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Oncology Supportive Care I. ANTIEMETICS A. Important Definitions Pertaining to Chemotherapy-Induced Nausea and Vomiting (CINV) 1. Nausea is described as an awareness of discomfort that may or may not precede vomiting; nausea is accompanied by decreased gastric tone and decreased peristalsis....

Oncology Supportive Care I. ANTIEMETICS A. Important Definitions Pertaining to Chemotherapy-Induced Nausea and Vomiting (CINV) 1. Nausea is described as an awareness of discomfort that may or may not precede vomiting; nausea is accompanied by decreased gastric tone and decreased peristalsis. 2. Retching is the labored movement of abdominal and thoracic muscles associated with vomiting without the expulsion of vomitus (also called dry heaves). 3. Vomiting (emesis) is the ejection or expulsion of gastric contents through the mouth. a. Acute onset: Occurs 0–24 hours after chemotherapy administration and commonly resolves within 24 hours (intensity peaks after 5–6 hours) b. Delayed onset: Occurs more than 24 hours after chemotherapy administration i. Delayed symptoms are best described with cisplatin, although they are commonly reported in association with other agents (carboplatin or doxorubicin). ii. The distinction between acute and delayed symptoms with respect to time of onset is somewhat arbitrary, and it becomes blurred when chemotherapy is administered for several consecutive days. iii. The importance of the distinction between acute and delayed (and anticipatory) symptoms is that they likely have different mechanisms and therefore different management strategies. 4. Anticipatory vomiting (or nausea) is triggered by sights, smells, or sounds and is a conditioned response; it is more likely to occur in patients whose previous post-chemotherapy nausea and vomiting was not well controlled. 5. Breakthrough emesis occurs despite prophylactic treatment or necessitates additional rescue medications. 6. Refractory emesis is emesis that occurs during treatment cycles when antiemetic prophylaxis or rescue therapy has failed in previous cycles. B. Risk Factors for CINV 1. Patient-related risk factors a. Younger age (younger than 50) b. Female sex c. History of motion sickness d. History of nausea or vomiting during pregnancy e. Previous history of drug treatment for CINV f. Little or no previous alcohol use g. Anxiety/high pretreatment expectation of nausea 2.  Emetogenicity of chemotherapy agents: Several schemes for assessing emetogenicity have been proposed. a. Originally, emetogenic risk was classified as “none,” “mild,” “moderate,” or “severe.” b. The Hesketh model, proposed in 1997, classified emetogenic risk as levels ranging from level 1 (less than 10% frequency of emesis) to 5 (more than 90% frequency of emesis). c. Current model includes four levels for parenteral chemotherapy and two levels for oral chemotherapy. d. Levels for parenteral chemotherapy (e.g., minimal, low, moderate, high emetogenic risk) are defined by the percentage of patients expected to experience emesis when not receiving antiemetic prophylaxis. (See Table 1) e. Levels for oral chemotherapy (e.g., prophylaxis recommended or as needed) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-32 Oncology Supportive Care 3. Radiation therapy can also cause nausea and vomiting. The incidence and severity of radiation-induced nausea and vomiting vary by site of radiation and size of radiation field. a. Mildly emetogenic: Radiation to the head and neck or to the extremities b. Moderately emetogenic: Radiation to the upper abdomen or pelvis or craniospinal radiation c. Highly emetogenic: Total body irradiation, total nodal irradiation, and upper-half-body irradiation C. General Principles for Managing CINV and Radiation-Induced Nausea and Vomiting 1. Prevention is the key. Prophylactic antiemetics should be administered before moderately or highly emetogenic agents and before moderately and highly emetogenic radiation. 2. Antiemetics should be scheduled for delayed nausea and vomiting for select chemotherapy regimens (e.g., cisplatin, doxorubicin/cyclophosphamide (AC)), and rescue antiemetics should be available if prolonged acute symptoms or ineffective antiemetic prophylaxis occurs. 3. Patients need to be protected throughout the full period of risk for nausea/vomiting: a. 3 days for highly emetogenic regimens b. 2 days for moderately emetogenic regimens 4. Begin with an appropriate antiemetic regimen based on the emetogenicity of the chemotherapy drugs. a. For multidrug regimens, select antiemetic therapy according to the drug with the highest emetic risk. b. The most common antiemetic regimen for highly emetogenic chemotherapy and radiation is the combination of a neurokinin 1 (NK1) receptor antagonist, a serotonin receptor antagonist, and dexamethasone. Adding a corticosteroid to a serotonin receptor antagonist for highly (or moderately) emetogenic anticancer therapy increases efficacy by 10%–20%. Based on randomized clinical trial data, the AC regimen (see Table 1) should always include a three-drug regimen with an NK1 receptor antagonist, a serotonin receptor antagonist, and dexamethasone. c. Both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines now recommend a four drug regimen for highly emetogenic chemotherapy to include a neurokinin 1 receptor antagonist, a serotonin receptor antagonist, dexamethasone, and olanzapine as the preferred prophylactic regimen. The standard three-drug regimen is still recommended as an option for highly emetogenic chemotherapy. d. For moderately emetogenic chemotherapy, the most common antiemetic regimen now includes a serotonin receptor antagonist and dexamethasone. Addition of an NK1 receptor antagonist may be considered after risk stratification. e. Single-agent phenothiazine, butyrophenone, or steroids are used for mildly emetogenic regimens and are given on either a scheduled or an as-needed basis for prolonged symptoms (i.e., breakthrough symptoms). Olanzapine is now a preferred option for breakthrough treatment. f. Consider using a histamine-2 blocker or proton pump inhibitor for dyspepsia (which can mimic nausea). g. Cannabinoids are generally used after other regimens have failed. h. Potential drug interactions between antineoplastic agents or antiemetics and other drugs should always be considered. However, no clinically significant drug-drug interactions have emerged to date in randomized clinical trials of anticancer agents with antiemetics. This is likely because of the short duration of antiemetic use in this population. i. Follow-up is essential. The response to the emetogenic regimen should always guide the choice of antiemetic regimen for subsequent therapy courses. