaxel Cytarabine (low dose) Docetaxel Doxorubicin (liposomal) Eribulin Etoposide 5-Fluorouracil Floxuridine Gemcitabine Interferon alfa (>5 and <10 MIU/m 2 ) Ixabepilone Methotrexate (>50 to <250 mg/m 2 ) Mitomycin Mitoxantrone Paclitaxel Paclitaxel albumin Pemetrexed Pentostatin Pralatrexate Romidepsin Thiotepa Topotecan Minimal (<10%) Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Chlorambucil (oral) Cladribine Cytarabine <100 mg/m 2 Decitabine Denileukin diftitox Dexrazoxane Fludarabine Interferon alfa ( 5 MIU/m 2 ) Ipilimumab Methotrexate <50 mg/m 2 Nelarabine Ofatumumab Panitumumab Pegaspargase Peginterferon Rituximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vinorelbine Patients are now able to do home monitoring, and let us know exactly how their diabetes is affected by receiving dexamethasone as part of their antiemetic regimen. In many cases, it s really not a problem for patients to receive a corticosteroid and have a diagnosis of diabetes as well, but it is always in the patient s best interest to continue close follow-ups. Richard Gralla: The physician and nurse need to decide on how the patient should alter their diabetic medicine during this period depending on what happens to the blood sugar, which might be different than what they would do 99% of the time, but in these 3 or 4 days might be pretty important. Rebecca Clark-Snow: I ll add that this is a good teaching moment between a nurse and a patient, to inform them that their glucose may be elevated while they re taking the corticosteroid, and not to be overly alarmed, that in most instances it s something that can be managed by their physician and nurse. Question: Do the guidelines indicate any preference regarding their recommendations for fosaprepitant versus aprepitant? Richard Gralla: In most instances the guidelines simply say an NK-1 antagonist, but ASCO updated their guidelines in 2011 to say that for highly emetic circumstances, such as this cisplatin case, they re equivalent. [Basch 2011] (See Sidebar 1. NK-1 Receptor Antagonists for the Prevention of Acute/Delayed CINV) So one can use fosaprepitant 150 mg IV, which is an elevated dose and is indicated for just 1 day, or one can use the 3-day oral aprepitant regimen if so desired. Those are interchangeable and equivalent, and ASCO states that very well. NCCN more or less says the same thing. [NCCN 2012] MASCC and ESMO are in the process of updating their guidelines to include fosaprepitant. Question: Are there differences in the guidelines regarding the use of the 5-HT 3 receptor antagonists? Richard Gralla: There are. All of the guideline groups recommend palonosetron as the preferred 5-HT 3, or serotonin type-3 receptor antagonist, for chemotherapies with a moderate emetic risk. (Boasch 2011; Roila 2010; NCCN 2012] Only NCCN has specifically recommended palonosetron for both high and moderate emetic risk chemotherapies. [NCCN 2012] The other guideline groups basically say it s your choice of a serotonin antagonist with highly emetic regimens. (See Sidebar 2. Comparative Efficacy of First and Second Generation Serotonin 5-HT3 Receptor Antagonists) Question: This patient also received a prescription for ondansetron for days 2 and 3. Is a follow-on 5-HT 3 antagonist generally recommended? Richard Gralla: This is probably the area where people in practice differ most from the guidelines. As a general rule, none of the guideline groups recommend follow-on 5-HT 3 antagonists of any sort for delayed emesis. The reason for that dates more than anything from a 2005 meta-analysis published in JCO that says that if you use a follow-on serotonin antagonist days 2 to 5, you only get a 2.6% boost if you re using corticosteroids as well, as the guidelines have recommended. [Geling 2005] So if you only get a 2.6% benefit, which was not statistically significant, then the guideline groups have said it s not worth it. Looking at ondansetron specifically, and also dolasetron, which is not used too much anymore, the FDA has asked for more studies with these agents regarding their effect on prolonging the QTc interval. ASCO mentions in their updated guidelines that the FDA has this under review and that physicians need to be aware of it. [Basch 2011] 4 Oncology Consultations

