New Directions in the Management of Chemotherapy-Induced Nausea and Vomiting David S. Ettinger, MD Alex Grass Professor of Oncology Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Disclosure of Conflicts of Interest David S. Ettinger, MD, discloses that he has served as an advisor/consultant for Gilead, Roche/Genentech, Boehringer Ingelheim, Biodesix, Lilly, and Helsinn Therapeutics.

Learning Objectives Describe the pathophysiology of chemotherapy-induced nausea and vomiting (CINV) Assess the risk for nausea and vomiting in cancer patients scheduled to receive chemotherapy Differentiate antiemetic strategies for delayed, breakthrough, and refractory nausea and vomiting

Physiology of CINV Wickham, 2012.

Neurotransmitters in Emesis This slide depicts some of the neurotransmitters involved in vomiting: dopamine, acetylcholine, histamine, opiates, substance P, and serotonin. The influence of these neurotransmitters on emetic response varies in relative importance. The role of dopamine in vomiting is limited; for example, some drugs that induce vomiting show little, if any, response to dopamine antagonists. In addition, the precise roles of histamine and acetylcholine in vomiting are unclear. Drugs that target opiate receptors have been shown to prevent vomiting in laboratory animals, but have not been proven to be effective in humans. Two other important neurotransmitters implicated in vomiting are serotonin and substance P. These neurotransmitters are explained further on the following slides. Hesketh et al, 2003; Wickham, 2012.

Serotonin and the 5-HT3 Receptor Pathway Pathway first recognized with high-dose metoclopramide Introduction of 5-hydroxytryptamine (5-HT3) receptor antagonists offered an improved treatment option Effective in acute vomiting; variable efficacy for delayed events Primary mechanism of action appears to be peripheral The role of serotonin antagonism was first recognized with high-dose metoclopramide. Unlike other dopamine receptor antagonists, metoclopramide showed efficacy against cisplatin-induced emesis, which led to research into pharmacologic effects other than dopamine antagonism. The discovery of highly selective 5-HT3 receptors and our improved understanding of serotonin has had many positive, long-term effects. The development of selective 5-HT3 receptor antagonists offered an improved treatment option for CINV. In addition, their discovery has fueled further interest in continued research regarding emetic pathways. Clinical studies have shown that a regimen containing a 5-HT3 receptor antagonist is highly effective in preventing acute vomiting, but demonstrates variable efficacy for delayed events. On the basis of the vast accumulated literature to date, the primary mechanism of action for 5-HT3 receptor antagonists is thought to be a blockade of 5-HT3 receptor activation mediated by serotonin release in the gut. Miner & Sanger, 1986; Andrews et al, 1998; Hesketh et al, 2003; Wickham, 2012.

Substance P and the NK1 Receptor Pathway Substance P relays noxious sensory information to the brain (ie, modulates nociception) High density of substance P/neurokinin-1 (NK1) receptors located in brain regions is implicated in the emetic reflex Primary mechanism of NK1 receptor blockade action appears to be central Effective for both acute and delayed events Augments antiemetic activity of a 5-HT3 receptor antagonist and a corticosteroid The discovery of substance P was first reported in 1931. Some 70 years later, we now understand that this neurotransmitter plays an integral role in relaying noxious sensory information to the brain. As a modulator of nociception, it is involved in several physiologic activities, including the vomiting reflex. Substance P, which belongs to the group of peptides known as neurokinins, exerts its effect by binding to the NK1 receptor. High concentrations of substance P/NK1 receptors are located in brain regions implicated in the emetic reflex, such as the nucleus tractus solitarius and area postrema. Unlike 5-HT3 receptor antagonists, which work primarily at a peripheral site, the primary mechanism of NK1 receptor antagonists appears to be central. Interesting preclinical research by Tattersall and colleagues (1996) demonstrated that for an NK1 receptor antagonist to provide antiemetic efficacy, an NK1 compound needs to enter the central nervous system. In addition, animal and human studies show that NK1 receptor antagonists inhibit both acute and delayed emetic events. Several clinical trials have demonstrated that the most effective use of an NK1 receptor antagonist is with a 5-HT3 receptor antagonist and a corticosteroid. DeVane, 2001; Hargreaves, 2002; Hesketh et al, 2003; Hesketh, 2001; Tattersall et al, 1996; Wickham, 2012.