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-33 Oncology Supportive Care D. Emetogenic Potential of Parenteral Chemotherapy Agents Table 1. Emetogenic Potential of Parenteral Chemotherapy Agents (per NCCN guidelines) High Emetic Risk (> 90% frequency of emesis) Doxorubicin ≥ 60 mg/m 2 Epirubicin > 90 mg/m 2 Ifosfamide ≥ 2 g/m 2/dose Mechlorethamine Melphalan > 140 mg/m 2 Sacituzumab govitecan-hziy Streptozocin AC (combination defined as any chemotherapy regimen that contains an anthracycline and cyclophosphamide) Carboplatin AUC ≥ 4 Carmustine > 250 mg/m 2 Cisplatin Cyclophosphamide > 1500 mg/m 2 Dacarbazine Moderate Emetic Risk (30%–90% frequency of emesis) Aldesleukin > 12–15 million IU/m 2 Amifostine > 300 mg/m 2 Amivantamab-vmjw Azacitidine Bendamustine Busulfan Carboplatin AUC < 4 Carmustine ≤ 250 mg/m 2 Clofarabine Cyclophosphamide ≤ 1500 mg/m 2 Cytarabine > 200 mg/m 2 Dactinomycin Daunorubicin Dual-drug liposomal encapsulation of cytarabine and daunorubicin Dinutuximab Doxorubicin < 60 mg/m 2 Epirubicin ≤ 90 mg/m 2 Fam-trastuzumab deruxtecan-nxki Idarubicin Ifosfamide < 2 g/m 2/dose Irinotecan Irinotecan (liposomal) Lurbinectedin Melphalan < 140 mg/m 2 Methotrexate ≥ 250 mg/m 2 Naxitamab-gqgk Oxaliplatin Romidepsin Temozolomide Trabectedin Low Emetic Risk (10%–30% frequency of emesis) Ado-trastuzumab emtansine Aldesleukin ≤ 12 million IU/m 2 Amifostine ≤ 300 mg/m 2 Arsenic trioxide Axicabtagene ciloleucel Belinostat Brexucabtagene autoleucel Brentuximab vedotin Cabazitaxel Carfilzomib Copanlisib Cytarabine (low dose) 100–200 mg/m 2 Docetaxel Doxorubicin (liposomal) Enfortumab vedotin-ejfv Eribulin Etoposide Floxuridine Fluorouracil (5-FU) Floxuridine Gemcitabine Gemtuzumab ozogamicin Idecabtagene vicleucel Inotuzumab ozogamicin Isatuximab-irfc Ixabepilone Lisocabtagene maraleucel Loncastuximab tesirine-lpyl Methotrexate > 50 mg/m 2 to < 250 mg/m 2 Mitomycin and mitomycin pyelocalyceal solution Mitoxantrone Mogamulizumab-kpkc Moxetumomab pasudotox-tdfk Necitumumab Omacetaxine Paclitaxel Paclitaxel/albumin Pemetrexed Pentostatin Polatuzumab vedotin-piiq Pralatrexate Tafasitamab-cxix Tagraxofusp-erzs Talimogene laherparepvec Thiotepa Tisagenlecleucel Tisotumab vedotin-tftv Topotecan Ziv-aflibercept ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-34 Oncology Supportive Care Table 1. Emetogenic Potential of Parenteral Chemotherapy Agents (per NCCN guidelines) (Cont’d) Minimal Emetic Risk (< 10% frequency of emesis) Alemtuzumab Asparaginase Atezolizumab Avelumab Belantamab mafodotin-blmf Bevacizumab Bleomycin Blinatumomab Bortezomib Cemiplimab-rwlc Cetuximab Cladribine Cytarabine < 100 mg/m 2 Daratumumab Daratumumab and hyaluronidase-fihj Decitabine Denileukin diftitox Dexrazoxane Dostarlimab-gxly Durvalumab Elotuzumab Fludarabine Ipilimumab Luspatercept-aamt Margetuximab-cmkb Methotrexate ≤ 50 mg/m 2 Nelarabine Nivolumab Obinutuzumab Ofatumumab Panitumumab Pembrolizumab Pertuzumab Pertuzumab/trastuzumab and hyaluronidase-zzxf Ramucirumab Rituximab Rituximab and hyaluronidase Siltuximab Temsirolimus Trastuzumab Trastuzumab and hyaluronidase-oysk Valrubicin Vinblastine Vincristine Vincristine (liposomal) Vinorelbine E. Emetogenic Potential of Oral Chemotherapy Agents (Table 2) Table 2. Emetogenic Potential of Oral Chemotherapy Agents (per NCCN guidelines) Moderate to High Emetic Risk (≥ 30% frequency of emesis); Prophylaxis Recommended Altretamine Avapritinib Azacytidine Binimetinib Bosutinib > 400 mg/day Busulfan ≥ 4 mg/day Cabozantinib Ceritinib Crizotinib Cyclophosphamide ≥ 100 mg/m 2/day Dabrafenib Enasidenib Encorafenib Estramustine Etoposide Fedratinib Imatinib > 400 mg/day Lenvatinib > 12 mg/day Lomustine (single day) Midostaurin Mitotane Mobocertinib Niraparib Olaparib Procarbazine Rucaparib Selinexor Temozolomide > 75 mg/m 2/day ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-35 Oncology Supportive Care Table 2. Emetogenic Potential of Oral Chemotherapy Agents (per NCCN guidelines) (Cont’d) Minimal to Low Emetic Risk (< 30% frequency of emesis); As Needed Abemaciclib Acalabrutinib Afatinib Alectinib Alpelisib Asciminib Axitinib Belzutifan Bexarotene Bosutinib ≤ 400 mg/day Brigatinib Busulfan < 4 mg/day Capecitabine Capmatinib Chlorambucil Cobimetinib Cyclophosphamide < 100 mg/m 2/day Dacomitinib Dasatinib Decitabine and cedazuridine Duvelisib Entrectinib Erdafitinib Erlotinib Everolimus Fludarabine Gefitinib Gilteritinib Glasdegib Hydroxyurea Ibrutinib Idelalisib Infigratinib Imatinib ≤ 400 mg/day Ivosidenib Ixazomib Lapatinib Larotrectinib Lenalidomide Lenvatinib ≤ 12 mg/day Lorlatinib Melphalan Mercaptopurine Methotrexate Neratinib Nilotinib Osimertinib Palbociclib Pazopanib Pemigatinib Pexidartinib Pomalidomide Ponatinib Pralsetinib Regorafenib Ribociclib Ripretinib Ruxolitinib Selpercatinib Sonidegib Sorafenib Sotorasib Sunitinib Talazoparib tosylate Tazemetostat Temozolomide ≤ 75 mg/m 2/day Tepotinib Thalidomide Thioguanine Tivozanib Topotecan Trametinib Tretinoin Trifluridine/tipiracil Tucatinib Umbralisib Vandetanib Vemurafenib Venetoclax Vismodegib Vorinostat Zanubrutinib F. Antiemetics 1. Serotonin-3 receptor antagonists (dolasetron, granisetron, ondansetron, and palonosetron) a. Mechanism of action (MOA): Block serotonin receptors peripherally in the gastrointestinal tract and centrally in the medulla b. Adverse events: Headache and constipation, occurring in 10%–15% of patients. May increase liver function tests and cause QT prolongation (especially with high dosages or intravenous push administration). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-36 Oncology Supportive Care c.  olasetron, granisetron, ondansetron, and palonosetron are considered equally efficacious at D equivalent dosages. Therefore, the antiemetic drug of choice is often based on cost and organizational contract. d. Dosage forms: Granisetron and ondansetron are available in oral and parenteral forms (including an orally disintegrating tablet for ondansetron). Dolasetron is now indicated only in CINV in its oral form. Granisetron is also available in a transdermal patch (34.3 mg applied about 24–48 hours before the first dose of chemotherapy; maximal duration of patch is 7 days) as well as an extended-release subcutaneous formulation (10 mg at least 30 minutes before first dose of chemotherapy; not to be administered more often than every 7 days). e. Palonosetron is indicated to prevent acute CINV for highly emetogenic chemotherapy and acute and delayed CINV for moderately emetogenic chemotherapy. i. Half-life: About 40 hours (longer compared with other serotonin antagonists) ii. Dosage: 0.25 mg intravenous push 30 minutes before chemotherapy administration iii. An oral capsule form is available but only as a combination product with an NK1 antagonist (netupitant/palonosetron). iv. One dose may be used before the start of a 3-day chemotherapy regimen instead of several daily doses of oral or parenteral serotonin-3 receptor antagonists. v. Adverse events: Headache and constipation (same as other serotonin antagonists) 2. Corticosteroids (dexamethasone, methylprednisolone) a. MOA: Unknown; thought to act by inhibiting prostaglandin synthesis in the cortex b. Adverse effects associated with single doses and short courses of steroids are infrequent; they may include euphoria, anxiety, insomnia, increased appetite, and mild fluid retention; rapid parenteral administration may be associated with transient and intense perineal, vaginal, or anal burning. c. Dexamethasone has been studied more often in clinical trials than methylprednisolone. d. Corticosteroid antiemetic premedication should be avoided with immune checkpoint inhibitors when administered without cytotoxic chemotherapy. e. Corticosteroid antiemetic premedication should be avoided for 3–5 days before and 90 days after CAR (chimeric antigen receptor) T-cell therapies. Antiemetic regimens used during lymphodepleting chemotherapy regimens should also use a corticosteroid-sparing approach to antiemetic prophylaxis. 3. NK1 receptor antagonists (aprepitant, aprepitant injectable emulsion, fosaprepitant, rolapitant) a. All NK1 receptor antagonists must be used in combination with a serotonin receptor antagonist and dexamethasone and are approved for preventing acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy known to cause these problems, including highly emetogenic chemotherapy. b. MOA: Aprepitant is a selective high-affinity antagonist of human substance P/NK1. c. Aprepitant improved the overall complete response (defined as no emetic episodes and no use of rescue therapy) by about 20% when added to a serotonin receptor antagonist and dexamethasone. d. Aprepitant oral dosage: 125 mg on day 1, then 80 mg on day 2 and 80 mg on day 3. Intravenous aprepitant dosing is 130 mg on day 1 only for highly emetogenic chemotherapy and 100 mg on day 1 only for moderately emetogenic chemotherapy. e. Fosaprepitant dosage (prodrug): 150 mg intravenously on day 1 only (parenteral formulation) f. Metabolized primarily by cytochrome P450 (CYP) 3A4 (all NK1 agents), with aprepitant and fosaprepitant having minor metabolism by CYP1A2 and CYP2C19 i. Dexamethasone: Fosaprepitant and aprepitant may increase area under the curve of dexamethasone. Decrease dosage by about 40% on day 2 or 3 if dexamethasone given orally (not necessary if given intravenously because of first-pass metabolism). Rolapitant does not inhibit dexamethasone metabolism. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-37 Oncology Supportive Care ii. Oral contraceptives: May reduce the effectiveness of oral contraceptives. Would recommend another form of birth control for women of childbearing age when taking with aprepitant/ fosaprepitant iii. Warfarin: May decrease international normalized ratio (clinically significant). After receiving fosaprepitant or aprepitant, patients should have their international normalized ratios checked within 7–10 days. iv. Caution NK1 use in patients with lymphoma: Studies suggest neuropathy is more common in patients on R-CHOP receiving aprepitant, because of aprepitant’s CYP3A4 inhibition. Other NK1 agents have CYP3A4 inhibition, and caution should be used with these as well. g. Adverse events: Asthenia, dizziness, and hiccups h. MOA: Rolapitant substance P/NK1 receptor antagonist indicated in combination with dexamethasone and serotonin antagonist in adults with cancer for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy. i. Rolapitant dosage: 180 mg orally on day 1 only j. Adverse events: Loss of appetite, neutropenia, and hiccups 4. NK1 receptor antagonist/serotonin-3 combination (netupitant/palonosetron and fosnetupitant/palonosetron) a. MOA: Fixed combination of netupitant/fosnetupitant, a substance P/NK1 receptor antagonist, and palonosetron, a serotonin-3 receptor antagonist indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including highly emetogenic chemotherapy. Oral palonosetron prevents nausea and vomiting during the acute phase, and netupitant/fosnetupitant prevents nausea and vomiting during both the acute and delayed phases after cancer chemotherapy. b. Netupitant/palonosetron dosage: 1 capsule once on day 1 (capsule contains 300 mg of netupitant/ palonosetron 0.5 mg) c. Fosnetupitant/palonosetron dosage: Intravenously once daily on day 1 (contains 235 mg of fosnetupitant/palonosetron 0.25 mg) d. Adverse effects: Headache, asthenia, dyspepsia, fatigue, constipation, and erythema e. Caution in patients with hepatic dysfunction, severe renal impairment, or end-stage renal disease 5. Benzamide analogs (metoclopramide) a. MOA: Blockade of dopamine receptors in the chemoreceptor trigger zone; stimulation of cholinergic activity in the gut, increasing (forward) gut motility; and antagonism of peripheral serotonin receptors in the intestines. These effects are dose related. b. Adverse events: Mild sedation and diarrhea, as well as extrapyramidal reactions (e.g., dystonia, akathisia), which may be mitigated by diphenhydramine or benztropine. c. Historically, higher dosages of metoclopramide were used for desired results (1–2 mg/kg intravenously). Guidelines now recommend 10–20 mg every 6 hours, if needed. 