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Oncology Supportive Care 6. Treatment of patients with febrile neutropenia includes a risk assessment for complications and severe infection. a. Characteristics of low-risk neutropenia include the following: ANC of 100 cells/mm3 or more and absolute monocyte count of 100 cells/mm3 or more...

Oncology Supportive Care 6. Treatment of patients with febrile neutropenia includes a risk assessment for complications and severe infection. a. Characteristics of low-risk neutropenia include the following: ANC of 100 cells/mm3 or more and absolute monocyte count of 100 cells/mm3 or more, normal chest radiograph, almost normal renal and hepatic function, severe neutropenia (100 cells/mm3 or less) for less than 7 days and resolution expected in less than 10 days, no parenteral access site or catheter site infection, early evidence of bone marrow recovery, malignancy in remission, peak oral temperature of less than 102°F, no neurologic or mental status changes, no appearance of illness, absence of abdominal pain, and no comorbid complications (e.g., shock, hypoxia, pneumonia, other deep organ infection, vomiting, diarrhea). b. The Multinational Association for Supportive Care in Cancer has developed a scoring index to help identify patients with low-risk febrile neutropenia. Scores are assessed on the basis of factors such as those listed previously. A MASCC risk index score of less than 21 indicates high-risk febrile neutropenia, whereas a score of 21 or greater indicates low-risk febrile neutropenia. c. The Clinical Index of Stable Febrile Neutropenia (CISNE) provides another risk categorization for risk of serious complications, including mortality in patients with neutropenic fever. Risk stratification is validated in adults. A CISNE score of 3 or greater indicates high-risk febrile neutropenia, and a score of less than 3 indicates low-risk febrile neutropenia. d. Febrile neutropenia that is considered to carry a low risk of complications may be treated with either oral or parenteral antibiotics in an outpatient or inpatient setting. e. Patients with high-risk febrile neutropenia (i.e., patients who do not have low-risk characteristics, as noted earlier) should receive parenteral antibiotics in the hospital. 7. Considerations in the initial selection of an antibiotic include the potential infecting organism, potential sites and source of infection, local antimicrobial susceptibilities, and organ dysfunction potentially affecting antibiotic clearance or toxicity, and drug allergy. The most common source of infection is endogenous flora, which could be gram-negative or gram-positive bacteria; the more prolonged the neutropenia (and the more prolonged the administration of antibacterial antibiotics), the greater chance of fungi playing a role in the infection. 8. Recommendations for initial empiric treatment for patients with high-risk febrile neutropenia include broad-spectrum monotherapy with an antipseudomonal β-lactam such as cefepime, a carbapenem, or piperacillin/tazobactam. 9. Parenteral combination therapy can be considered (aminoglycosides, fluoroquinolones, and/or vancomycin), especially for management of complications (e.g., hypotension and pneumonia) or if antimicrobial resistance is expected. 10. Vancomycin is not recommended as standard initial therapy in patients with febrile neutropenia but may be considered for combination therapy with an antipseudomonal β-lactam for the following: sepsis (hemodynamic instability); pneumonia (radiographic evidence); positive blood culture for grampositive bacteria; catheter-related infection; skin or soft tissue infection; colonization with methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus, or penicillin-resistant Streptococcus pneumoniae; or severe mucositis (if fluoroquinolone prophylaxis used). 11. All patients should be reassessed after 3–5 days of antibiotic therapy, and antibiotics should be adjusted accordingly. Empiric antifungal therapy and investigation for invasive fungal infections should be considered for patients with persistent or recurrent fever after 4–7 days of antibiotics whose overall duration of neutropenia is expected to be more than 7 days. 12. Prophylactic antibiotics (fluoroquinolones, trimethoprim/sulfamethoxazole) may be considered for patients who are receiving chemotherapy who are expected to be profoundly neutropenic for more than 7 days. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-49 AL GRAWANY Oncology Supportive Care IV. USE OF COLONY-STIMULATING FACTORS FOR PREVENTION OF FEBRILE NEUTROPENIA A. CSFs improve both the production and the function of their target cells. Four products and six biosimilars are currently available in the United States: Granulocyte colony-stimulating factor (G-CSF, or filgrastim [Neupogen]) or tbo-filgrastim (Granix), pegylated granulocyte colony-stimulating factor (PEG-G-CSF, pegfilgrastim [Neulasta]) granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]). The biosimilars are filgrastim-sndz (Zarxio), filgrastim-aafi (Nivestym), pegfilgrastim-bmez (Ziextenzo), pegfilgrastim-cbqv (Udenyca), pegfilgrastim-apgf (Nyvepria), and pegfilgrastim-jmdb (Fulphila). B. P  egfilgrastim, the long-acting agent, and the biosimilars pegfilgrastim-apgf, pegfilgrastim-bmez, pegfilgrastim-cbqv, and pegfilgrastim-jmdb are approved for use in patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy associated with a high incidence of febrile neutropenia. C. Studies have shown that G-CSF and GM-CSF reduce the incidence, magnitude, and duration of neutropenia after chemotherapy and bone marrow transplantation. D. Guidelines for the use of CSFs were established by the American Society of Clinical Oncology in 1994; the most recent update was published in 2015. E. CSFs are recommended for primary prophylaxis with chemotherapy regimens associated with a 20% or greater risk of febrile neutropenia. 