Considerations for Medications Commonly Utilized in the Oncology Population in the Intensive Care Unit

Abstract

An increasing number of oncologic patients are presenting to the intensive care unit with complications from both their chronic disease states and cancer therapies due to improved survival rates. The management of these patients is complex due to immunosuppression (from the malignancy and/or treatment), metabolic complications, and diverse medication regimens with the potential for significant drug-drug interactions and overlapping adverse effects. This chapter will provide clinicians with an overview of non-chemotherapy medications frequently encountered in the critically ill oncologic patient, with a focus on practical considerations.

Introduction

As advances in cancer therapies continue to improve, a growing number of patients are living with cancer. As such, there is an increased probability for critical care providers to encounter cancer patients within the intensive care unit (ICU). Furthermore, oncologic patients require increased utilization of resources in the ICU due to disease-related complications and/or treatment-related adverse events [124]. Metabolic complications present difficult challenges in the management of critically ill cancer patients [72]. Immunosuppression, secondary to the cancer itself or cancer-related therapies (e.g., chemotherapy, corticosteroids, hematopoietic cell transplant, etc.), places patients at an increased risk for infection. In addition, many new chemotherapy and targeted therapies have numerous adverse effects that not only increase the risk for ICU admission but require multiple other therapies to help manage these side effects.

Medication regimens for critically ill cancer patients are complex. Many patients require a large number of concomitant medications to manage the critical, oncologic, and supportive care issues encountered. Accordingly, avoidance and detection of drug-drug interactions and overlapping adverse effect profiles is of high concern. The intent of this chapter is to provide critical care practitioners with an overview of non-chemotherapy medications that are frequently encountered during the care of a critically ill cancer patient in hopes of increasing awareness of such therapy. It should be emphasized that this chapter is not all-inclusive in respect to the medications discussed and details provided, and clinicians are advised to seek additional information as applicable. In addition, medication doses are reflective of a patient with normal renal function and clinicians should refer to drug dosing references for organ dysfunction adjustments unless otherwise noted.

Antimicrobial Agents

Gram Positive Agents

Risk for methicillin resistant staphylococcus aureus (MRSA) and vancomycin resistant enterococcus (VRE) as shown in Table 1 may be heightened in the oncology population due to increased exposure to the healthcare setting and antimicrobials [11]. While initial therapy of patients with febrile neutropenia may not require coverage for MRSA, empiric antibiotic regimens for all patients progressing to sepsis or septic shock or those patients with additional risk factors should be broadened to include an agent targeting aerobic gram positive cocci [102]. For MRSA, consider early addition of vancomycin, linezolid, or daptomycin. For VRE, consider early addition of linezolid or daptomycin. Selection of a specific agent should be based on patient-specific (e.g., end organ function) as well as an infection-specific factors (e.g., source of infection). As mentioned in Table 2, use of linezolid may compromise bone marrow function; this does not preclude use of linezolid in patients with pancytopenia or thrombocytopenia, but it does justify a risk-benefit analysis inclusive of alternative options prior to therapy initiation [126]. Consider an infectious diseases (ID) consult if MRSA or VRE is isolated in the context of systemic infection [11, 43]. Discontinuation of MRSA and/or VRE therapy should be considered if a pathogen is not identified within 48–72 h of obtaining all pertinent cultures.

Table 1.

Considerations for MRSA/VRE coverage

MRSA	VRE
Vascular access devices	Previous VRE infection
Gram positive bacteremia prior to speciation	High rates of hospital endemicity
Known colonization or prior infection with MRSA	Known colonization
Clinical instability (hypotension or shock)
Skin or soft tissue infection
Pneumonia requiring ICU admission
Penicillin resistant Streptococcus pneumoniae
High rates of hospital endemicity
Severe mucositis if FQ prophylaxis + ceftazidime is employed as empiric therapy

MRSA methicillin resistant staphylococcus aureus, VRE vancomycin resistant enterococcus, ICU intensive care unit, FQ fluoroquinolone

Adapted from [11, 43]

Table 2.