6. Phenothiazines (prochlorperazine, chlorpromazine, promethazine) a. MOA: Block dopamine receptors in the chemoreceptor trigger zone b. Adverse events: Drowsiness, hypotension, akathisia, and dystonia 7. Butyrophenones (haloperidol, droperidol) a. MOA: Similar to phenothiazines b. They are at least as effective as the phenothiazines, and some studies indicate they are superior; they offer a different chemical structure that may bind differently to the dopamine receptor and offer an initial alternative when a phenothiazine fails. c. Adverse events: Sedation; hypotension is less common than with phenothiazines; extrapyramidal symptoms are also seen. d. The use of droperidol as an antiemetic has fallen out of favor because of the risk of QT prolongation or torsades de pointes. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-38 Oncology Supportive Care 8. Benzodiazepines (lorazepam) a. Lorazepam as a single agent has minimal antiemetic activity. However, several properties make lorazepam useful in combination with or as an adjunct to other antiemetics. i. Anterograde amnesia helps prevent anticipatory nausea and vomiting. ii. Relief of anxiety iii. Management of akathisia caused by phenothiazines, butyrophenones, or metoclopramide iv. Adverse events: Amnesia, sedation, hypotension, perceptual disturbances, and urinary incontinence. Note that amnesia and sedation may, in fact, be desirable. 9. Atypical antipsychotic (olanzapine) a. Approved by the U.S. Food and Drug Administration (FDA) to treat schizophrenia and bipolar disorder, this thienobenzodiazepine is used off label as an alternative agent for preventing nausea and vomiting in highly emetogenic regimens and may be used as an option for breakthrough nausea and vomiting. b. MOA: Blocks multiple neurotransmitters, including dopamine, serotonin, catecholamines, acetylcholine, and histamine c. Adverse effects: Sedation, dry mouth, increased appetite, weight gain, postural hypotension, QTc prolongation, and dizziness d. Olanzapine has been associated with an elevated risk of hyperlipidemia, hyperglycemia, and new-onset diabetes. Use with caution in older adults because olanzapine use in this patient population has been associated with an elevated risk of death and an elevated incidence of cerebrovascular adverse events in patients with dementia-related psychosis (black box warning) e. A phase III study compared olanzapine with aprepitant in highly emetogenic chemotherapy regimens. Overall response rates were similar in both groups for acute and delayed nausea and vomiting. The proportion of patients without nausea was similar between the two groups in the acute period but was higher in the olanzapine arm in the delay period, resulting in a higher rate of nausea control. As an alternative to, or in combination with, aprepitant, an olanzapine-based regimen is an option in highly or moderately emetogenic regimens according to the most recent National Comprehensive Cancer Network (NCCN) guidelines. 10. Cannabinoids (dronabinol, nabilone) a. MOA: Cannabinoid receptors may mediate at least some of the antiemetic activity of this class of agents. Additional antiemetic mechanisms that have been proposed include inhibition of prostaglandins and blockade of adrenergic activity. b. Adverse events: Drowsiness, dizziness, euphoria, dysphoria, orthostatic hypotension, ataxia, hallucinations, and time disorientation ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-39 AL GRAWANY Oncology Supportive Care G. Emesis Prevention Algorithms (Tables 3 and 4) Table 3. Emesis Prevention Algorithm for Parenteral Chemotherapy (per NCCN Guidelines)a Level of Emetogenicity Emesis Treatment Day 1 Emesis Treatment Days 2, 3, and 4 High NK1 antagonist - Aprepitant 125 mg PO once - Aprepitant injectable emulsion 130 mg IV once - Fosaprepitant 150 mg IV once - Netupitant 300 mg/palonosetron 0.5 mg combination PO once - Fosnetupitant 235 mg/palonosetron 0.25 mg combination IV once - Rolapitant 180 mg PO once -A  prepitant 80 mg PO daily on days 2 and 3 (only if aprepitant PO used on day 1) - Dexamethasone 8 mg PO/IV daily on days 2, 3, 4 -O  lanzapine 5–10 mg PO daily on days 2, 3, 4 (if olanzapine PO used on day 1) AND Serotonin-3 antagonist AND Dexamethasone 12 mg PO/IV once ± Olanzapine 5–10 mg PO once ± Lorazepam ±H  istamine-2 blocker or proton pump inhibitor OR Moderate Olanzapine-containing regimen: 1. Olanzapine 5–10 mg PO once 2. Palonosetron 0.25 mg IV once 3. Dexamethasone 12 mg PO/IV once ± Lorazepam ±H  istamine-2 blocker or proton pump inhibitor OR Serotonin-3 antagonist Serotonin-3 antagonist AND OR Dexamethasone 12 mg PO/IV once Steroid monotherapy Dexamethasone 8 mg PO/IV daily on days 2, 3 WITH/WITHOUT NK1 antagonist PO/IV (may consider adding NK1 for patients with additional risk factors or previous treatment failure with serotonin-3 antagonist and dexamethasone) ± Lorazepam ± Histamine-2 blocker or proton pump inhibitor OR Olanzapine-containing regimen: 1. Olanzapine 5–10 mg PO once 2. Palonosetron 0.25 mg IV once 3. Dexamethasone 12 mg IV once ± Lorazepam ± Histamine-2 blocker or proton pump inhibitor Olanzapine 5–10 mg PO days 2–4 OR - I f aprepitant PO given day 1, aprepitant 80 mg PO daily on days 2, 3 ± dexamethasone 8 mg PO/IV days 2, 3 - I f fosaprepitant or rolapitant given day 1, no further NK1 antagonists needed on days 2 and 3 ± dexamethasone days 2, 3 OR Olanzapine-containing regimen: Olanzapine 5–10 mg PO days 2, 3 ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-40 Oncology Supportive Care Table 3. Emesis Prevention Algorithm for Parenteral Chemotherapy (per NCCN Guidelines) (Cont’d) Level of Emetogenicity Emesis Treatment Day 1 Emesis Treatment Days 2 and 3 Low Dexamethasone 8-12 mg PO/IV once Repeat day 1 selection daily for multi-day doses of chemotherapy only OR Metoclopramide 10-20 mg PO/IV once OR Prochlorperazine 10 mg PO/IV once OR Serotonin-3 antagonists (oral therapy) ± Lorazepam ± Histamine-2 blocker or proton pump inhibitor Minimal No routine prophylaxis No routine prophylaxis A four-drug regimen containing an NK1 antagonist, a serotonin antagonist, dexamethasone, and olanzapine is now the preferred first-line prophylactic option for highly emetogenic regimens according to the most recent NCCN and ASCO antiemetic guidelines. IV = intravenous(ly); NK1 = neurokinin 1; PO = orally. a Table 4. Emesis Prevention Algorithm for Oral Chemotherapy per NCCN Guidelines Level of Emetogenicity Moderate to high emetic risk Minimal to low emetic risk Emesis Treatment (start before chemotherapy and continue daily) Serotonin-3 antagonist (choose one): Dolasetron 100 mg daily Granisetron 1–2 mg (total dose) PO daily or 3.1 mg/24-hr transdermal patch every 7 days Ondansetron 8-16 mg PO daily ± Lorazepam ± Histamine-2 blocker or proton pump inhibitor Metoclopramide 10–20 mg PO and then q6hr PRN OR Prochlorperazine 10 mg PO and then q6hr PRN (maximum 40 mg/day) OR Serotonin-3 antagonist (choose one): Dolasetron 100 mg PO daily PRN Granisetron 1-2 mg (total dose) PO daily PRN Ondansetron 8–16 mg PO daily PRN ± Lorazepam ± Histamine-2 blocker or proton pump inhibitor BID = twice daily; PRN = as needed; q = every. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-41 Oncology Supportive Care Patient Case Questions 1 and 2 pertain to the following case. A 60-year-old woman was recently given a diagnosis of advanced non–small cell lung cancer. She will begin treatment with cisplatin 100 mg/m 2 plus vinorelbine 30 mg/m 2. 1. Which is the most appropriate antiemetic regimen for preventing acute emesis? A. Aprepitant plus palonosetron plus dexamethasone. B. Aprepitant plus prochlorperazine plus dexamethasone. C. Aprepitant plus granisetron plus ondansetron. D. Lorazepam plus ondansetron plus metoclopramide. 2. If the patient has anticipatory nausea and vomiting with her next cycle, which regimen would be most appropriate? A. Aprepitant plus palonosetron plus dexamethasone. B. Aprepitant plus prochlorperazine plus dexamethasone. C. Aprepitant plus granisetron plus metoclopramide. D. Aprepitant plus ondansetron plus dexamethasone plus lorazepam. II. PAIN MANAGEMENT A. Principles of Cancer Pain Management 1. The most important step in treating pain is the assessment. 2. The oral route is preferred, when available. Although the ratio of oral to parenteral potency of morphine is commonly 6:1, clinical observation of chronic morphine use indicates that this ratio is closer to 3:1. 3. Choose the analgesic drug and dosage to match the patient’s degree of pain. 4. For persistent severe pain, use a product with a long duration of action. Pain medications should always be administered on a scheduled basis or around the clock, not as needed. a. It is always easier to prevent pain from recurring than to treat it once it has recurred. b. As-needed dosing should be used for breakthrough pain, which is pain that “breaks through” the regularly scheduled opioid; an immediate-release, short-acting opioid should always accompany a long-acting opioid. 5. Reevaluate pain and pain relief often, especially when initiating pain therapy; if more than two as-needed doses are necessary for breakthrough pain in a 24-hour period, consider modifying the regimen. Before adding or changing to another drug, maximize the dosage and schedule of the current analgesic drug. 6. Provide medications to prevent other potential side effects from opioid therapy (e.g., constipation). 7. Use appropriate adjuvant analgesics and nondrug measures to maximize pain control. 8. Goals of pain management (The “5 A’s”) a. Optimize analgesia. b. Optimize activities of daily living. c. Minimize adverse effects. d. Avoid aberrant drug taking. e. Relationship between pain and mood (affect) 9. Survival is linked to symptom control and pain management, which contribute to broad quality-of-life improvement. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-42 Oncology Supportive Care 10. For acute, severe pain or pain crisis, consider hospital or inpatient hospice admission. 11. Optimal use of disease-specific therapies is essential to managing tumor-related pain. B. Diagnosis and Assessment of Pain 1. Best addressed by proper pain assessment including comprehensive history and physical examination 2. Evaluation of pain management: Pain intensity, pain relief, and medication adverse effects or allergies must be assessed and reassessed. 3. Objective observations such as grimacing, limping, or tachycardia may be helpful in assessment. 4. Clinicians must accept the patient’s report of pain. C. Pain Rating Scales 1. Use pain assessment tools to evaluate pain intensity at baseline and to assess how well a pain medication regimen is working. a. Numeric rating scale of 0–10, with 0 = no pain and 10 = worst pain imaginable b. Pediatric patients: Faces-of-Pain Scale, poker chip method 2. Because pain is subjective, it is best evaluated by the patient (i.e., not a caregiver and not the health professional). D. Treatment of Pain: The Analgesic Ladder 1. For mild pain (pain rating of 1–3 on a 10-point scale), the first step is a nonopioid analgesic drug: Nonsteroidal anti-inflammatory drug (NSAID), aspirin, or acetaminophen, or consider slow titration of short-acting opioids either as needed or as scheduled. 2. For persistent or moderate pain (pain rating of 4–7 on a 10-point scale), add a weak opioid: Codeine or hydrocodone, available in combination with nonopioid analgesic drugs. Slow titration of a short-acting opioid may also be considered and should be administered every 3–4 hours as needed. If four or more doses of a short-acting opioid are consistently needed per day, consider adding or increasing the dose of a long-acting opioid on the basis of the total daily dose. 3. For persistent or for severe pain (pain rating of 8 or greater on a 10-point scale), replace the weak opioid with a strong opioid: Morphine, oxycodone, or similar drug. In opioid-naive patients experiencing severe pain, short-acting opioids should be rapidly titrated. Once a patient with persistent pain is taking stable dosages of short-acting opioids, the drug should be changed to an extended-release or long-acting formulation with breakthrough short-acting opioids. When converting to long-acting opioids, the initial range will be around 50%–100% of the usual daily requirement (depending on expected pain natural history). 4. For acute, severe pain crisis, consider hospital or inpatient hospice admission to achieve patient-specific goals for comfort and function. E. Nonopioid Analgesics: NSAIDs 1. MOA: Act peripherally to inhibit the activity of prostaglandins in the pain pathway 2. There is a ceiling effect to the analgesia provided by NSAIDs. 