1. G-CSF, tbo-filgrastim, GM-CSF, filgrastim-sndz, and filgrastim-aafi are all dosed at 5 mcg/kg and are given by daily subcutaneous injection. 2. To date, no large trials have compared G-CSF and GM-CSF. Therefore, although it cannot be stated unequivocally that the two are therapeutically equivalent, they are often used interchangeably. However, they have varying adverse effect profiles (increased in fluid retention and fevers with GM-CSF). 3. A meta-analysis of tbo-filgrastim and filgrastim resulted in tbo-filgrastim being noninferior to filgrastim for reducing the incidence of febrile neutropenia. Toxicities are considered similar between the two agents. 4. Pegfilgrastim is given as a single 6-mg subcutaneous dose, generally administered 24–72 hours after chemotherapy. Pegfilgrastim on-body injector is also available for administration in the outpatient setting. The on-body single-use injector can be applied on the same day of chemotherapy, but it is designed to deliver the actual dose the next day about 27 hours later. Data are available both for and against sameday dosing of pegfilgrastim, but the dosing schedule with FDA approval (day after chemotherapy) is still recommended. 5. A single dose of pegfilgrastim is as effective as 11 daily doses of G-CSF 5 mcg/kg in reducing the frequency and duration of severe neutropenia, promoting neutrophil recovery, and reducing the frequency of febrile neutropenia. After a dose of pegfilgrastim is administered, chemotherapy should not be given for 10–14 days. 6. Tbo-filgrastim was approved in an original biologics license application by the FDA in 2012. The FDA has not approved tbo-filgrastim as a biosimilar to Neupogen (filgrastim). 7. Filgrastim-sndz was the first biosimilar approved by the FDA (March 2015). Filgrastim-aafi was FDA approved in July 2018 as another biosimilar option to filgrastim. 8. The choice of CSF (pegfilgrastim vs. filgrastim) should be based on the expected duration of neutropenia and the specific anticancer regimen (e.g., short courses of a daily CSF rather than one dose of pegfilgrastim) with chemotherapy administration on a weekly schedule. 9. Adverse events associated with all three preparations appear similar; they include bone pain (most common) and fever. 10. The CSF should be initiated 24–72 hours after the completion of chemotherapy. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-50 Oncology Supportive Care 11. The package literature recommends continued administration of G-CSF until the post-nadir ANC is greater than 10,000 cells/mm3; however, both G-CSF and GM-CSF are usually discontinued when adequate neutrophil recovery is evident. To decrease cost without compromising patient outcome, many centers continue the CSF until ANC is greater than 2000–5000 cells/mm3. Note that the ANC will decrease about 50% per day after the CSF is discontinued if the marrow has not recovered (i.e., if the CSF is discontinued before the ANC nadir is reached). 12. Avoid the concomitant use of CSF in patients receiving chemotherapy and radiation therapy; the potential exists for worsening myelosuppression. F. See the American Society of Clinical Oncology guidelines for the following indications: increasing chemotherapy dosage intensity, using as adjuncts to progenitor cell transplantation, administering to patients with myeloid malignancies, and using in pediatric populations. G. American Society of Clinical Oncology Guidelines for Secondary CSF Administration (secondary prophylaxis) 1. If chemotherapy administration has been delayed or the dosage reduced because of prolonged neutropenia, then CSF use can be considered for subsequent chemotherapy cycles; administering CSF in this setting is considered secondary prophylaxis. 2. Dosage reduction of chemotherapy should be considered the first option (i.e., instead of a CSF) after an episode of neutropenia in patients being treated with the intent to palliate (i.e., not a curative intent). H. Use of CSFs for Treatment of Established Neutropenia 1. Administering CSFs in patients who are neutropenic but not febrile is not recommended. 2. Administering CSFs in patients who are neutropenic and febrile may be considered in the presence of risk factors for complications (e.g., sepsis syndrome, age older than 65, ANC less than 100 cells/mm3, neutropenia expected to be more than 10 days in duration, pneumonia, invasive fungal infection or other clinically documented infections, hospitalization at time of fever, prior episode of febrile neutropenia); CSFs may be used in addition to antibiotics to treat neutropenia in patients with these risk factors. 3. Pegfilgrastim is not approved for the treatment of established neutropenia. Patient Case Questions 5 and 6 pertain to the following case. A 50-year-old woman is receiving adjuvant chemotherapy for stage II breast cancer. She received her third cycle of AC (doxorubicin and cyclophosphamide) 10 days ago. Her CBC today includes WBC 600 cells/mm3, segmented neutrophils 60%, band neutrophils 10%, monocytes 12%, basophils 8%, and eosinophils 10%. She is afebrile. 5. Which best represents this patient’s ANC? A. 600 cells/mm 3. B. 360 cells/mm3. C. 240 cells/mm3. D. 420 cells/mm3. 6. Given this ANC, which statement is most appropriate? A. The patient should be initiated on a CSF. B. The patient should begin prophylactic treatment with either a quinolone antibiotic or trimethoprim/ sulfamethoxazole. C. The patient, who is neutropenic, should be monitored closely for signs and symptoms of infection. D. Decrease the dosages of AC with the next cycle of treatment. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-51 Oncology Supportive Care V. THROMBOCYTOPENIA A. M  egakaryocytes (platelets) = a normal range of 140,000–440,000 cells/mm3 with a circulating life span of 5–10 days. B. T  hrombocytopenia is defined as a platelet count less than 100,000 cells/mm3; however, the risk of bleeding is not substantially elevated until the platelet count is 20,000 cells/mm3 or less. Practices for platelet transfusion vary widely from institution to institution. Many institutions do not transfuse platelets until the patient becomes symptomatic (ecchymosis, petechiae, hemoptysis, or hematemesis). Other institutions transfuse when the platelet count is 10,000 cells/mm3 or less, even in the absence of bleeding. C. Caution should be used in patients receiving antiplatelet therapy. Monitor closely and consider interventions as clinically needed (i.e., holding low-molecular-weight heparin product if platelet count is less than 50,000 cells/mm3). VI. ANEMIA AND FATIGUE A. Overview of Anemia 1. Occurs in 3.4 million Americans each year and most common in women, African Americans, and older adults 2. Defined as hemoglobin (Hgb) less than 13 g/dL in men or 12 g/dL in women 3. A nemia defined as a reduction of RBC mass, number of RBCs, and Hgb concentration of RBCs 4. Caused by a deficiency, impaired bone marrow function, and peripheral causes. 5. Signs and symptoms of anemia include weakness and fatigue, irritability, tachycardia and palpitations, shortness of breath, chest pain, pale appearance, dizziness, decreased mental acuity, ecchymoses, blood in urine or stool, and hematomas. 6. There are several types of anemia, including microcytic (iron deficiency anemia), macrocytic/ megaloblastic anemia (vitamin B12 deficiency, folic acid deficiency), anemia of chronic disease (including chemotherapy-induced anemia), anemia of critical illness, hemolytic anemias, and drug-induced anemias. 7. Hematologic laboratory values: Table 5. Hematologic Laboratory Values Test Hgb Hct MCV MCHC MCH RBC Reticulocyte count RDW EPO Serum iron Reference Range M 13.5–17.5 g/dL F 12–16 g/dL M 41–53% F 36%–46% 80-96 fL 31%–37% 26-34pg 4.5-5.9 million/m3 0.5%-1.5% 11%-16% 0-19 mU/mL M 50-160 mcg/dL F 12-150 mcg/dL Definition Hgb per volume of whole blood Percentage of total blood volume composed of RBCs (3 - Hgb) Average volume of RBCs (Hct/RBC) Weight of Hgb per volume (Hgb/Hct) Percentage volume of Hgb in RBC (Hgb/RBC) RBCs per unit blood Immature RBCs RBC distribution width Endogenous erythropoietin Concentration of iron bound to transferrin Transferrin is a glycoprotein that binds and transports iron in the blood to various tissues throughout the body ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-52 Oncology Supportive Care Table 5. Hematologic Laboratory Values (Cont’d) Test TIBC Ferritin Folate Vitamin B12 Transferrin saturation Reference Range 250-400 mcg/dL M 15-200 ng/mL F 12-150 ng/mL 1.8-1.6 ng/mL 100-900 pg/mL >30% Definition Iron binding capacity of transferrin Stored iron concentration Serum folic acid Serum vitamin B12 Serum iron divided by TIBC EPO = erythropoietin; F = female; Hct = hematocrit; Hgb = hemoglobin; M = male; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cells; RDW = RBC distribution width; TIBC = iron binding capacity of transferrin. B. Microcytic Anemia 1. Iron deficiency is the most common nutritional deficiency, with laboratory values reflecting a decreased RBC, Hgb/Hct, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), iron, ferritin, and transferrin. Total iron binding capacity (TIBC) and RBC distribution width (RDW) are increased. 2. Treatment includes oral iron supplementation: 200 mg elemental iron divided twice daily or three times daily for 3–6 months. 3. Available oral iron products (multiple branded agents): Table 6. Available Oral Iron Products (multiple branded agents) Product % Elemental Elemental Iron (mg) 20 12 33 100 100 65 39 33 150 50 Ferrous sulfate 325-mg tablet Ferrous gluconate 325-mg tablet Ferrous fumarate 100-mg tablet Polysaccharide iron complex 150-mg capsule Carbonyl iron 50 mg caplet 4. Iron adverse effects include constipation and nausea or vomiting. 5. Iron products should be taken with food to avoid gastrointestinal discomfort (but absorption will be decreased). Vitamin C may increase the absorption of iron and is often used to increase the efficacy of iron products. Iron therapy may cause dark stools. 6. Parental iron products: Table 7. Parental Iron Products Iron Dextran Elemental 50 mg/mL iron Preservative None Indication Warning IDA where PO not an option Boxed warning: anaphylactic type reactions IM injection Yes Sodium Ferric Gluconate Iron Sucrose Ferumoxytol Ferric Carboxymaltose Ferric Derisomaltose 62.5 mg/5 mL 20 mg/mL 30 mg/mL 50 mg/mL 100 mg/mL Benzyl alcohol 9 mg/5 mL 20% IDA in patients on chronic HD receiving EPO Hypersensitivity reactions None None None None IDA in patients on chronic HD receiving EPO Boxed warning: anaphylactic type reactions Yes IDA with CKD Hypersensitivity reactions IDA with non–dialysisdependent CKD Hypersensitivity reactions No No IDA with non-dialysisdependent CKD Hypersensitivity reactions; iron overload No No ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-53 Oncology Supportive Care Table 7. Parental Iron Products (Cont’d) Usual dosage Test dose Common adverse events Iron Dextran Sodium Ferric Gluconate Iron Sucrose Ferumoxytol 100 mg IV push (no faster than 50 mg/min) *Large single-dose (1000 mg) infusions have