[NCCN 2012] Table 2. Emetic Risk of Various Oral Chemotherapeutic Agents According to the NCCN Guidelines Emetic Risk Moderate to High Minimal to Low Agents Altretamine Busulfan 4 mg/day Cyclophosphamide 100 mg/m 2 /day Estramustine Bexarotene Busulfan <4 mg/day Capecitabine Chlorambucil Cyclophosphamide <100 mg/m 2 /day Dasatinib Erlotinib Everolimus Fludarabine Gefitinib Hydroxyurea Imatinib Lapatinib Lenalidomide Etoposide Lomustine (single day) Procarbazine Temozolomide >75 mg/m 2 /day Melphalan Mercaptopurine Methotrexate Nilotinib Pazopanib Sorafenib Sunitinib Temozolomide 75 mg/m 2 /day Thalidomide Thioguanine Topotecan Tretinoin Vandetanib Vorinostat QTc prolongation is not really much of an issue with granisetron, and is not even in the label with palonosetron. Rebecca Clark-Snow: In most clinical situations when patients receive these medications, we don t routinely get electrocardiograms, and just as Dr Gralla mentioned, we have a long history of being able to use these medications safely, and we ll continue to do so. Table 3. Patient-Specific [NCCN 2012] Risk Factors for CINV Increased Risk Sex (Female) Age (<50 years old) History of motion sickness Previous episodes of nausea and vomiting Decreased Risk History of chronic alcoholism Richard Gralla: I think it s important to say that none of the serotonin antagonists are indicated as follow-on medicines for delayed emesis, and second, no oncologist that I know thinks that electrocardiograms are warranted for any of these agents you would have to have some other reason to order one. Another issue regarding ondansetron that I think nurses and physicians need to be aware of is that most hospital-based pharmacies pay very little for ondansetron. But when you send your patient out to the retail pharmacy, the charge is very high. So be aware of these issues because they have real impacts on your patients in terms of copay or in terms of running through whatever is covered for retail drugs. Question: How can nurses assist patients with recording their experiences at home? Rebecca Clark-Snow: This is a significant issue for nurses and patients. Nurses are so busy that we very rarely have an opportunity to follow up with patients after they ve left the clinic or call them for several days afterwards to see how they re doing. In most instances we rely on patients to provide that information by either calling us if they re having a problem, or when we see them for their return visit, we learn that in fact they ve had either a really good response or they ve had some issues with control. So I think it is important to give patients all of the information they will need in the form of patient teaching, but also to provide them with a tool if necessary. There is a very easy-to-use tool that s been developed by MAS- CC for nurses and physicians to administer to patients, who with proper instruction will be able to document the number of emetic episodes, as well as the degree of nausea they ve had while at home. The MASCC Antiemesis Tool (MAT) provides a format for patients beginning 24 hours after chemotherapy and continuing for 4 days after chemotherapy to keep track of just how well they did post treatment. Patients are encouraged to bring the completed MAT to their next clinic visit, and share this important information with their nurses and physicians, who can make changes if necessary to their antiemetic regimen for the next cycle of chemotherapy. Richard Gralla: Every doctor and nurse can get this on the web. It s a free download available at: http://www.mascc.org/mc/page.do?site PageId=88036 Not only is this something that can be printed out or given electronically to patients, but it s available in multiple languages including the most common languages in the United States and in Canada. And it also can be used as a continuous improvement project if a nursing group wants to do so. It even comes with the spreadsheet. One should also watch the MASCC website regarding the MAT because an app for this is likely to be available soon. Rebecca Clark-Snow: This tool has been validated and is reliable. Several individuals including physicians and nurses developed the MAT, hoping that it would provide useful information to assist with supportive care decisions. Question: Are there any other concerns or issues regarding Case 1 that you would like to mention? Richard Gralla: Regarding the NK-1 antagonists, the only 2 that are commercially available are aprepitant and its prodrug, fosaprepitant. Again, the recent study by Grunberg et al showed that the 1-day dose of 150 mg of fosaprepitant is equivalent to the 3-day regimen of aprepitant. [Grunberg 2011] There are also other investigational NK-1 antagonists. These include casopitant, where the research seems to have slowed down, and the drugs netupitant and rolapitant which are now in phase 3 trials. One other issue I d like to bring up on Case 1 is that this patient was treated with cisplatin, which is the preferred platinum drug in adjuvant therapies, although some controversy exists as to which platinum can be used in the treatment of patients with advanced disease. While meta-analyses favor cisplatin, sometimes doctors favor carboplatin. The question is, if you re going to use carboplatin, do you need to use 3 antiemetic agents or not? So far the guideline groups say that a 5-HT 3 antagonist and a corticosteroid are sufficient, but one must be aware of a recent randomized study by Rapoport et al that included 848 patients, which did show a similar advantage of approximately 8% to 13% absolute benefit with regard to complete control if one uses 3 drugs, even in carboplatin circumstances, although the guideline groups have not yet made this recommendation. [Rapoport 2010] Oncology Consultations 5