3. Adverse events: Consider inhibition of platelet aggregation and the effects of inhibition of renal prostaglandins. NSAIDs in patients with hematologic disorders are generally not recommended because of platelet inhibition. In addition, there are concerns about the possibility that NSAIDs will mask fever in a patient with neutropenia who is potentially febrile. All NSAIDs with systemic administration have been associated with renal toxicities. 4. Remember, NSAIDs are generally used in addition to, not instead of, opioids. 5. NSAIDs are often used for patients with metastatic bone pain. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-43 Oncology Supportive Care F. Nonopioid/Opioid Combinations 1. Aspirin or acetaminophen or ibuprofen plus codeine or hydrocodone or oxycodone is commonly used. 2. Be aware of the risk of acetaminophen overdose with these products. As with any combination product, dosage escalation of one component necessitates escalation of the others. For patients needing high dosages, pure opioids are preferred. 3. Oxycodone/acetaminophen is available in several strengths; however, use caution when taking multiple tablets per day because of the acetaminophen daily maximum recommendations. G. Opioid Analgesics 1. Mechanism: Opioids act centrally in the brain (periaqueductal gray region) and at the level of the spinal cord (dorsal horn) at specific opioid receptors. 2. The opioids have no analgesic ceiling. 3.  Morphine a. Morphine is the standard with which all other drugs are compared; opioids may differ in duration of action, relative potency, oral effectiveness, and adverse event profiles, but none is clinically superior to morphine. b. Flexibility in dosage forms and administration routes: Oral (sustained release, immediate release), sublingual, parenteral, intrathecal/epidural, subcutaneous, and rectal c. Long duration of action: Sustained-release products last 8–12 hours or, for some preparations, 24 hours. d. Morphine is one of the least expensive opioids, but it should be used with caution in patients with renal dysfunction because of the metabolite. 4.  Oxycodone a. Available in oral formulation only b. Available as a single drug (i.e., not in combination) in both long- and short-acting formulations c. Alternative to morphine in the setting of renal dysfunction 5.  Fentanyl a. Fentanyl is available as a parenteral formulation; a sublingual, intranasal, or transdermal preparation; an oral transmucosal preparation; and a buccal tablet. Transmucosal and buccal fentanyl are used for breakthrough pain. b. Each transdermal patch provides sustained release of drug and can provide pain relief for 48–72 hours. These should not be used in opioid-naive patients. c. Consider the implications for dosing transdermal fentanyl in cachectic patients: Fentanyl initially forms a depot in subcutaneous tissue, and patients with little or no fat may not achieve pain relief or may achieve only inconsistent pain relief. d. Slow onset and long elimination after patch application and removal, respectively e. Bioavailability is greater with buccal tablets than with the transmucosal preparation; thus, equivalent dosages are higher for transmucosal and lower for buccal tablets. 6.  Hydromorphone a. Available in parenteral and oral formulations (short- and long-acting) b. Considered a semisynthetic compound c. Alternative to morphine with higher potency d. Alterative option in patients with renal dysfunction 7.  Oxymorphone a.  Semisynthetic opioid analgesic b. Most commonly seen as immediate- and extended-release tablets c. Used for moderate to severe pain d. Should not be implemented in patients who are not currently on an opioid regimen e. On June 8, 2017, the FDA has requested that the extended-release formulation of oxymorphone be removed from the market because of risks related to abuse. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-44 Oncology Supportive Care 8.  Methadone a. Semisynthetic used in maintenance treatment for opioid-dependent patients and as an effective analgesic in patients taking opioids long term for moderate to severe pain b. Has activity not only at the opioid receptors but also at the N-methyl-d-aspartate receptor, which may confer benefit to patients with neuropathic pain c. Complex pharmacokinetics with extended half-life (8–59 hours), which creates difficulties in dosing and transitioning from one opioid to another d. Associated with QT prolongation and torsades de pointes e. Start low and titrate slowly (only escalating after 3–5 days) because of the changing conversion ratios with increasing morphine equivalents. f. If using methadone as a long-acting opioid, a short-acting opioid should also be provided for breakthrough pain 9. Adverse events a. Sedation: Tolerance usually develops within several days; remember that more sedation may be expected in a patient who has been unable to sleep because of uncontrolled pain. For patients who are intolerant of sedation and have good pain control, a dosage reduction may be considered. If dosage reduction compromises pain control, adding a stimulant (e.g., dextroamphetamine, methylphenidate) may be considered. Other central nervous system adverse events include dysphoria and hallucinations. b. Constipation is very common, and tolerance does not develop to this effect. Decreased intestinal peristalsis is caused by decreased intestinal tone; delayed gastric emptying may also occur. Regular use of stool softeners in addition to a stimulant laxative is imperative to manage constipation. c. Nausea and vomiting are common. As seen with sedation, tolerance develops within about a week. Nausea and vomiting may have a vestibular component, developing as pain relief promotes increased mobility. Agents used in the treatment of vertigo (e.g., meclizine, dimenhydrinate) may be useful in managing the vestibular component, although these agents should be used with caution because combination use with opioids may increase sedation. Nausea and vomiting may also occur because of stimulation of the chemoreceptor trigger zone. Drugs that block dopamine receptors (e.g., phenothiazines) provide relief of this component of nausea and vomiting until tolerance develops. d. Urinary retention and bladder spasm are more common in older adults and in patients taking longacting formulations. H. Bisphosphonates 1. Bisphosphonates decrease the worsening of pain by preventing disease progression in the bone and the number of skeletal-related events in patients with bone metastases from solid tumors or osteolytic lesions from multiple myeloma when given for 1 year. Skeletal-related events include pathologic fracture, need for radiation therapy to bone, surgery to bone, and spinal cord compression. 