Chemotherapy-Induced Nausea and Vomiting

Chemotherapy-Induced Nausea and Vomiting

3. M.C., a 54-year-old woman with breast cancer, is in the clinic today to receive her first cycle of “AC” (doxorubicin and cyclophosphamide) chemotherapy. She will receive paclitaxel and trastuzumab after the completion of the AC. Her chemotherapy doses will be intravenous (IV) doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² IV for one dose on day 1 of each cycle. This will be repeated every 21 days for four cycles. M.C. does not drink alcohol or smoke. Her only other medical condition is adult onset diabetes, which is controlled with metformin and diet. She has had four children, now all grown, and had substantial morning sickness with each of her pregnancies. M.C.'s neighbor has told her that all chemotherapy causes severe nausea and vomiting. How likely is M.C. to experience nausea and vomiting?

Chemotherapy-induced nausea and vomiting (CINV) occurs in many patients receiving chemotherapy for cancer. The mechanisms of the emetic response described at the beginning of this chapter apply to CINV as well. The major neurotransmitter receptors involved in these pathways include serotonin, NK-1 and dopamine receptors. CINV can occur in different patterns. Acute phase CINV symptoms occur within a few hours after the administration of the chemotherapy. These symptoms often peak several hours after administration and can last for

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the first 24 hours. Some antineoplastic agents can also cause nausea and vomiting symptoms for a longer period of time after chemotherapy administration. Delayed CINV symptoms peak in about 2 to 3 days and can last 6 to 7 days. Some patients who have received previous chemotherapy treatments may experience a conditioned response in which they have symptoms even before the chemotherapy starts. This is called anticipatory nausea and vomiting and it is difficult to treat because it is primarily triggered by poor nausea and vomiting control in previous cycles. Breakthrough nausea and vomiting occur if the primary prophylactic antiemetics fail to work completely. Of course, regardless of the time course and cause, these are very distressing, unpleasant, and disruptive symptoms for the patient.

Table 7-1 Medications for Prevention or Treatment of Motion Sickness in Adults

Medication (Trade name) Dosage Recommended Use Adverse Effects Scopolamine (Transderm-Scop) 1.5 mg TOP behind the ear Q 3 days. Apply at least 3 hrs (preferably 6–8 hrs) before exposure Long term exposure (>6 hrs) of moderate-intense stimulus. Alternative treatment for shorter or milder stimulus. Dry mouth, drowsiness, blurred vision, confusion, fatigue, ataxia Dimenhydrinate (Dramamine) 50–100 mg PO Q 4–6 h (max 400 mg/day). May be taken PRN or on scheduled basis if required. Short- or long-term exposure to mild to moderate stimulus. Alternative for other situations. Drowsiness, dry mouth, thickening of secretions, dizziness Promethazine (Phenergan) 25 mg PO Q 4–6 h. May be taken PRN or on scheduled basis if required. 25–50 mg IM Q 4–6 h for established severe symptoms. May be taken PRN or on scheduled basis if required. In combination with dextroamphetamine for short exposure of intense stimulus. Alternative for other situations. Drowsiness, orthostatic hypotension, dry mouth Meclizine (Antivert, Bonine) 12.5–50 mg PO Q 6–24 h. May be taken PRN or on scheduled basis if required. Alternative for mild stimulus or in combination for moderate to severe stimulus Drowsiness, dry mouth, thickening of secretions, dizziness Dextroamphetamine (Dexedrine) 5–10 mg PO Q 4–6 h. May be taken PRN or on scheduled basis if required. In combination with promethazine for short exposure of intense stimulus. Restlessness, abuse potential, insomnia, overstimulation, tachycardia, palpitations, hypertension Cyclizine (Marezine) 50 mg PO Q 4–6 h (max 200 mg/day). May be taken PRN or on scheduled basis if required. Alternative for mild stimulus situations. Drowsiness, dry mouth, IM, intramusculare; PO, oral; PRN, as needed; Q, every; TOP, topically. Adapted from reference 2, with permission.

Table 7-2 Emetogenicity of Selected Antineoplastic Agents

High Emetogenicity (>90% of patients developing nausea or vomiting [N/V]) Antineoplastic Altretamine (PO) Cisplatin (IV) (≥50 mg/m2) Cyclophosphamide (IV) (≥1,500 mg/m2) Dacarbazine (IV) Dactinomycin (IV) Mechorethamine (IV) Procarbazine (PO) Combination of doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide (IV) Moderate Emetogenicity (30% to 90% of patients developing N/V) Aldesleukin (IV) (>12–15 million units) Amifostine (IV) Arsenic Trioxide (IV) Carboplatin (IV) Cisplatin (IV) (<50 mg/m2) Cyclophosphamide (PO) Cyclophosphamide (IV) (<1,500 mg/m2) Cytarabine (IV) (>1g/m2) Daunorubicin (IV) Doxorubicin (IV) Epirubicin (IV) Etoposide (PO) Idarubicin (IV) Ifosfamide (IV) Imantinib (PO) Irinotecan (IV) Methotrexate (IV) (250 mg to >1 g/m2) Oxaliplatin (IV) Temozolamide (PO) Low Emetogenicity (10% to 30% of patients developing N/V) Antineoplastic Bortezomib (IV) Capecitabine (PO) Cetuximab (IV) Cytarabine (IV) (100–200 mg/m2) Docetaxel (IV) Etoposide (IV) Fluorouracil (IV) Gemcitabine (IV) Lapatinib (PO) Mitoxantrone (IV) Methotrexate (IV) (<1g/m2) Paclitaxel (IV) Panitumumab (IV) Pemetrexed (IV) Topotecan (IV) Trastuzumab (IV) Vorinostat (IV) Minimal Emetogenicity (<10% of patients developing N/V) Bevacizumab (IV) Bleomycin (IV) Chlorambucil (PO) Dasatinib (PO) Decitabine (IV) Erlotinib (PO) Fludarabine (IV) Gefitinib (PO) Gemtuzumab ozogamicin (IV) Hydroxyurea (PO) Lenalidomide (PO) Methotrexate (PO) Nelarabine (IV) Rituximab (IV) Sorafenib (PO) Sunitinib (PO) Thalidomide (PO) Thioguanine (PO) Vinblastine (IV) Vincristine (IV) Vinorelbine (IV) Adapted from references 11, 13, 14, with permission.