Case 2 Presentation and Treatment A 39-year-old woman presents with invasive ductal carcinoma after a screening mammogram detected a 1.3-cm abnormality. She has been remarkably healthy with no significant past medical problems. She is G2P2A0, with her first child born when she was 23 years of age. Her pregnancies proceeded to term without complications, with the exception of fairly marked emesis of pregnancy in both cases. She has no family history of breast cancer. She is a never smoker, rarely drinks any alcohol, and is not obese. The cancer was resected by lumpectomy; sentinel node sampling was negative. The tumor was ER+ / PR+ and HER 2. She recovered well from the surgical procedure without complications. Based on the above findings, her physicians recommended doxorubicin + cyclophosphamide (AC) with 4 cycles planned, followed by paclitaxel for 4 cycles as adjuvant chemotherapy, which the patient followed. The anti-emetic regimen recommended consisted of: ` Palonosetron 0.25 mg IV on day 1, plus 10 mg IV on day 1 (for acute emesis) She was also given a prescription for granisetron 1 mg PO to begin the night of chemotherapy and every 12 hours for 3 days (for delayed emesis prevention) Question: What is the emetogenic potential of an AC-based regimen for this patient? What are some concerns? Rebecca Clark-Snow: I believe it s well known, and most of the major oncology groups have noted, that AC is a highly emetogenic chemotherapy treatment for women with breast cancer, who need to receive the most appropriate antiemetic regimen, which would be the combination of an NK-1 antagonist, a serotonin antagonist, and a corticosteroid. Richard Gralla: This is a change over the past several years, but all major international guideline groups say that women treated with AC should be treated from the first cycle on with the triple therapy just outlined. ASCO and NCCN have classified AC-type chemotherapy, that is, chemotherapy based on an anthracycline and cyclophosphamide, as highly emetic. [Basch 2011; NCCN 2012] MASCC and ESMO recommend the same 3-drug treatment, but put it in a separate category called AC chemotherapy. [Roila 2010] All of the guidelines groups say first cycle, every cycle, one should prescribe the triple regimen. It s not something to wait and see on, and it s not an area where there s disagreement among the evidence-based guideline groups. Question: How would this patient s characteristics affect risk and how do you factor these in when deciding on a prophylactic strategy? Richard Gralla: This woman is really at quite high risk. She s relatively young. She is, of course, female. And she has a low alcohol intake history. And to make matters even more risky for her, she had emesis during both of her pregnancies. Because of that, all the monitoring and education that Rebecca discussed in the last case really need to be brought to bear on this patient. Question: What are the recommendations to prevent delayed emesis? Richard Gralla: The guidelines from all of the groups say that if you followed the proper day-1 recommendations you don t need to continue with the serotonin antagonist after day 1. Again, this is partially based on the meta-analysis that I quoted before and on individual clinical trials. Remember, while the serotonin antagonists are quite well tolerated, the headache and especially the constipation are still bothersome to patients. It s not that we don t know how to treat those issues, but with supportive care agents, we like not to have to support the supportive care agent whenever possible. Some recent trials, one by Aapro et al, looked at giving the steroids on day 1 but not giving follow-up steroids. And the control for the patient was very, very similar. [Aapro 2010] So for AC-type chemotherapy emerging literature may indicate that follow-on corticosteroids may end up being optional. Now while I agree with those findings, in this case before we have more evidence, with the very high personal characteristics of risk that this patient brings to the table, I probably would continue the corticosteroids. Sidebar 1 NK-1 Receptor Antagonists for the Prevention of Acute/Delayed CINV NK-1 receptor antagonists have been shown to reduce emesis triggered by a variety of stimuli by interfering with