2. Most recently updated in October 2017 the American Society of Clinical Oncology published initial guidelines for the use of bisphosphonates in breast cancer. a. It is recommended that patients with breast cancer who have evidence of bone metastases on plain radiographs receive either pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3–4 weeks. Dosage adjustments for renal dysfunction are necessary according to package insert recommendations. b. Women with abnormal bone scan and abnormal computed tomographic scan or magnetic resonance imaging showing bone destruction but a normal radiograph should also receive the previously recommended bisphosphonates. c. Therapy should continue until the patient has evidence of a substantial decline in performance status. d. Bisphosphonates may be used in combination with other pain therapies in patients with pain caused by osteolytic disease. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-45 Oncology Supportive Care e. A new guideline for adjuvant bisphosphonate use in breast cancer by the American Society of Clinical Oncology published in March 2017 recommends that zoledronic acid 4 mg over 15 minutes every 6 months be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. 3. Most recently updated in 2018, the American Society of Clinical Oncology published guidelines for the use of bisphosphonates in multiple myeloma. a. Patients with lytic bone destruction seen on plain radiographs should receive either pamidronate 90 mg intravenously over at least 2 hours or zoledronic acid 4 mg over 15 minutes every 3–4 weeks (dosing once every 3 months may be considered in patients with stable/responsive disease). b. Therapy should continue until there is evidence of substantial decline in a patient’s performance status. c. Patients with osteopenia but no radiologic evidence of bone metastases or compression fracture can receive bisphosphonates. d. Bisphosphonates are not recommended for patients with solitary plasmacytoma, smoldering or indolent myeloma, or monoclonal gammopathy of undetermined significance. e. Bisphosphonates may be used in patients with pain caused by osteolytic disease. 4. Standard dosing for bisphosphonates in solid tumor metastases is once every 3–4 weeks. However, recent data analyses have supported less-frequent dosing. Dosing once every 12 weeks did not increase the risk of skeletal events within 2 years in patients with at least one site of bone involvement compared with once-every-4-week dosing. 5.  Adverse events: Low-grade fevers, nausea, anorexia, vomiting, hypomagnesemia, hypocalcemia, hypokalemia, nephrotoxicity, and atypical femur fractures a. Serum creatinine should be monitored before each dose (see package insert for specific recommendations). b. Package insert recommends initiating patients on oral calcium 500 mg plus vitamin D 400 international units/day to prevent hypocalcemia. c. Several reports of osteonecrosis of the jaw occurring in patients receiving bisphosphonates have appeared in the literature. Osteonecrosis of the jaw usually follows a dental procedure or dental disorder. The long half-life of bisphosphonates in bone makes this adverse event difficult to prevent and manage. Patient education and education of dentists are important. Patients should have a dental examination with preventive dentistry before treatment with bisphosphonates. I. J. Receptor Activator of NF-κB Ligand (RANKL) Inhibitor 1. Denosumab: Fully human monoclonal antibody that targets and inhibits RANKL, a protein that acts as the primary signal to promote bone removal 2. Indication: Prevention of skeletal-related events in patients with bone metastases from solid tumors and in patients with multiple myeloma. 3. Dosage: 120 mg subcutaneously every 4 weeks 4. Adverse events: Urinary and respiratory tract infections, cataracts, constipation, rashes, hypocalcemia (especially in patients with CrCl less than 30 mL/minute), osteonecrosis of the jaw, and joint pain 5. Contraindications: Hypocalcemia. Patients should be taking calcium and vitamin D. 6. No adjustment for hepatic or renal dysfunction is needed.  djuvant analgesics are drugs whose primary indication is other than pain; they are used to manage specific A pain syndromes. Most often, adjuvant analgesics are used in addition to, rather than instead of, opioids. 1. Antidepressants (e.g., amitriptyline, duloxetine) and anticonvulsants (e.g., gabapentin, carbamazepine, pregabalin) are used for neuropathic pain (e.g., phantom limb pain, nerve compression caused by tumor). 2. Transdermal lidocaine is useful in localized neuropathic pain. 3. Corticosteroids are useful in pain caused by nerve compression or inflammation, lymphedema, bone pain, or elevated intracranial pressure. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-46 Oncology Supportive Care 4. Benzodiazepines: Diazepam, lorazepam. Useful for muscle spasms; baclofen is another alternative for intractable muscle spasms 5. Strontium-89: Radionuclide for treatment of bone pain caused by osteoblastic lesions; a single dose may provide relief for several weeks or even months; however, it is myelosuppressive. 6. NSAIDs are recommended for treating pain caused by bone metastases. Prostaglandins sensitize nociceptors (pain receptors) to painful stimuli, thus providing a rationale for using NSAIDs. K. Risk Evaluation and Mitigation Strategy (REMS) for Extended-Release/Long-Acting Opioid Analgesics 1. On June 9, 2012, the FDA announced it would require manufacturers of extended-release and longacting opioid analgesics to provide training for health care professionals who prescribe these agents. 