The likelihood of CINV depends on several factors.¹¹ Patient-related factors that increase the risk of acute-phase CINV include age <50 years, female gender, poor control of symptoms in prior cycles, history of motion sickness or nausea with pregnancy, anxiety, or depression. A significant history of alcoholism actually protects against CINV. Delayed symptoms are more common in women and in those who have had poor emetic control in the acute phase.

Recently, a new predictive model has been developed to identify patients at highest risk for serious CINV symptoms.¹² The predictive factors most associated with acute CINV symptoms included age, disease site and stage, comorbid conditions, chemotherapy agent (Table 7-2), absence of alcohol abuse, increasing number of chemotherapy cycles, and nonprescription

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drug use. The factors associated with increased delayed CINV included age, type of antiemetics used, prior nausea and vomiting, including that with pregnancy, increasing number of chemotherapy cycles, previous acute CINV, and nonprescription drug use.

Chemotherapy-related factors also predict the likelihood of symptoms. Factors, such as shorter infusion time, higher dose, and more chemotherapy cycles, increase the risk of CINV. With multiday chemotherapy regimens, the symptoms usually peak on about the third to fourth day of chemotherapy, when the acute symptoms caused by the later days' doses are overlapping with the delayed symptoms from the first days' doses. The most predictive factor, however, is the chemotherapy agent's inherent ability to cause CINV, or its emetogenicity.^11,12,13,14 Antineoplastics that are most likely (>90% of patients) to cause symptoms are classified as highly emetogenic chemotherapy. Agents that cause nausea and vomiting in 30% to 90% of patients are classified as moderate-risk agents. Low emetogenicity agents cause symptoms in 10% to 30% of patients. Other chemotherapy agents have a minimal risk, causing CINV in <10% of patients. Table 7-2 lists selected chemotherapy agents in the various emetogenicity classes. References differ in the estimation of emetic risk for some antineoplastic agents. Note, for some agents, that the emetogenicity depends on the dosage used.

Certain antineoplastic agents are more likely to cause delayed CINV symptoms. These include cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, and ifosfamide. Patients receiving more than one of these agents are at high risk for delayed symptoms.

Most chemotherapy agents are given in combinations, rather than as single agents. Estimating the emetogeniticity of chemotherapy combinations has always been difficult. One method¹⁵ using a mathematical formula for estimating the total effect, is based on a five-level classification of emetogenicity. No method has been prospectively evaluated or unanimously accepted, however. Chemotherapy regimens that contain cyclophosphamide and an anthracycline, such as doxorubicin, are highly emetogenic (symptoms in >90% of patients.) The primary literature should be examined for the incidence of nausea and vomiting for established chemotherapy combination regimens. In the absence of specific information regarding the risk of CINV in certain combinations, the antiemetic regimen should be geared toward the chemotherapy agent with the highest emetogenicity level given on that day.^11,14,16 For example, for a chemotherapy combination with one agent with a high risk and one with a moderate risk, the antiemetic regimen should be appropriate for the high-risk chemotherapy agent.

Antiemetic efficacy, or complete emetic response, is usually defined as no emesis and no nausea or only mild nausea in the first 24 hours after chemotherapy administration. With currently recommended antiemetic regimens, most but not all patients will be protected from emesis in the acute phase (first 24 hours). Nausea, however, is more difficult to control. In addition, delayed CINV symptoms are more difficult to prevent.

4. Our patient, M.C., is at high risk for acute CINV. Her personal risk factors include female gender, history of morning sickness with pregnancy, and being a nondrinker. The chemotherapy regimen she will receive (cyclophosphamide and doxorubicin) is highly emetogenic in the acute phase and also has a high risk of delayed symptoms. What antiemetics are available for M.C.?

Appropriate antiemetic therapy is based on the emetogenicity of the chemotherapy regimen and patient risk factors. Because the pathophysiologic response of nausea and vomiting involves many neurotransmitters, combinations of antiemetics from different therapeutic classes will be more effective in most situations than a single agent. The predominant classes of antiemetics used for CINV include serotonin (5HT3) antagonists, the neurokinin-1 antagonist and corticosteroids.

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