Oncologic considerations for select antibiotics

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Linezolid [67, 109]	Treatment of gram positive resistant organisms (MRSA, VRE)	Dosing PO, PT, IV: 600 mg q12h Administration PO, PT: Administer without regard to food IV: Administer over 30–120 min	Monitoring Obtain weekly CBC AE/toxicities Serotonin syndrome, lactic acidosis (rare) Bone marrow suppression (thrombocytopenia is the most common)	MAO inhibitors (caution with concurrent use or within 2 weeks)	• Prolonged therapy (≥ 2 weeks) may increase risk of serious hematologic toxicity • IV formulation contains 600 mL/day D5W (caution in fluid overload and/or hyponatremia) • Not a preferred agent in resistant E. faecalis infections susceptible to beta-lactams
Aminoglycosides [14, 51, 89, 92, 97, 99, 111]	MDROs, including pseudomonas and enterobacteriaceae	Dosing Tobramycin/Gentamicin IV: 5–7 mg/kg/dose Amikacin IV: 15–20 mg/kg/dose Repeat dosing based on predicted trough	Monitoring Draw 4 h and 10 h random levels to calculate expected peak and trough Target peak for EIAD: Tobramycin/Gentamicin 20 mcg/mL; Amikacin 40 mcg/mL (For organisms with MICs of 2 mcg/mL and 4 mcg/mL, respectively) Target trough for EIAD: Tobramycin/Gentamicin < 2 mcg/mL, Amikacin < 4 mcg/mL AE/toxicities Ototoxicity Nephrotoxicity	Avoid/minimize concomitant use of neurotoxic and nephrotoxic medications	• EIAD approach aims to facilitate peak of 10 x MIC and minimize trough / probability of accumulation • Peak levels are associated with efficacy while trough concentrations are associated with nephrotoxicity • Nephrotoxicity is also exposure dependent and may develop with prolonged therapy despite EIAD approach • Use with caution in patients with neuromuscular disorders

MRSA methicillin resistant staphylococcus aureus, VRE vancomycin resistant enterococcus, PO by mouth, PT per enteral tube, IV intravenous, CBC complete blood count, AE adverse effects, MAO monoamine oxidase, D5W 5% dextrose in water, MDROs multidrug resistant organism, EIAD extended interval aminoglycoside dosing, MIC minimum inhibitor concentration

Gram Negative Agents

Empiric intravenous (IV) antibiotics with anti-pseudomonal coverage should be initiated immediately in high-risk patients with febrile neutropenia and may include piperacillin/tazobactam, ceftazidime, cefepime, meropenem, or imipenem-cilastatin [11, 43]. Unfortunately, frequent exposure to antimicrobials and repeated hospitalization result in greater risk of acquiring resistant gram-negative organisms [114].

Oncology patients are at increased risk of infections with gram negative organisms from translocation from the gastrointestinal (GI) tract, particularly in patients with mucositis or graft versus host disease (GVHD). Risk of acquiring multi-drug resistant (MDR) gram negative organisms is increased by the use of prophylactic fluoroquinolones in patients with chemotherapy-induced neutropenia [33, 71, 78]. Initial empiric coverage of extended spectrum beta lactamase (ESBL) organisms and carbapenem resistant enterobacteraciae (CRE) should be based on patient-specific factors including prior exposure of antipseudomonal prophylaxis for febrile neutropenia patients and prior infections or microbiologic culture results. Double antipseudomonal gram-negative coverage may be warranted in patients with a history of P. aeruginosa or other MDR organism colonization or in hemodynamically unstable patients. Combination therapy with an aminoglycoside should be preferred in patients recently treated with fluoroquinolone prophylaxis (Table 2) [11]. Consider an infectious disease consult for patients with multidrug resistant organisms (MDRO).