the action of Substance P, a regulatory peptide in the central nervous system and the gastrointestinal tract. The first NK-1 receptor antagonist developed was the oral drug aprepitant. Two randomized clinical studies compared adding aprepitant on a 3-day schedule with standard therapy (day 1, ondansetron + dexamethasone; days 2-4, dexamethasone) in patients receiving a cisplatinbased chemotherapy regimen. [Hesketh 2003; Poli-Bigelli 2003] The addition of aprepitant significantly improved emesis efficacy rates in both the acute and delayed phases compared with standard treatment. However, there was no significant improvement in nausea. In another study of 866 patients with breast cancer treated with an anthracycline plus cyclophosphamide, the addition of aprepitant to standard therapy (odansetron plus dexamethasone) significantly improved complete response rates (51% versus 42%, P =.015) and acute phase complete response rates (defined as no vomiting or use of rescue agents; 76% versus 69%, P =.034), but no difference was observed in the delayed phase. [Warr 2005] In addition, although significantly more patients in the aprepitant arm reported no vomiting (76% vs 59%; P <.001), no difference was observed in the use of rescue medication. Fosaprepitant is a prodrug of aprepitant, and is available as an intravenous formulation. In a randomized equivalency study that was conducted in 2322 patients receiving cisplatin-based chemotherapy a single intravenous dose of fosaprepitant demonstrated equivalent antiemetic protection compared with the standard 3-day oral aprepitant schedule. [Grunberg 2011] References 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(11):1495-1501. Hesketh PJ, Grunberg SM, Gralla RJ, et al; Aprepitant Protocol 052 Study Group. 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. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Aprepitant Protocol 054 Study Group. 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. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapyinduced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23(12):2822-2830. 6 Oncology Consultations

Table 4. Expert Guideline Recommendation Highlights for Managing Acute/Delayed CINV: High Emetic Risk Chemotherapy NCCN [NCCN 2012] ASCO [Basch 2011] [Roila 2010] MASCC/ESMO 3-Drug Regimen: NK-1 antagonist (aprepitant days 1-3 or fosaprepitant day 1 only) 5-HT 3 receptor antagonist Palonosetron is the preferred 5-HT3 receptor antagonist because of higher receptor affinity, longer half-life, and efficacy in preventing both acute and delayed emesis Lorazepam days 1-4 may also be considered Histamine 2 blocker or proton pump inhibitor may be beneficial in some cases to prevent dexamethasone-induced gastritis 3 Drug Regimen: NK-1 antagonist (aprepitant days 1-3 or fosaprepitant day 1 only) (days 1-3 or 1-4) 5-HT 3 receptor antagonist (day 1 only) Anthracycline plus cyclophosphamide-based chemotherapy now classified as highly emetogenic 3 Drug Regimen: NK-1 antagonist (aprepitant or fosaprepitant) 5-HT 3 receptor antagonist (single dose prior to chemotherapy) Regarding 5-HT 3 receptor antagonists, the panel noted: The lowest tested, fully effective dose should be used No schedule is better than a single dose given before chemotherapy Adverse events are comparable IV and oral formulations are equally effective and safe First-generation agents show comparable efficacy. Palonosetron has been shown to be more protective with regard to emesis, but studies are needed to demonstrate superiority when combined with an NK-1 receptor antagonist Table 5. Expert Guideline Recommendation Highlights for Managing Acute/Delayed CINV: Moderate Emetic Risk Chemotherapy NCCN [NCCN 2012] ASCO [Basch 2011] [Roila 2010] MASCC/ESMO Day 1 Regimen: 5-HT 3 receptor antagonist plus dexamethasone with or without an NK-1 antagonist Days 2 and 3, 1 of the following 3 regimens: 5-HT 3 antagonist (ondansetron, granisetron or dolasetron; palonosteron is not given on days 2-3) Aprepitant with or without dexamethasone Palonosetron is the preferred 5-HT 3 receptor antagonist because of higher receptor affinity, longer half-life, and efficacy in preventing both acute and delayed emesis 2-Drug Regimen: Palonosetron (day 1 only) (days 1-3) If palonosetron is unavailable, other first generation 5-HT 3 receptor antagonists may be substituted. Administration of dexamethasone or a 5-HT 3 receptor antagonist is recommended for delayed CINV For non-ac-based chemotherapy, a 2-drug regimen consisting of palonosetron plus dexamethasone is recommended. AC-based chemotherapy is recognized as a particularly potent emetogenic regimen, and prophylactic therapy with the 3-drug regimen recommended for high-emetic-risk chemotherapies should be used. If aprepitant