Side Effects Most Distressing to Patients Receiving Emetogenic Chemotherapy Identical surveys conducted before and after the availability of 5-HT3 antagonists showed little change in patient perceptions 1983 1995 Rank Symptoms 1 Vomiting Nausea 2 Loss of hair 3 de Boer-Dennert et al, 1997.

Classification of CINV Acute Occurs and resolves within 24 hours of chemotherapy Generally peaks within 5 to 6 hours Delayed Occurs 1 to 6 days after chemotherapy Common with administration of cisplatin, carboplatin, cyclophosphamide, and doxorubicin Breakthrough Occurs despite prophylactic treatment Requires rescue therapy Can be acute or delayed Refractory Occurs during chemotherapy cycle after prophylaxis and/or rescue therapy has failed in earlier cycles National Comprehensive Cancer Network (NCCN), 2014.

Characterizing Nausea Less understood at neurochemical level than vomiting Results of direct treatment not as effective as treating vomiting Impact of nausea on quality of life (QOL) often overlooked Grunberg, 2012.

Characterizing Nausea (cont.) Vomiting an objective event Nausea a subjective symptom Nausea commonly suffered in silence (difficult to grade) Grunberg, 2012.

Impact of Nausea on QOL Nausea has more of a deleterious effect on QOL and sense of well-being than emesis Patients rate severe nausea worse for QOL than vomiting with or without nausea Börjeson et al, 2002; Bloechl-Daum et al, 2006; Sun et al, 2005; Grunberg, 2012.

The Importance of Treating Nausea Nausea duration may result in even greater distress and altered QOL than severity of nausea Reduction of nausea rather than emesis has been shown to guide patient preference in antiemetic treatment Grunberg, 2012.

CINV Risk Factors Treatment-related risk factors High emetogenicity of chemotherapy drugs High drug dose Patient-related risk factors Younger age Female gender No/minimal history of alcohol use Susceptibility to motion sickness Poor control with prior chemotherapy Anxiety NCCN, 2014.

CINV Risk Factors (cont.) Medical procedures such as surgery and radiation Medications such as digitalis derivatives, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antibiotics Uremia Hypercalcemia Hepatic dysfunction Increased intracranial pressure Gastrointestinal abnormalities: obstruction, ascites, hepatomegaly, paraneoplastic syndrome, gastroparesis, gastric outlet syndrome NCCN, 2014.

Highly Emetogenic Chemotherapy Prevalence of CINV: Highly Emetogenic Chemotherapy (HEC) Before the advent of NK1 receptor antagonists, the standard of care for prevention of CINV included a combination of a 5-HT3 receptor antagonist and a corticosteroid. However, despite treatment with these agents, clinical trials showed that patients still experienced CINV. For patients receiving highly emetogenic chemotherapy, data were analyzed from a multicenter, randomized, double-blind, controlled trial involving chemotherapy-naive patients (N = 521) receiving a chemotherapy regimen that included cisplatin ≥70 mg/m2. The primary end point was complete response (defined as no emetic episodes and no use of rescue therapy). Results from this study show that 48% of patients experienced CINV even after prophylaxis with ondansetron 32 mg IV and dexamethasone 20 mg PO on Day 1 and dexamethasone 8 mg PO bid on Days 2 through 4. These data suggest the need for better risk assessment and treatment of CINV associated with highly emetogenic chemotherapy. Warr et al, 2005; Hesketh et al, 2003.

Incidence of CINV with Common HEC Regimens The incidence of CINV with many of the most frequently used HEC regimens today remains quite high. This table shows the incidence of vomiting and nausea reported in trials of key HEC regimens in breast, lung, and ovarian cancers. The incidence of vomiting observed in the commonly used AC (doxorubicin + cyclophosphamide) regimen was 42%, with a reported incidence of nausea of 82%. The incidence of CINV with the pemetrexed + cisplatin regimen in lung cancer patients was 86%, with a similar proportion (82-91%) reporting CINV with regimens commonly used in ovarian cancer patients. The level of CINV reported in controlled clinical trials of commonly used HEC regimens indicates a high and unacceptable prevalence in clinical practice. Steps should be taken to minimize this difficult side effect in patients. Jones et al, 2006; Neijt et al, 2000; Piccart et al, 2003; Manegold et al, 2000.