Antiviral Agents

Oncology patients, particularly those with hematologic malignancy and/or history of HCT, are at risk for viral infections as a result of their underlying malignancy, chemotherapy, prolonged neutropenia, impaired cell-mediated immunity, and/or treatment complications (e.g., GVHD) [136]. Infection with herpes simplex (HSV), herpes zoster (HZ), cytomegalovirus (CMV), and respiratory viruses (e.g., respiratory syncytial virus [RSV]) are of prominent concern. A review of the pharmacologic options for management of these infections is presented in Table 3.

Fig. 1.

How to calculate CrCL as mL/min/kg with modified Cockcroft and Gault equation for Foscarnet dosing. (Reference: (1) Foscarnet package insert)

Table 3.

Oncologic considerations for select antivirals

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Acyclovir [54, 136, 137]	HSV/HZ prophylaxis and treatment	Dosing Prophylaxis: PO, PT: 400–800 mg BID OR IV: 5 mg/kg or 2.5 mg/m2 q8–12 h (AdjBW) Treatment: IV: 10 mg/kg IBWq8h (Use adjBW for obese patients) Administration Administer over 1 h to reduce nephrotoxicity	Monitoring BUN, SCr, urine output AE/toxicities Nephrotoxicity	Monitor closely when used with other nephrotoxic medications	• Maintain adequate hydration • Avoid rapid infusion • Available as suspension for NG tube administration • Alternatively, valacyclovir, prodrug of acyclovir, may be utilized (not available IV)
Cidofovir [18, 53, 80]	Treatment of adenovirus Treatment of CMV	Dosing IV: 5 mg/kg q7 days OR 1 mg/kg 3x/week Administration High dose cidofovir must be given concomitantly with IV hydration and probenecid (2 gm PO 3 h prior to cidofovir dose, then 1 gm PO 2 and 8 h after completion of the infusion)	Monitoring SCr, urine output, and urine protein (at baseline and within 48 h of each dose), WBC AE/toxicities Nephrotoxicity Metabolic acidosis Neutropenia	Monitor closely when used with other nephrotoxic medications	• Inadequate HSV/HZ coverage when used as monotherapy – acyclovir/valacyclovir prophylaxis should be continued • Last line for CMV treatment given toxicity profile • Refer to package insert or [18] for renal dosage adjustment
Foscarnet [16, 38, 82]	Treatment of CMV	Dosing Induction: IV: 60 mg/kg q8h OR 90 mg/kg IV q12h Maintenance: IV: 90 mg/kg q24h Induction and maintenance is a minimum of 3 weeks; absolute duration also based on CMV PCR results Administration Administration rate not to exceed 1 mg/kg/minute. If given via peripheral IV, must be diluted not to exceed final concentration of 12 mg/mL	Monitoring CBC, SCr, urine output, electrolytes (Ca, Mg, K, Phos) Consider EKG AE/toxicities Nephrotoxicity, hypokalemia, hypomagnesemia, hypocalcemia, hypophosphatemia N/V/D Seizures (related to electrolyte imbalance) Diabetes insipidus (nephrogenic) QTc prolongation Anemia Granulocytopenia	Monitor closely when used with other nephrotoxic medications Monitor closely when used with other QTc prolonging medications	• Considered second line treatment for CMV if patient not responding/resistant to ganciclovir or as an alternative to avoid ganciclovir-associated myelosuppression • May be used to treat other viruses such as HHV6 • Provides HSV/HZ coverage-acyclovir/valacylovir prophylaxis should be discontinued upon initiation of treatment • Use as prophylaxis has fallen out of favor given toxicity profile • Refer to package insert for renal dose adjustment (See Fig. 1 for calculation of CrCL in mL/min/kg)