been used in clinical practice Yes Pain, stinging at injection site, local discoloration at injection site, hypotension, flushing, chills, fever, myalgia, anaphylaxis 125 mg diluted in 100 ml NS over 60 min (IV injection at 12.5 mg/min) 100 mg at 1 mL undiluted solution/ min into dialysis line *Larger doses have been used off-label for convenience No Leg cramps and hypotension 510 mg IV 750 mg IV injection 1000 mg IV injection repeated repeated 7 days injection × 1 dose 3–8 days later later or 1000 mg IV injection as a single dose No Cramps, nausea or vomiting, flushing, hypotension, rash, pruritus Ferric Carboxymaltose Ferric Derisomaltose No No No Hypophosphatemia, Hypophosphatemia, Diarrhea, dizziness, nausea nausea, rash constipation, nausea, dizziness, hypotension, peripheral edema CKD = chronic kidney disease; EPO = erythropoietin; HD = hemodialysis; IDA = iron deficiency anemia; IM = intramuscular; IV = intravenous; NS = normal saline; PO = by mouth. C. Macrocytic Anemia 1. Vitamin B12 and folate deficiency are the most common causes of macrocytic anemia. Causes of B12 deficiency include inadequate intake, malabsorption, and inadequate utilization. Folate deficiency is caused by inadequate intake, decreased absorption, hyperutilization, and inadequate utilization. 2.  In B12 deficiency RBC, Hgb and Hct, and serum B12 are decreased, with an increase in MCV, MCH, methylmalonic acid, and homocysteine. Hypersegmented polymorphonuclear leukocytes may also be present on the peripheral smear. 3. In folate deficiency, RBC, Hgb and Hct, and serum folic acid are decreased, with an increase in MCV and MCH. B12 will be normal (will need to rule out this deficiency). 4.  In B12 deficiency, patients may experience neurological changes, glossitis, weakness, loss of appetite, and possibly thrombocytopenia, leucopenia, and pancytopenia. Folate deficiency also presents with glossitis and other central nervous system symptoms including weakness, forgetfulness, headache, syncope, and loss of appetite. 5. Treatment options for vitamin B12 deficiency include oral replacement daily or intramuscular replacement weekly for 1 month, then monthly. 6. Folate deficiency anemia should be treated with 1 mg of folate daily for 4 months. Pregnant women should take supplements to prevent neural tube defects in the fetus. D. A  nemia of Chronic Disease (Specifically Chemotherapy-Induced Anemia): Causes of Anemia and Fatigue in Adult Patients with Cancer 1. Unmanaged pain or other symptoms can increase fatigue. 2. Decreased RBC production because of anticancer therapy, either radiation or chemotherapy 3. Decreased or inappropriate endogenous erythropoietin production or decreased responsiveness to endogenous erythropoietin 4. Decreased body stores of vitamin B12, iron, or folic acid 5. Increased destruction of RBCs 6. Blood loss 7. Although anemia can certainly contribute to or worsen fatigue, there are probably other (perhaps many) mechanisms of fatigue (e.g., cytokines) that are independent of Hgb concentration. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-54 Oncology Supportive Care E. Principles of Anemia and Fatigue 1. Fatigue is estimated to affect 60%–80% of all patients with cancer. 2. Fatigue may be caused by the disease or treatment. 3. Fatigue can be assessed with a numeric rating scale, 0 = no fatigue and 10 = worst fatigue imaginable, or with any of several questionnaires (e.g., FACT-An). 4. Drugs used in the treatment of anemia and fatigue a. Epoetin and darbepoetin alfa (erythropoiesis-stimulating agents [ESAs]) are approved for treating chemotherapy-induced anemia, the end point of treatment being a decreased need for transfusion. Darbepoetin has additional carboxy chains, resulting in a longer half-life compared with epoetin. b. In May 2018, the FDA approved the first biosimilar for the treatment of anemia, epoetin alfaepbx, for all indications of the originator product. This biosimilar has been studied in patients with chronic kidney disease, but data are limited in patients with cancer. However, a related biosimilar, epoetin zeta, has been approved for use as a biosimilar in Europe since 2007. c. Reports of a detrimental effect of ESAs (e.g., increased deaths, reduced chemotherapy outcomes) have led to changes in practice guidelines and reimbursement for these agents. Hgb targets are lower than they were previously, and Hgb is carefully monitored. According to the most recent guidelines, ESAs are initiated once a patient’s Hgb drops below 10 g/dL. d. It is important to distinguish between the use of these agents for chemotherapy-associated anemia and cancer-associated anemia. The latter is not an approved use. These agents should be used only in the noncurative setting. e. Adverse events: Hypertension and seizures, venous thromboembolism, and pure red cell aplasia (rare) f. The use of these agents requires baseline and follow-up monitoring to determine whether agents need titration or discontinuation. 5. Transfusions are an option if patients are symptomatic. Transfusion goal is to maintain Hgb at 8–10 g/dL. When considering RBC transfusion, see the AABB 2016 clinical practice guidelines. F. Dosing of Erythropoiesis-Stimulating Agents Table 8. Dosing of Erythropoiesis-Stimulating Agents Agent Epoetin alfa or epoetin alfaepbx (Procrit, Epogen, Retacrit [biosimilar]) Darbepoetin (Aranesp) Starting Dosage 150 units/kg subcutaneously 3 times/wk 40,000 units subcutaneously weekly 2.25 mcg/kg subcutaneously weekly 500 mcg every 3 wk Dosage Increase 300 units/kg subcutaneously 3 times/wk 60,000 units subcutaneously weekly 4.5 mcg/kg subcutaneously weekly Not applicable Dosing Parameters Hgb must be < 10 to initiate and continue therapy Evaluate after 4 wk and increase dosage if rise is < 1 g/dL Decrease by ~25% if rapid rise in Hgb Discontinue therapy if no response after 8 wk Hgb must be < 10 to initiate and continue therapy Evaluate after 6 wk and increase dosage if rise is < 1 g/dL Decrease by ~40% if rapid rise in Hgb Discontinue therapy if no response after 8 wk G. REMS for ESAs 1. Historically the FDA required these agents to be prescribed and monitored under a risk management program to ensure their safety. 