CINV: Predictability and Preventability CINV is a common, often predictable, and often preventable adverse reaction to chemotherapy Consider using preventive measures for CINV with cycle 1 of chemotherapy CINV negatively affects patients’ overall chemotherapy experience Preventing CINV on first exposure to chemotherapy can reduce the risk for developing anticipatory CINV in subsequent cycles As Lau and colleagues (2004) have reported, CINV is a common, often predictable, and often preventable adverse reaction to chemotherapy. Yet CINV remains a common adverse drug reaction. To prevent this high incidence of CINV, American Society of Clinical Oncology guidelines suggest that preventive measures for CINV must be used with cycle 1 of chemotherapy, rather than waiting to assess patients’ emetic response to chemotherapy. Osoba and colleagues (1997) reported that CINV negatively affects patients’ overall chemotherapy experience. In addition, Aapro and colleagues (2005) concluded that preventing nausea and vomiting on first exposure to chemotherapy can reduce the risk of anticipatory CINV in subsequent cycles. Lau et al, 2004; Basch et al, 2011; Osoba, Zee, Warr, et al, 1997; Aapro et al, 2005; Fernández-Ortega et al, 2012.

Risk Factors for CINV: Chemotherapy-Specific Use of emetogenic regimens such as: AC (anthracycline + cyclophosphamide) Carboplatin-based regimens Cisplatin-based regimens Cyclophosphamide-based regimens FOLFOX/FOLFIRI (oxaliplatin + leucovorin + 5-fluorouracil/irinotecan + leucovorin + 5-fluorouracil) ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) Short IV infusion time Repeated cycles of chemotherapy NCCN, 2014a; Basch et al, 2011.

Cisplatin: Prototypical Highly Emetogenic Chemotherapy Cisplatin is the cornerstone of therapy for many cancers Risk of emesis is universal Agent causes emesis in all patients (there is >99% risk without antiemetics) Well-characterized emetogenic profile serves as a model for antiemetic testing Efficacy shown with cisplatin is predictive of antiemetic efficacy with other chemotherapy drugs Cisplatin is prototypical of highly emetogenic chemotherapy. Although other factors can increase emetogenic risk, the risk of emesis with cisplatin is universal. Research indicated a >99% risk of emesis with cisplatin when antiemetics are not used. As a result of numerous well-conducted trials involving cisplatin, its emetogenic profile is well characterized and serves as a model for antiemetic testing. Antiemetic efficacy demonstrated with cisplatin is predictive of the antiemetic efficacy of other chemotherapy drugs. Basch et al, 2011.

Cisplatin: Biphasic Pattern of CINV The chronology and intensity of CINV seen with cisplatin have been well characterized. Traditionally, the pattern of CINV with cisplatin, as shown in this graph, displays an initial peak in intensity within the first 24 hours after administration, followed by a second, more prolonged phase of lesser intensity occurring during Days 2 through 5. However, acute phase CINV has been arbitrarily defined as occurring within the first 24 hours after chemotherapy. Closer examination of the data demonstrates that maximal emetic intensity actually is seen within 6 to 8 hours after chemotherapy. This corresponds with data from Wilder-Smith and colleagues (1993), who observed a peak of urinary serotonin metabolite excretion at 6 hours after chemotherapy, with levels returning to baseline by 16 hours. Maximal emetic intensity seen within 24 hours post dose Distinct second phase occurs during Days 2–5 post chemotherapy Tavorath & Hesketh, 1996; Wilder-Smith et al, 1993.