Ganciclovir [40]	Treatment of CMV	Dosing Induction: IV: 5 mg/kg q12h Maintenance: IV: 5 mg/kg q24h Induction and maintenance is a minimum of 3 weeks; absolute duration also based on CMV PCR results Administration Administer by slow IV infusion over at least 1 h	Monitoring CBC, SCr AE/toxicities Pancytopenia Nephrotoxicity – especially in elderly and with use of concomitant nephrotoxic agents	Monitor closely when used with other nephrotoxic medications	• Considered treatment of choice for CMV • Provides HSV/HZ coverage-acyclovir/valacylovir prophylaxis should be discontinued upon initiation of treatment • Pancytopenia may occur at any time, but usually occurs during the first 1 to 2 weeks of treatment • May need to provide additional support with growth factors, red blood cell transfusion, or platelets • Use as prophylaxis has fallen out of favor given toxicity profile • Refer to package insert for renal dose adjustment
Letermovir [30, 84]	CMV prophylaxis	Dosing PO/IV: 480 mg daily PO/IV: 240 mg daily if patient also receiving cyclosporine Started between Day 0 and Day 28 after allogeneic HCT in CMV sero-positive recipients and continued through day 100	Monitoring CMV reactivation, SCr AE/toxicities Tachycardia Atrial fibrillation N/V/D Peripheral edema	Inhibits: CYP3A4 (moderate)	• Currently only FDA approved for prophylaxis of CMV • If patient unable to swallow tablet whole, use IV administration of letermovir (do not crush or administer via feeding tube). • With IV therapy, monitor serum creatinine closely in patients with CrCl <50 mL/min (IV vehicle, hydoxypropyl betadex, may accumulate leading to kidney injury)
Oseltamivir [21, 52]	Influenza	Dosing PO: 75 mg BID x 5–10 days Data in immunocompromised patients is lacking for dose and duration, but given prolonged viral shedding and increased risk for progression to LRTI, higher doses and longer duration may be considered	Monitoring Signs/symptoms of unusual behavior – rare occurrence for neuropsychiatric events, SCr AE/toxicities Headache Vomiting Diarrhea/dyspepsia with suspension (contains sorbitol)	N/A	• IDSA and CDC consider patients with malignancy and/or immunosuppressive therapy to be high risk for influenza progression to LRTI • Treatment should be initiated in symptomatic immunocompromised patients regardless of duration of symptoms prior to diagnosis • Available as suspension for administration via feeding tube • Refer to package insert for renal dose adjustment
Ribavirin [22, 23, 42, 49, 58, 59, 60]	RSV treatment	Dosing Inhaled: 2 gm via SPAG unit over 3 h q8h x 5 days (Due to teratogenicity – must be administered in a scavenging tent) Two common PO / PT dosing strategies:  1. Fixed dose of 600 mg q8h  2. LD of 10 mg/kg followed by 20 mg/kg/day divided into three doses Optimal dose and duration of oral ribavirin not yet established	Monitoring Hemoglobin LFTs AE/toxicities Hemolytic anemia	N/A	• Due to short duration for treatment of RSV compared to Hepatitis C, adverse effects associated with long-term use not common • Ribavirin solution commercially available or can be compounded for administration via feeding tube • Recent increase in cost of inhaled ribavirin (~$30,000/day) –alternative methods for administration are being explored given lack of randomized controlled trials, concerns about occupational exposure, and high cost • Refer to [59] and [60] for dosing recommendations in renal dysfunction