2. Components of the REMS program a. Prescriber education: Information on extended-release or long-acting opioid analgesics; information on assessing patients for treatment with these drugs; initiating therapy, modifying dosing, and discontinuing use of extended-release or long-acting opioid analgesics; managing therapy and monitoring patients; and counseling patients and caregivers about the safe use of these drugs. Prescribers will also learn how to recognize evidence of potential opioid misuse, abuse, and addiction. b. Patient counseling: Patient counseling documents for providers will be developed to assist prescribers in counseling patients about their responsibilities for using these medications safely. Patients will receive an updated medication guide, together with their prescription, that contains information on the safe use and disposal of extended-release or long-acting opioid analgesics from their pharmacist. Guide will include instructions for patients to consult their health care professional before changing dosages, signs of potential overdose and emergency contact instructions, and advice on safe storage to prevent accidental exposure of family members. c. Short-acting opioid products are not included in this program. Patient Case Questions 3 and 4 pertain to the following case. A 75-year-old man has metastatic prostate cancer. The main sites of metastatic disease are regional lymph nodes and bone (several hip lesions). He has aching pain with occasional shooting pains. The latter are thought to be the result of nerve compression by enlarged lymph nodes. He has been taking oxycodone/acetaminophen 5 mg/325 mg 2 tablets every 4 hours and ibuprofen 400 mg every 8 hours. His current pain rating is 8/10, and he states that his pain cannot be controlled. 3. Which is the best recommendation to manage his pain at this time? A. Increase oxycodone/acetaminophen to 7.5 mg/325 mg, 2 tablets every 4 hours. B. Increase oxycodone/acetaminophen to 10 mg/325 mg, 2 tablets every 4 hours. C. Discontinue oxycodone/acetaminophen, discontinue ibuprofen, and add morphine sustained release every 12 hours. D. Discontinue oxycodone/acetaminophen and add morphine sustained release every 12 hours. 4. Which is the most appropriate adjunctive medication for this patient’s pain? A. Naproxen. B. Single-agent (single ingredient) acetaminophen. C. Gabapentin. D. Baclofen. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-47 Oncology Supportive Care III. TREATMENT OF FEBRILE NEUTROPENIA A. Principles of Chemotherapy-Induced Bone Marrow Suppression 1. Bone marrow suppression is the most common dose-limiting toxicity associated with traditional cytotoxic chemotherapy. 2. W BC = Usual range of 4.8–10.8 × 100 cells/mm3 with a circulating life span of 6–12 hours; decreased WBC = leucopenia or granulocytopenia; the risk is life-threatening infections; the risk increases with absolute neutrophil count (ANC) less than 500 cells/mm3, and the risk is greatest with ANC less than 100 cells/mm3. Because neutrophils have the fastest turnover, the effects of cytotoxic chemotherapy are greatest on neutrophils (compared with platelets or red blood cells [RBCs]). a. The nadir (usually defined by the ANC) is the lowest value to which the blood count falls after cytotoxic chemotherapy. Usually occurs 10–14 days after chemotherapy administration, with counts usually recovering by 3–4 weeks after chemotherapy; exceptions include mitomycin, decitabine, azacitidine, bleomycin, vincristine, and nitrosoureas (carmustine and lomustine), which have nadirs of 28–42 days after chemotherapy and recovery of neutrophils 6–8 weeks after treatment b. General rule for calculating ANC: ANC = WBC × percentage granulocytes or neutrophils (segmented neutrophils plus band neutrophils). Example: A patient’s WBC = 4500 cells/mm3 with 10% segmented neutrophils and 5% band neutrophils. What is the ANC? 4500 × (0.1 + 0.05) = 675 cells/m3. c. To receive chemotherapy, in general, a patient should have a WBC greater than 3000 cells/mm3 or an ANC greater than 1000 cells/mm3 and a platelet count of 100,000 cells/mm3 or more. In some protocols, consideration of the patient’s clinical status and FDA labels or package inserts specify different (lower) thresholds for administering chemotherapy; if cytopenia is attributable to disease in the bone marrow, chemotherapy (full dose) may in fact be indicated and will normalize cytopenia when disease improves with treatment; some drugs are nonmyelosuppressive (e.g., vincristine, bleomycin, monoclonal antibodies). d. The potential curability of the disease influences what action will be taken during the next cycle of chemotherapy, either dosage reduction of myelosuppressive chemotherapy (palliative intent) or support with a CSF (curative intent). Exceptions to the use of CSFs in the curative setting exist because of potential toxicities with various regimens. Use of CSFs is usually avoided in Hodgkin lymphoma with the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen because various retrospective studies have found that patients receiving ABVD who develop neutropenia rarely develop infection complications and appear to have the potential for increased pulmonary toxicities with bleomycin if CSFs are used. 3. Other factors affecting myelosuppression include previous chemotherapy, previous radiation therapy, and direct bone marrow involvement by tumor. The development of rare blood disorders (e.g., thrombotic microangiopathy or disseminated intravascular coagulation) must be ruled out in patients with malignancies who received myelosuppressive chemotherapy but experienced an unexplained delay in recovery of platelets and hemoglobin. B. Neutropenia and Febrile Neutropenia 1. Infectious Diseases Society of America guidelines for antibiotic use were updated in 2010. 2. Neutropenia is defined as an ANC of 500 cells/mm3 or less or a count of less than 1000 cells/mm3, with a predicted decrease to less than 500 cells/mm3 during the next 48 hours. 3. Febrile neutropenia is defined as neutropenia and a single oral temperature of 101°F or more or a temperature of 100.4°F or more for at least 1 hour. 4. Neutropenic patients are at an elevated risk of developing serious and life-threatening infections. 5. The usual signs and symptoms of infection (e.g., abscess, pus, infiltrates on chest radiograph) are absent, with fever often being the only indicator. In addition, cultures are typically negative. Therefore, febrile neutropenia necessitates prompt investigation and treatment. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-48