Comparison of Biphasic and Monophasic Patterns of Emesis This slide depicts the difference in patterns of emesis between cisplatin and cyclophosphamide or carboplatin, all commonly prescribed chemotherapeutic agents. By observing a side-by-side comparison of the incidence of acute nausea and vomiting following the administration of such agents, the difference in patterns of emetogenicity can easily be seen. Two distinct patterns of emesis have been observed for these cancer chemotherapy agents. The biphasic pattern of emesis is represented by cisplatin, with an early initial peak in the acute phase that is intense with severe vomiting episodes followed by remission, and then a second, more prolonged peak in the delayed phase that is less intense in the severity of vomiting episodes. The monophasic pattern is represented by cyclophosphamide and carboplatin, with the onset of acute emesis usually occurring in the early-to-mid acute phase, with continuing emesis into the delayed phase. Martin, 1996.

Considerations While Selecting the Right Initial Antiemetic Emetogenicity of chemotherapeutic regimen Side-effect profile of antiemetic(s) Other symptoms Cost Ease of administration

High Emetogenic Potential of Selected Antineoplastic Agents Drugs with >90% emetic risk: Cisplatin Dacarbazine Streptozocin Cyclophosphamide ≥1,500 mg/m2 Ifosfamide ≥2 g/m2 per dose Doxorubicin ≥60 mg/m2 Adriamycin cyclophosphamide (AC) combination defined as either doxorubicin or epirubicin with cyclophosphamide NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Moderate Emetogenic Potential of Selected Antineoplastic Agents Drugs with 30–90% emetic risk: Oxaliplatin Cyclophosphamide ≤1500 mg/m2 Carboplatin Ifosfamide <2 g/m2 per dose Irinotecan Cytarabine >200 mg/m2 Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) Methotrexate ≥250 mg/m2 NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Low Emetogenic Potential of Selected Antineoplastic Agents Drugs with 10–30% emetic risk: Cytarabine (low dose) Gemcitabine Topotecan Paclitaxel Docetaxel Pemetrexed NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Minimal Emetogenic Potential of Selected Antineoplastic Agents Drugs with <10% emetic risk: Vincristine Vinblastine Vinorelbine Fludarabine Bleomycin Rituximab Bevacizumab Trastuzumab Cetuximab NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Antiemetics Used in CINV Management Anticholinergics: scopolamine transdermal patch Antihistamines: diphenhydramine Barbiturates: pentobarbital, secobarbital Benzodiazepines: lorazepam Butyrophenones: droperidol, haloperidol Cannabinoids: dronabinol, nabilone Phenothiazines: prochlorperazine, chlorpromazine, promethazine Atypical antipsychotics: olanzapine NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Antiemetics Used in CINV Management (cont.) NK1 inhibitors: aprepitant, fosaprepitant Serotonin antagonists: ondansetron, granisetron, dolasetron mesylate, palonosetron Steroids: dexamethasone, methylprednisolone Substituted benzamines: metoclopramide NCCN, 2014; Basch et al, 2011; Roila et al, 2010.

Potential Side Effects of Antiemetics Anticholinergics: dry mouth, drowsiness, blurred vision, disorientation, restlessness, confusion Antihistamines: drowsiness, restlessness (eg, restless legs), confusion, dizziness, blurred vision/diplopia, tinnitus, dry mouth/nose/throat, urinary retention, frequency, rash, hypotension, palpitations Wickham, 2012.

Potential Side Effects of Antiemetics (cont.) Barbiturates: drowsiness, lethargy, hangover, respiratory depression, Stevens-Johnson syndrome, angioedema Benzodiazepines: drowsiness, sedation, disorientation Butyrophenones: restlessness, sedation, extrapyramidal reactions, respiratory depression, tachycardia, hypotension, prolonged QT interval (time between Q wave and T wave, inversely proportional to heart rate) Wickham, 2012.

Potential Side Effects of Antiemetics (cont.) Cannabinoids: mood changes; disorientation; dizziness; brief impairment of perception, coordination, and sensory functions; tachycardia; hypotension NK1 inhibitors: weakness, dizziness, diarrhea, constipation, flatus, abdominal discomfort, reflux symptoms, hiccups, headache Serotonin antagonists: diarrhea, constipation, headache, increased liver function tests Wickham, 2012.