HSV herpes simplex virus, HZ herpes zoster, PO by mouth, PT per enteral tube, BID twice daily, IV intravenous, AdjBW adjusted body weight, IBW ideal body weight, BUN blood urea nitrogen, sCr serum creatinine, AE Adverse effects, N/A not available, NG nasogastric, CMV cytomegalovirus, SCr serum creatinine, WBC white blood count, PCR polymerase chain reaction, CBC complete blood count, Ca calcium, Mg magnesium, K potassium, Phos phosphorus, EKG electrocardiogram, N/V/D nausea/vomiting/diarrhea, HHV6 human herpesvirus 6, CrCl creatinine clearance, HCT hematopoietic cell transplant, FDA Food and Drug Administration, LRTI lower respiratory tract infection, n/a not applicable, IDSA Infectious Disease Society of America, CDC Center for Disease Control, NG nasogastric, RSV respiratory syncytial virus, SPAG small particle aerosol generator, LD loading dose, LFTs Liver function tests

Many oncology patients admitted in the ICU may already be receiving antiviral prophylaxis against herpes simplex virus (HSV) and herpes zoster (HZ) with acyclovir or valacyclovir. In addition to HSV/HZ, another common pathogen observed in patients with hematologic malignancy/post-HCT is cytomegalovirus (CMV). CMV is a beta herpes virus with a seroprevalence in the United States (US) of around 60% [130]. Typically, most people are asymptomatic when primary infection with CMV occurs and then the virus enters a latent infectious state in mononuclear leukocytes. Reactivation can occur in many instances, but in relation to the oncology patient population, this can be seen during times of immunosuppression (e.g., chemotherapy administration) and critical illness as well as in the elderly [34]. Prophylaxis against CMV is not routine, given the toxicity profile of traditional anti-CMV therapy (i.e., ganciclovir and foscarnet); rather a strategy of pre-emptive monitoring has been adopted with treatment reserved for patients with presumed or documented infection [136]. Recently, the Federal Drug Agency (FDA) approved letermovir for CMV prophylaxis in HCT CMV seropositive recipients. Given the more acceptable toxicity profile of this agent and the morbidity/mortality associated with CMV infection, use of letermovir will likely increase in hopes of preventing CMV reactivation [84].

Despite preventive strategies and increased awareness, respiratory viral infections may occur, with RSV, influenza, parainfluenza, and human metapneumovirus responsible for the majority of cases. Progression to lower respiratory tract infection often presents as dyspnea and hypoxia, which can prove fatal. Unfortunately, limited options currently exist for managing these viral infections (e.g., neuraminidase inhibitors for influenza, ribavirin for RSV) and therapy is primarily supportive. Studies are needed to further elucidate high-risk patients and determine efficacy of novel antiviral agents [23]. Other viruses that may be notable for complications in cancer patients include adenovirus, human herpesvirus 6 (HHV6), polyomaviruses (BK and JC), and Epstein-Barr virus (EBV).

Antifungal Agents

Antifungal coverage should be considered in febrile neutropenic patients on broad-spectrum antibiotics who have had a persistent fever for 4–7 days and no identified fever source [43]. Antifungal therapy should also be considered in critically ill ICU patients (regardless of the presence or absence of malignancy) with suspected infection who do not improve after 72 h of broad-spectrum antibiotics [110]. For empiric coverage of Candida, use of an echinocandin (anidulafungin, micafungin, or caspofungin) is preferred, especially in patients who have been recently treated with other antifungal agents, or if Candida glabrata or Candida krusei is suspected from previous culture data [47, 114].

Hematologic malignancy patients with prolonged neutropenia, status post allogeneic HCT, and/or chronic corticosteroid exposure (e.g., GVHD) are at risk for invasive aspergillosis infections [101]. Posaconazole or voriconazole are often utilized for prophylaxis against invasive aspergillosis in high-risk patients [29, 139, 146]. In the absence of contraindications (i.e., organ dysfunction, adverse effects) or development of a breakthrough infection, antifungal prophylactic regimens should be continued following ICU admission. For patients who develop breakthrough invasive aspergillosis while receiving prophylactic azole therapy, therapeutic drug monitoring (TDM) should be performed to assess adequacy of the current regimen, if available; however, the patient will likely need to be switched to another class of medications. Voriconazole remains the treatment of choice for Aspergillus infections (Table 4). However, if the patient is unable to tolerate voriconazole therapy, isavuconazonium or the liposomal formulation of Amphotericin B (AmB) are appropriate alternative options for initial therapy. Posaconazole can be considered for salvage therapy [101].

Table 4.