2. In 2017, the FDA determined that the ESA REMS, which was limited to the use of erythropoietin (Procrit, Epogen) and darbepoetin (Aranesp) to treat patients with anemia caused by chemotherapy, is no longer required. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-55 Oncology Supportive Care 3. Although the ESA REMS may no longer be required, clinicians should keep these risks in mind and continue to discuss the risk-benefit of using ESAs with each patient before initiating therapy. Patient Case 7. A 45-year-old woman is beginning her third cycle of chemotherapy for the adjuvant treatment of breast cancer. At diagnosis, her Hgb was 10 g/dL; however, today, it is less than 10 g/dL. The patient has fatigue that is interfering with her activities of daily living. Which is the most appropriate treatment option? A. Treatment with epoetin should be considered. B. Treatment with darbepoetin should be considered when Hgb decreases to less than 9 g/dL. C. The patient is being treated in the curative setting and therefore is not eligible to receive an ESA. D. The patient should not receive RBC transfusions because she is symptomatic. VII. CHEMOPROTECTANTS A. Properties of an Ideal Protectant Drug for Chemotherapy- and Radiation-Induced Toxicities 1. Easy to administer 2. No adverse events 3. Prevents all toxicities, including non–life-threatening (e.g., alopecia) toxicities, irreversible morbidities (e.g., neuropathies, ototoxicity), and mortality (e.g., severe myelosuppression, cardiotoxicity) 4. Does not interfere with the efficacy of the cancer treatment 5. To date, no such drug has been identified. B. Dexrazoxane 1. The anthracyclines (daunorubicin, doxorubicin, idarubicin, and epirubicin) and anthracenedione (i.e., mitoxantrone) can cause cardiomyopathy that is related to the total lifetime cumulative dosage. 2. Dexrazoxane acts as an intracellular chelating agent; iron chelation leads to a decrease in anthracycline-induced free radical damage. a. Dexrazoxane may be considered for patients who have received doxorubicin 300 mg/m 2 or more and who may benefit from continued doxorubicin, considering the patient’s risk of cardiotoxicity with continued doxorubicin use. b. Dexrazoxane is dosed in relation to doxorubicin at a ratio of 10:1 dexrazoxane to doxorubicin dose. c. Dexrazoxane may increase the hematologic toxicity of chemotherapy at high doses (greater than 750 mg). d. An early study suggested that dexrazoxane decreases the response rate to chemotherapy. More recent data suggest this is not the case, but dexrazoxane is still not indicated for patients with early (curable) breast cancer. 3. Dexrazoxane is also approved for use as an antidote for the extravasation of anthracycline chemotherapy. C. Amifostine 1. Amifostine is used to prevent nephrotoxicity from cisplatin. 2. It is also used to decrease the incidence of both acute and late xerostomia in patients with head and neck cancer who are undergoing fractionated radiation therapy. 3. Adverse events associated with amifostine include sneezing, allergic reactions, warm or flushed feeling, metallic taste in mouth during infusion, nausea and vomiting, and hypotension. The latter two are the most clinically significant toxicities. Prevention of hypotension includes withholding antihypertensive medications, using hydration, and close blood pressure monitoring. Because of the problems with nausea and vomiting (30%–60%) and the incidence of hypotension, this agent is not often used in clinical practice. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-56 Oncology Supportive Care D. Mesna (sodium-2-mercaptoethane sulfonate) 1. The metabolite acrolein is produced from metabolism of both cyclophosphamide and ifosfamide, and it has been implicated in sterile hemorrhagic cystitis. 2. Mesna inactivates acrolein by binding to the urotoxic metabolite and preventing its interaction with host cells in the bladder. 3. Mesna is always used with ifosfamide and may be used with cyclophosphamide (in dosages of 1500 mg/m2 or greater), although this is not a label indication. 4. Mesna may be given intravenously or orally and is usually 60%-100% of the ifosfamide dose. The oral dose is twice the parenteral dose. Several dosing schedules may be used. With any schedule, mesna must begin concurrently with or before ifosfamide or cyclophosphamide and end after ifosfamide or cyclophosphamide because of its short half-life (i.e., mesna must be present in the bladder when acrolein is present in the bladder). E. Leucovorin 1. Leucovorin rescue may be used after methotrexate doses greater than 100 mg/m2; in general, methotrexate doses greater than 500 mg/m2 require leucovorin rescue. 2. Factors that increase the likelihood of methotrexate toxicity include renal dysfunction (causing delayed elimination), third-space fluid (e.g., pleural effusion, ascites), and administration of other drugs that may delay methotrexate (pump inhibitors). Toxic reactions include mucous membrane toxicity (e.g., oral mucositis), renal and hepatic toxicity, central nervous system toxicity, and myelosuppression. 