Guidelines for CINV Prevention: Highly Emetogenic Chemotherapy NCCN 5-HT3 (Day 1) + dexamethasone PO or IV (Day 1) and PO (Days 2–4) aprepitant PO (125 mg Day 1, 80 mg Days 2–3) or fosaprepitant IV (150 mg Day 1 only) ± lorazepam PO or IV olanzapine PO (10 mg Days 1–4) palonesetron IV (0.25 mg Day 1) dexamethazone IV (20 mg Day 1) ± lorazepam NCCN, 2014.

Guidelines for CINV Prevention: Highly Emetogenic Chemotherapy (cont.) ASCO (American Society of Clinical Oncology) 5-HT3 (Day 1) + dexamethasone (Days 1–3 or 1–4) aprepitant PO (125 mg Day 1, 80 mg Days 2–3) or fosaprepitant IV (150 mg Day 1 only) MASCC (Multinational Association of Supportive Care in Cancer/ESMO (European Society for Medical Oncology) 5-HT3 (Day 1) + dexamethasone (Days 1–4) aprepitant PO (125 mg Day 1, 80 mg Days 2–3) or fosaprepitant IV (150 mg Day 1 only) Basch et al, 2011; Roila et al, 2010.

Guidelines for CINV Prevention: Moderately Emetogenic Chemotherapy NCCNa 5-HT3 (Day 1–3) + dexamethasone PO or IV (Days 1–3) fosaprepitant IV (150 mg Day 1 only) or olanzapine-containing regimen aNCCN guidelines classify an antiemetic regimen including aprepitant as Category 2A of evidence (based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate). NCCN, 2014.

Guidelines for CINV Prevention: Moderately Emetogenic Chemotherapy (cont.) ASCO 5-HT3 (Day 1, palonosetron preferred PO or IV) + dexamethasone PO or IV (Days 1–3) b MASCC/ESMOa 5-HT3 (Day 1) + dexamethasone PO or IV (Day 1) aprepitant PO (125 mg Day 1) aprepitant PO (80 mg Days 2–3)c aAnthracycline + cyclophosphamide-based moderately emetogenic chemotherapy. bASCO states that limited evidence supports adding aprepitant to this combination; there was no data on fosaprepitant in moderate-risk settings. If used, aprepitant is dosed at 125 mg on Day 1, 80 mg on Days 2-3. cMASCC level of scientific confidence/consensus = moderate/moderate. ESMO level of evidence/grade of recommendation = II/B. Basch et al, 2011; Roila et al, 2010.

CINV Prevalent With Some Common HEC Regimens Despite 5-HT3 Use This table shows the incidence of vomiting and nausea reported in trials of key HEC regimens in breast, lung, and ovarian cancers. The incidence of vomiting observed in the commonly used TAC (docetaxel + doxorubicin + cyclophosphamide) regimen was 44.5%, with a reported incidence of nausea of 80.5%. The incidence of CINV with the pemetrexed + cisplatin regimen in lung cancer patients was 86%, with a similar proportion of ovarian cancer patients (82%) reporting CINV with intraperitoneal cisplatin + paclitaxel. aReported as CINV. TAC = docetaxel + doxorubicin + cyclophosphamide; NSCLC = non-small cell lung cancer; IP = intraperitoneal. Martin et al, 2005; Manegold et al, 2000; Piccart et al, 2003.

CINV Prevalent With Some Common MEC Regimens Despite 5-HT3 Use (cont.) This table shows the incidence of vomiting and nausea reported in major trials of key MEC regimens in breast, lung, colorectal, and ovarian cancers. The incidence of vomiting ranged from 14% with the TC (docetaxel plus cyclophosphamide) regimen in breast cancer patients to 42% in the FOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) regimen in colorectal cancer patients, despite 5-HT3 treatment. The incidence of nausea ranged from 44.3% with a regimen of carboplatin + paclitaxel in lung cancer to 78% with the carboplatin + docetaxel regimen in ovarian cancer patients. MEC = moderately emetogenic chemotherapy; TC = docetaxel + cyclophosphamide. Jones et al, 2006; Mok et al, 2009; Tournigand et al, 2004; Vasey et al, 2004.

Management of Breakthrough of Nausea and Vomiting Around-the-clock (ATC) a better option than as needed (prn) Use drug(s) from different class than previously used NCCN guidelines list specific choices from multiple classes of agents NCCN, 2014.