is unavailable, palonosetron plus dexamethasone is recommended. Prophylactic therapy for delayed emesis should be used if the risk is significant: Multiday dexamethasone is recommended for non-ac chemotherapy when palonosetron is used for acute prophylaxis Aprepitant is recommended for patients with breast cancer receiving AC-based chemotherapy Table 6. Expert Guideline Recommendation Highlights for Managing Acute/Delayed CINV: Low or Minimal Emetic Risk Chemotherapy NCCN [NCCN 2012] ASCO [Basch 2011] [Roila 2010] MASCC/ESMO For low-emetic-risk chemotherapy, dexamethasone, metoclopramide or prochlorperazine are recommended No routine prophylaxis needed for minimal-emetic-risk; dexamethasone, metoclopramide or prochlorperazine may be used if CINV develops is suggested for low emetic risk chemotherapy No antiemetic is recommended for minimal-emetic-risk chemotherapy Single agent therapy is recommended when the emetic risk level is low (eg, dexamethasone, 5-HT 3 receptor antagonist, or dopamine receptor antagonist). However, level of evidence and confidence for this recommendation is low No prophylactic antiemetic therapy is recommended for chemotherapy with minimal emetic risk. Single-agent prophylaxis may be used for subsequent cycles if nausea and/or vomiting does occur Question: What would you do if this patient developed breakthrough or refractory nausea and vomiting? Rebecca Clark-Snow: The recommendation is to reevaluate the emetic risk, including the patient s disease status, if they have any concurrent illnesses, and take a good look at what medication she is receiving. It s possible that there may be another medication such as a narcotic that could be causing the patient to have nausea and vomiting aside from the chemotherapy. Then go through all the steps that we would normally go through as far as identifying the best antiemetic. After it s been determined that the best regimen is being given for the emetic risk, we can consider possibly adding some adjunctive medication such as lorazepam or alprazolam. One of the medications that some physicians are using, or considering using, is olanzapine. Or perhaps substitute high-dose intravenous metoclopramide instead of the serotonin antagonist or add a dopamine antagonist. So there are several different things that can be looked into, and reevaluated in order to make sure that this patient does have a better outcome as far as her control of nausea and vomiting is concerned. Richard Gralla: Of course, when I find out this patient didn t do well, I m very concerned. As Rebecca said, go back and find out if there is something else going on such as other medications, bronchodilators, other things that could be contributing. What was the pattern of emesis? Was it not typical for the chemotherapy? If the patient had ovarian cancer instead, could there be an intestinal obstruction, or something else going on? Also look not only at what medications were recommended, but what did she actually take? Often when patients do well on day 1, they ll say they just didn t want to take any more medicines, and who Oncology Consultations 7

Sidebar 2. Comparative Efficacy of First and Second Generation Serotonin 5-HT 3 Receptor Antagonists There are currently four 5-HT 3 antagonists available in the United States. The firstgeneration antagonists (ie, dolasetron, granisetron, and ondansetron) exhibit similar efficacy, while the newer agent palonosetron has shown an increased ability to control increased CINV symptoms. [Roila 2010; Basch 2011, NCCN 2012] Headache is the most common adverse event observed with all agents. Palonosetron has been compared with the first-generation 5-HT 3 receptor antagonists in several randomized trials. In 1 study, palonosetron (0.25 mg or 0.75 mg intravenously) was compared with dolasetron (100 mg intravenously) in 569 patients receiving moderately emetogenic chemotherapy. [Eisenberg 2003] Overall complete response rates were significantly higher for both doses of palonosetron (0.25 mg: 46%, P =.021; 0.75 mg: 47%, P =.012) compared with dolasetron (34%). Delayed complete response rates were also significantly higher with both doses of palonosteron, but only the 0.25 mg dose was superior in the acute phase. A second randomized trial compared ondansetron (32 mg) to palonosetron at the same 2 doses in patients receiving moderately emetogenic chemotherapy. [Gralla 2003] In this trial, the complete response rate (no emetic episode and no rescue medication) was superior with palonosetron at the 0.25 mg dose (69%, P <.001), but not the 0.75 mg dose (59%, P =.1192), compared with ondansetron (50%). Palonosteron (0.25 mg and 0.75 mg) has also been compared with ondansetron (32 mg) in patients receiving highly emetogenic chemotherapy. [Aapro 