3. The dosage of leucovorin depends on the methotrexate dosage or concentration and the time since completing methotrexate. Methotrexate concentrations are usually obtained 24–48 hours after intermediate-or high-dose methotrexate, and leucovorin is continued until the methotrexate concentration decreases to less than 0.1 mM (less than 1 × 10-7 M). This regimen is typically protocol driven. 4. In contrast with its use with methotrexate, leucovorin is given in combination with fluorouracil in colorectal cancer to improve activity, not to rescue normal cells F. Glucarpidase 1. Glucarpidase, a carboxypeptidase enzyme, is now approved and indicated for treating toxic methotrexate concentrations (greater than 1 micromole/L) in patients with delayed methotrexate clearance because of renal dysfunction. 2. Administered as a single intravenous dose of 50 units/kg. 3. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for at least 3 days. However, caution must be used with administering leucovorin in conjunction with glucarpidase. 4. Leucovorin should not be administered within 2 hours before or after a dose of glucarpidase because glucarpidase can decrease leucovorin concentrations. Both are used to prevent methotrexate toxicities, so proper timing of administration is key. G. Trilaciclib 1. Approved to decrease the incidence of chemotherapy-induced myelosuppression prior to platinum/ etoposide regimens or topotecan-containing regimens for small cell lung cancer. 2. Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6, on which hematopoietic stem cells and progenitor cells in the bone marrow depend to produce neutrophils, red blood cells, and platelets. 3. Administered at the dose of 240 mg/m^2 as a 30-minute intravenous infusion that must be completed within 4 hours before the start of chemotherapy on each day chemotherapy is administered. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-57 Oncology Supportive Care Patient Cases 8. A 38-year-old woman has a history of Hodgkin lymphoma. Two years ago, she completed six cycles of ABVD chemotherapy (i.e., doxorubicin, bleomycin, vinblastine, and dacarbazine). Each cycle included doxorubicin 50 mg/m2. Recently, she was given a diagnosis of stage IV breast cancer. She will be initiated on doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for four cycles. Which statement is most applicable? A. The patient has not reached the appropriate cumulative dosage of doxorubicin to consider dexrazoxane. B. The patient has reached the appropriate cumulative dosage of doxorubicin to consider dexrazoxane C. The patient should not receive any more doxorubicin because she is at an elevated risk of cardiotoxicity. D. The patient should not receive dexrazoxane because of the possibility of increased myelosuppression. 9. Which is the best sequence for administering mesna and ifosfamide? A. Mesna before ifosfamide and then at 4 and 8 hours after ifosfamide. B. Ifosfamide before mesna and then at 4 and 8 hours after mesna. C. Mesna and ifosfamide beginning and ending at the same time. D. Mesna on day 1 and ifosfamide on days 2–5. VIII. ONCOLOGIC EMERGENCIES A. Hypercalcemia 1. The most common tumors associated with hypercalcemia are lung (metastatic non–small cell lung cancer more than small cell lung cancer), breast, multiple myeloma, head and neck, renal cell, and non-Hodgkin lymphoma. 2. Cancer-associated hypercalcemia results from increased bone resorption with calcium release into the extracellular fluid; in addition, renal clearance of calcium is decreased. a. Some tumors cause direct bone destruction, resulting in osteolytic hypercalcemia. b. Other tumors release parathyroid hormone–related protein (i.e., humoral hypercalcemia). c. Immobile patients are also at an elevated risk of hypercalcemia because of increased resorption of calcium. d. Medications (e.g., hormonal therapy, thiazide diuretics) may precipitate or exacerbate hypercalcemia. e. Corrected Ca (mg/dL) = (4 – plasma albumin in g/dL) × 0.8 + serum calcium. f. Symptoms of hypercalcemia: Lethargy, confusion, anorexia, nausea, constipation, polyuria, and polydipsia 3. Management of hypercalcemia a. Mild hypercalcemia (corrected calcium less than 12 mg/dL) may not warrant aggressive treatment. Hydration with normal saline followed by observation is an option in asymptomatic patients with chemotherapy-sensitive tumors (e.g., lymphoma, breast cancer). b. Moderate hypercalcemia (corrected calcium 12–14 mg/dL) requires basic treatment of clinical symptoms with aggressive hydration. c. Severe hypercalcemia (corrected calcium greater than 14 mg/dL; symptomatic) requires aggressive inpatient treatment. i. Hydration with normal saline about 3–6 L in 24 hours ii. Loop diuretics may be administered after volume status has been corrected or to prevent fluid overload during hydration. iii. Thiazide diuretics are contraindicated in hypercalcemia because of the increase in renal tubular calcium absorption. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-58 Oncology Supportive Care iv. B  isphosphonates bind to hydroxyapatite in calcified bone, which prevents dissolution by phosphatases and inhibits both normal and abnormal bone resorption. The onset of action is 3–4 days. v. Calcitonin (intramuscular formulation) inhibits the effects of parathyroid hormone and has a rapid-onset (though short-lived) hypocalcemic effect. May cause tachyphylaxis vi. Steroids may be used to lower calcium in patients with steroid-responsive tumors (lymphoma and myeloma). vii.  Phosphate is reserved for patients who are both hypophosphatemic and hypercalcemic. Phosphate is seldom used because of the possibility of calcium and phosphate precipitation in soft tissue. viii. Dialysis may be needed in patients with hypercalcemia and renal failure. B. Spinal Cord Compression 1. Signs and symptoms include back pain, weakness, paresthesias, and loss of bowel and bladder function. 