Treatment for Breakthrough Nausea and Vomiting Atypical antipsychotic Olanzapine Benzodiazepine Lorazepam Cannabinoid Dronabinol Nabilone Other Haloperidol Metoclopramide Scopolamine NCCN, 2014.

Treatment for Breakthrough Nausea and Vomiting (cont.) Phenothiazine Prochlorperazine Promethazine Serotonin 5-HT3 antagonists Dolasetron Granisetron Ondansetron Steroid Dexamethasone NCCN, 2014.

Prevention and Treatment of Anticipatory Emesis Prevention is key Use optimal antiemetic therapy Behavioral therapy Relaxation/systemic desensitization Hypnosis/guided imagery Music therapy Acupuncture/acupressure Alprazolam or lorazepam NCCN, 2014.

Perception and Reality: Control of Emesis Physician and Nurse Estimates N = 24 Actual Patient Results N = 298a Acute emesis incidence (%) HEC MEC 17 13 12 Delayed emesis incidence (%) 22 15 50 28 a67 received HEC, 231 received MEC. Grunberg et al, 2004.

Are Antiemetic Guidelines Followed? High risk: cisplatin (N = 206) Acute guidelines: 5-HT3 + steroid Delayed guidelines: Steroid + MCP or 5-HT3 Acute Delayed Followed guidelines (%) 77 20 5-HT3 alone (%) 22 29 No antiemetic (%) 41 MP = metoclopramide. Roila et al, 2000.

Are Antiemetic Guidelines Followed? (cont.) High risk: non-cisplatin [moderate] (N = 1,061) Acute guidelines: 5-HT3 + steroid Delayed guidelines: Steroid + MCP or 5-HT3 Acute Delayed Followed guidelines (%) 57 4 5-HT3 alone (%) 40 No antiemetic (%) 35 Roila et al, 2000.

Are Antiemetic Guidelines Followed? (cont.) Low risk (N = 225) Acute guidelines: No preventive antiemetic Delayed guidelines: No preventive antiemetic Acute Delayed Followed guidelines (%) 5 85 5-HT3 alone (%) 45 5-HT3 + steroid (%) 20 11 MCP (%) 21 4 Roila et al, 2000.

NCCN Guidelines: Principles of CINV Control Current NCCN guidelines include the following principles: Prevention is the goal Risk of CINV lasts for at least 3 days with HEC and 2 days with MEC Consider the toxicity of specific antiemetic(s) Choose antiemetic(s) based on emetogenicity of therapy and patient factors Consider other potential causes of emesis in cancer patients (eg, bowel obstruction, electrolyte imbalance, brain metastases) NCCN, 2014.

Risk of Emesis Increases With Number of Risk Factors Despite 5-HT3 Antagonist Use There appears to be a direct relationship between the risk of emesis and the number of patient risk factors. Osoba and colleagues (1997) conducted a multivariate analysis in a population of 763 chemotherapy-naive patients undergoing chemotherapy to determine risk factors for CINV. Patients were scheduled to receive antiemetic therapy with a 5-HT3 antagonist with or without dexamethasone for highly or moderately emetogenic chemotherapy. In this analysis, the risk of emesis increased from 29% for those with zero risk factors to 72% for those with four risk factors. Osoba, Zee, Pater, et al, 1997.

CINV: Aim for Prevention Prevention of CINV is the goal Patients need protection for the full period of CINV risk Assess patient and chemotherapy factors related to CINV risk The choice of antiemetic(s) should be based on emetogenicity of therapy and patient risk factors Provide patient education and counseling tools for both in-office and take-home use They should be simple and easy to understand Consider a visual analog scale for nausea and patient diaries for vomiting MASCC Antiemesis Tool is available online at http://www.mascc.org/mat NCCN, 2014; Basch et al, 2011; Roila et al, 2010; Boogaerts et al, 2000; Osoba, Zee, Pater, et al, 1997.