2006] Two-thirds of the 667 patients in this study received concomitant dexamethasone. Overall, acute and delayed complete response rates were statistically equivalent between palonosetron and ondansetron treatment arms in the intent to treat analysis. In the subgroup of patients who also received dexamethasone, however, complete response rates were significantly higher with palonosetron compared with ondansetron overall (41% vs 25%; P =.005). Palonosteron was also superior in the delayed phase (42% vs 29%; P =.021). Finally, palonosetron (0.75 mg) plus dexamethasone was compared with granisetron (40 mcg/kg) plus dexamethasone in 1143 Japanese patients undergoing treatment with highly emetogenic chemotherapy (cisplatin or anthracycline/ cyclophosphamide). [Saito 2009] During the acute phase, the complete response rate was similar between arms (75% for palonosetron versus 73% for granisetron), but palonosteron significantly improved rates during the delayed phase (57% vs 44.5%; P <.0001). References 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. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189-4198. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapyinduced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, singledose trial versus dolasetron. Cancer. 2003;98(11):2473-2482. 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. NCCN Clinical Practice Guidelines inoncology: Antiemesis. V1.2012. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/pdf/ antiemesis.pdf. Accessed May 9, 2012. 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. 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. can blame them? But nonetheless the preventive role of the delayed emesis medications is so important. So did the patient really take what we had advised and did we communicate well what they should have been taking? Now, once all those situations are true, but the patient still has emesis, then there are some other considerations. Many people like to use benzodiazepines even in cycle 1 because they reduce anxiety. They re not really antiemetics, but they are adjuncts as part of supportive care. And this patient is at risk if she didn t do well in the first cycle of developing anticipatory emesis. The MASCC website is an excellent source of publications that are free downloads for each of these situations including anticipatory emesis. I don t recommend changing antiemetics entirely, but looking in to proper alterations. You want to know how much emesis she had. One episode? Two? Three? Because if she were not getting antiemetics at all, or if the antiemetics weren t helping at all, the average number of episodes would be 10 to 15. So we don t want to necessarily throw out the lessthan-perfect regimen if we are not certain as to how to improve upon it. There are investigative studies ongoing using the anti-psychotic drug olanzapine, as mentioned by Rebecca Clark-Snow, which are worth our attention to see whether they can be additive agents, but of course this is still in the investigative stage even though the drug is generically available. And then there are small steps. I don t treat such patients if they have problems on Thursdays or Friday. Patients with problems on the prior chemotherapy cycles are those that are particularly called the next day by our oncology nurses. There s a recent prospective observational study called the PEER (Pan European Emesis Registry) Study that indicates that if patients follow guidelines, they do significantly better and they have less of a need for an urgent care visit. [Aapro 2012]. This benefit in better contolled emesis also extended to better control of nausea as well, in those patients who received antiemetics consistent with evidence-based guidelines. References Aapro M, Fabi A, Nolè F, et al. Double-blind, randomised, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy. Ann Oncol. 2010;21(5):1083-1088. 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) [published online ahead of print March 6 2012]. Ann Oncol [abstract]. 2012. http://annonc.oxfordjournals.org/content/early/2012/03/06/annonc.mds021.abstract. Accessed May 9, 2012. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189-4198. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol. 2005;23(6):1289-1294. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapyinduced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--ease. J Clin Oncol. 2011;29(11):1495-1501. NCCN Clinical Practice Guidelines inoncology: Antiemesis. V1.2012. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed May 9, 2012. Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer. 2010;18(4):423-431. 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 Oncology Consultations 2012. Physicians Education Resource, LLC.