2. Treatment consists of dexamethasone and radiation therapy or surgery. C. Tumor Lysis Syndrome 1. Occurs secondary to the rapid cell death that follows the administration of chemotherapy in patients with leukemia or lymphoma or in patients with high tumor burdens from other diseases that are also highly chemosensitive. Tumor lysis syndrome (TLS) can occur spontaneously in hematologic malignancies, without being triggered by the administration of chemotherapy (i.e., some patients present in tumor lysis). 2. Manifestations include hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Uric acid and calcium/phosphorus may precipitate in the kidney and can lead to renal failure. 3. The primary management strategy is prevention with parenteral hydration (with normal saline) and allopurinol. 4. Rasburicase is a recombinant urate oxidase that converts uric acid into allantoin, which is 5–10 times more soluble in urine than uric acid. Rasburicase should be considered for patients at high risk of developing TLS, such as those with a serum uric acid concentration greater than 8 mg/dL, a large tumor burden, preexisting renal dysfunction, or an inability to take allopurinol. The drug is expensive, and currently it is not recommended for prophylaxis in all patients but may be used together with hydration for treatment of TLS. The approved dosage is 0.2 mg/kg intravenously for five doses. There is now increasing evidence for the use of an off-label, low, fixed, single dose (3–6 mg) of rasburicase for chemotherapy-induced hyperuricemia in adults. The FDA indication is management of uric acid concentrations. Rasburicase causes enzymatic degradation of the uric acid in blood, plasma, and serum samples, potentially resulting in spuriously low plasma uric acid assay readings. Blood must be collected in pre-chilled tubes containing heparin anticoagulant; immediately immerse plasma samples for uric acid measurement in an ice water bath. IX. MISCELLANEOUS ANTINEOPLASTIC PHARMACOTHERAPY A. Extravasation Injuries 1. A vesicant is an agent that, on extravasation, can cause tissue necrosis. Vesicant antineoplastic drugs include doxorubicin, daunorubicin, epirubicin, mechlorethamine, mitomycin, vincristine, vinblastine, vinorelbine, and streptozocin. 2. Anthracyclines cause the most severe tissue damage on extravasation. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-59 AL GRAWANY Oncology Supportive Care 3. The literature generally recommends administering vesicants by parenteral injection rather than infusion, but some exceptions exist. a. Some institutional policies require infusions for every drug or approved protocols. b. Vincristine has been incorrectly administered by intrathecal injection, with fatal consequences. Dilution of vincristine for administration as a short parenteral infusion has been recommended to prevent this error from occurring. c. Paclitaxel (an irritant with vesicant-like properties) is administered as an infusion (1, 3, or 24 hours, depending on the protocol). 4. Management of extravasation a. Cold for doxorubicin, daunorubicin, and epirubicin b. Heat for vincristine, vinblastine, and vinorelbine c. Sodium thiosulfate for mechlorethamine d. Topical dimethyl sulfoxide has been recommended for anthracyclines. Its use is not as well established as that of the antidotes given earlier. Hyaluronidase is recommended for vinca alkaloids, but hyaluronidase is of limited availability. Antidotes for mitomycin, streptozocin, paclitaxel, and oxaliplatin are not well documented in the literature. e. Dexrazoxane (Totect) for doxorubicin, daunorubicin, idarubicin, and epirubicin. Cold compress should be removed 15 minutes before dexrazoxane treatment. f. Many institutions do not allow the administration of vesicants through a peripheral vein but instead require that vesicants be administered through a central line with a venous access device. Although administering vesicants through a central line minimizes the likelihood of an extravasation injury, extravasation may still occur. Management of extravasation is intended for suspected or actual extravasation from a peripheral or central vein. B. Management of Diarrhea 1. Intensive loperamide therapy using dosages higher than recommended is sometimes necessary for irinotecan-induced diarrhea. Atropine is used to prevent cholinergic activity of acute irinotecan-induced diarrhea (given during administration of chemotherapy). There is no maximal dosage of loperamide when used for delayed diarrhea in this setting (greater than 24 hours after irinotecan administration). The recommended dosing regimen of loperamide is 4 mg by mouth, followed by 2 mg every 2 hours until diarrhea free. 2. Intensive antidiarrhea treatment is also used for other agents (e.g., fluorouracil, epidermal growth factor receptor inhibitors). 3. Diarrhea/colitis caused by immunotherapy (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab) may require steroid treatment to resolve symptoms. C. Dosage Adjustment for Organ Dysfunction 1. Conflicting recommendations for dosage adjustment have been reported. Many drugs have not been studied in patients with organ dysfunction. Consultation of oncology-specific drug information resources may be useful. 2. Dosage adjustment for renal dysfunction may be considered for methotrexate, carboplatin, cisplatin, etoposide, bleomycin, topotecan, capecitabine, and lenalidomide. 