Case Study 1: Delayed CINV Ms. DL is a 49-year-old attorney with node-positive invasive ductal carcinoma of the breast, estrogen and progesterone receptor positive, and human epidermal growth factor receptor 2 (HER2) negative. She undergoes a lumpectomy Oncologist recommends adjuvant chemotherapy with four cycles of AC chemotherapy: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV Day 1, every 3 weeks Patient is anxious and concerned about any side effects that might keep her from working

Case Study 1 (cont.) Which chemotherapy-induced side effects may be particularly important for this patient? Nausea and vomiting Alopecia Neutropenia All of the above

Case Study 1 (cont.) Which patient characteristic can increase the risk for CINV? Female sex Age <50 years Anxiety All of the above

Case Study 1 (cont.) What other risk factors for CINV might be important in this patient? History of motion sickness History of morning sickness History of low alcohol intake (<1.5 oz/d)

Case Study 1 (cont.) What steps can be taken to prevent CINV in this patient? Make prevention a goal of treatment Implement optimal prophylaxis to prevent both acute and delayed CINV Start antiemetic therapy before chemotherapy

Case Study 2: Breakthrough CINV Mr. CW is a 72-year-old engineer with stage IIA adenocarcinoma of the lung; status post right-upper lobectomy and mediastinal lymphadenopathy Oncologist recommends adjuvant chemotherapy with docetaxel 75 mg/m2 IV and cisplatin 75 mg/m2 IV Day 1, every 3 weeks for four cycles

Case Study 2 (cont.) Mr. CW’s regimen is considered highly emetogenic. True False

Case Study 2 (cont.) Oncologist reviews side effects associated with chemotherapy regimen Tells patient that 75% of patients experience some nausea and vomiting (grades 1 and 2) while approximately 24% experience severe nausea and vomiting (grades 3 and 4) Patient states he is very anxious about occurrence of nausea and vomiting

Case Study 2 (cont.) Since patient is receiving a regimen considered highly emetogenic, oncologist gives patient the following antiemetic regimen prior to starting chemotherapy: Fosaprepitant 150 mg IV Day 1 Palonosetron 0.25 mg IV Day 1 Dexamethasone 12 mg IV Day 1 and 8 mg PO Day 2, then 8 mg PO twice daily Days 3–4 Patient also given lorazepam 0.5 mg PO every 6 hours Days 1–4

Case Study 2 (cont.) Mr. CW experiences some nausea without vomiting during first 24 hours after chemotherapy Experiences progressive nausea and vomiting for next 96 hours Forty-eight hours after he received chemotherapy, patient calls oncology nurse, who recommends additional antiemetics for breakthrough nausea and vomiting

Case Study 2 (cont.) What regimen would you recommend for Mr. CW’s breakthrough nausea and vomiting? Add one agent from a different class to current regimen Consider increasing dose of lorazepam

Case Study 3: Refractory CINV Ms. WB is a 56-year-old woman with stage IV ovarian carcinoma with bulky abdominal metastases as well as liver metastases ECOG (Eastern Cooperative Oncology Group) performance status 2 Complains of abdominal pain for which she is receiving narcotics Started on paclitaxel 175 mg/m2 IV Day 1 and carboplatin with area under the curve (AUC) 6 IV Day 1 given every 3 weeks

Case Study 3 (cont.) With the first cycle of chemotherapy, Ms. WB received palonosetron 0.25 mg IV Day 1 and dexamethasone 12 mg IV Day 1 Developed nausea and vomiting on the evening of Day 1 extending through Day 2 With the second cycle, fosaprepitant 150 mg IV Day 1 was added to the previous antiemetic regimen Developed more nausea and vomiting that continued for a week

Case Study 3 (cont.) What is the appropriate management of refractory nausea and vomiting? Investigate other causes of nausea and vomiting (eg, liver metastases, bowel obstruction) Increase doses of antiemetics Switch antiemetics a and c

Antiemetic Treatment: Current Status and Future Considerations Marked advances in antiemetic therapy have occurred over past few decades and recently Best antiemetic control occurs when efficacy from clinical trials is emulated in clinical practice Advances have had major impact on patient QOL and patterns of treatment (move to ambulatory chemotherapy) Future studies need to concentrate on mechanisms of resistance and identification of patients at risk Research is needed on understanding and controlling nausea New agents are needed

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