3. Dosage adjustment for hepatic dysfunction is often based on total bilirubin concentrations and may be considered for anthracyclines, vinca alkaloids, taxanes, methotrexate, and other agents. D. Immunotherapy-Related Toxicities 1. There is a dynamic relationship between the immune system and cancer cells. Immune cells can detect genetic and cellular abnormalities located on cancer cells. The immune system has several mechanisms in place to regulate its activation and function. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-60 Oncology Supportive Care 2. However, malignant cells can also manipulate the activity of immune cells, allowing cancer cells to evade recognition and destruction by the immune system. 3. New breakthroughs in immunotherapy have led to many FDA approvals and treatment changes across various malignancies. These treatment developments include immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, as well as bispecific antibody therapies.. 4. Some of the most effective immunotherapies to date focus on targeting immune checkpoints that are exploited by cancers to decrease immune activity. Immune checkpoint proteins such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are closely regulated by immune cells to modulate T-cell activity. Cancer cells can disrupt various immune mechanisms, including immune checkpoints, to evade recognition by the immune system. 5. CTLA-4 and PD-1/PD-L1 inhibitors lead to the reactivation of T-cell populations inhibited by antitumor cells, allowing for immune response against cancer cells. a. CTLA-4 is expressed by CD4+ (helper), DC8+ (cytotoxic), and regulatory T cells and functions as an early inhibitory signal during the priming phase. CTLA-4 blockade results in more effector T-cell clones activating and proliferating while reducing the immunosuppressive activity of regulatory T cells. b. Ipilimumab is a CTLA-4 agent approved for various cancer types as monotherapy and in combination with the PD-1 inhibitor nivolumab. c. PD-1 receptor is present on various immune cells such as T cells, B cells, and natural killer cells. The ligands of PD-1 (PD-L1 and PD-L2) are expressed in a wide variety of tissue types. PD-L1 is commonly expressed on tumor cells, allowing for possible drug targets. PD-L2 is mainly expressed on hematopoietic cells. d. Currently available PD-1 inhibitors include cemiplimab-rwlc, dostarlimab-gxly, nivolumab, and pembrolizumab. e. Currently available PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab. 6. Because of the mechanism of immune checkpoint inhibitors, various toxicities may arise from these agents, including immune-related adverse events (irAEs). These toxicities may have an early or late onset and result from various distinct mechanisms that are not yet fully understood. One potential mechanism is T-cell activity directed at antigens present on both tumor cells and healthy tissue, leading to toxicity. a. Immune-related toxicities to monitor patients for include the following: diarrhea/colitis, fatigue, hepatitis, hypophysitis, thyroid disorders (hypo/hyperthyroidism), pneumonitis, myocarditis, nephritis, uveitis, and dermatitis. b. Patients should be monitored closely for irAEs and counseled on signs and symptoms of these toxicities. c. ASCO and NCCN have developed guidelines for the management of immune checkpoint inhibitor toxicities. d. General treatment recommendations for moderate to severe (grade 2–4) irAEs involve holding immunotherapy and initiating high-dose corticosteroid treatment with prednisone/methylprednisolone (1–2 mg/kg/day). Severe toxicity management may require inpatient admission and treatment with intravenous corticosteroids. Thyroid disorders are an exception and are not typically treated with corticosteroids. Instead, thyroid replacement therapy is used for hypothyroidism, and supportive care management is used for thyrotoxicosis. Thyrotoxicosis often evolves to hypothyroidism requiring thyroid replacement therapy (50%–90%). e. If patients have irAEs that are refractory to high-dose corticosteroid treatment (i.e., no improvement in 1–2 days), other immunosuppressive therapies such as infliximab can be used. Vedolizumab may be considered in patients whose disease is refractory to infliximab and/or for tumor necrosis factor (TNF) alpha blockers such as infliximab are contraindicated. Mycophenolate mofetil should be used for corticosteroid-refractory hepatitis instead of infliximab because of the potential risk of idiosyncratic liver failure with infliximab. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-61 Oncology Supportive Care 7. CAR T-cell adverse reactions a. Cytokine release syndrome (CRS) is a complication related to CAR T-cell administration that occurs in over 50% of patients receiving therapy. CRS results from a massive release of various cytokines (including interleukin [IL]-6, interferon, and TNF). Typical onset is after 2–3 days and typical duration is 7–8 days. Symptoms range from mild to severe and include flu-like symptoms, fever, fatigue, rash, nausea/vomiting, hypoxemia, and hypotension. Treatment involves symptom management, supportive care, and IL-6 inhibitors such as tocilizumab. Corticosteroids can be added to tocilizumab therapy for higher-grade CRS. b. Immune effector cell–associated neurotoxicity syndrome (ICANS) is another complication related to CAR T-cell therapy that occurs in around 30%–50% of patients. Typical time to onset is 4–10 days and typical duration is 14–17 days. Symptoms range from mild to severe and include seizure, encephalopathy, and cerebral edema. Management includes supportive care and intravenous fluids, corticosteroids, anti–IL-6 therapy (tocilizumab), and seizure management. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-62