Oncologic considerations for select antifungals

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Voriconazole [8, 50, 98, 101, 120]	Prophylaxis against invasive Aspergillosis Antifungal of choice for invasive Aspergillosis Step-down oral therapy for candidiasis due to C. krusei or C. glabrata (as feasible, following initial treatment with an echinocandin)	Dosing Treatment : PO (IV, PO: 6 mg/kg ABW) IV: 6 mg/kg ABW* q12h x2 doses, then 4 mg/kg q12h Prophylaxis: PO: 200 mg q12h • Administer 1 h before or 1 h after a meal. • Avoid grapefruit juice *For obese patients: use AdjBW	Monitoring Measure trough 2–5 days after initiation Prophylaxis: >1 mcg/mL Treatment: >1 mcg/mL Limited data, but target trough concentration< 5–6 mcg/mL to minimize toxicity AE/Toxicities Visual disturbances, hallucinations, skin reaction, neurotoxicity, QTc prolongation, hepatotoxicity	Inhibitor of CYP2C9, CYP3A4, and to a lesser extent, CYP2C19 P-gp inhibitor	• For subtherapeutic levels, increase IV therapy no more than 50% at a time (max 6 mg/kg twice daily). Increase PO therapy from 200 mg twice daily to 300 mg twice daily. Nonlinear pharmacokinetics result in unpredictable serum concentrations. • Caution with use of IV formulation in patients with renal dysfunction due to β-cyclodextrin solvent. Use PO therapy if feasible. • Suspension available for administration via feeding tube • Long-term use associated with rare cases of melanoma or squamous cell carcinoma • Long-term use associated with periostitis and skeletal disease due to elevated fluoride levels from triflourinated triazole chemical structure
Posaconazole [8, 56, 98, 101, 125]	Salvage therapy for invasive Aspergillosis Second line treatment for Mucormycosis	Dosing Treatment : IV/PO DR tablets: 300 mg q12h x2 doses, then 300 mg Prophylaxis: DR tablets: PO: 300 mg q12h x2 doses, then 300 mg q24h thereafter	Monitoring Measure trough 7 days after initiation Prophylaxis: >700 ng/mL Treatment: >1000 ng/mL Limited data on target trough concentration AE/Toxicities Nausea, vomiting, hepatotoxicity, QTc prolongation	Potent inhibitor of CYP3A4 Substrate and inhibitor of P-gp	• Long half-life of 26 to 31 h • The suspension form is not recommended. Variable bioavailability with food, fat, and acidity. DR tablets: • Not interchangeable with oral suspension due to increased absorption of tablet form. • Does not have to be administered with high-fat meal. • Can not be crushed for use in feeding tube. Use IV formulation in patients unable to swallow the tablet.
Isavuconazonium [41, 101, 119, 145]	Treatment for Mucormycosis Alternative primary therapy for invasive Aspergillosis	Dosing Treatment dose: IV/PO: 372 mg q8h x6 doses, then 372 mg q24h	AE/Toxicities Nausea, vomiting, diarrhea, skin reaction, hepatotoxicity	Substrate and moderate inhibitor of CYP3A4	• Limited data on isavuconazonium TDM. Does not need to be routinely monitored. • QTc shortening • IV formulation is β-cyclodextrin solvent free • Poor penetration to eyes, CNS, CSF fluid • Most well-tolerated anti-fungal from GI standpoint

IV intravenous, ABW actual body weight, PO oral, AdjBW adjusted body weight, AE adverse events, P-gp P-glycoprotein, NG nasogastric, DR delayed release, PK pharmacokinetics, TDM therapeutic drug monitoring, CNS central nervous system, CSF cerebral spinal fluid, GI gastrointestinal

Severe and prolonged immunosuppression also places patients at risk for mucormycosis infections. Posaconazole has been shown to be the most effective antifungal for prophylaxis against mucormycosis; of note, voriconazole is not active against mucormycosis. Liposomal AmB is recommended by the guidelines as the treatment of choice for mucormycosis infections; however, isavuconazonium has recently been approved with the indication as well [10]. Posaconazole is reserved for salvage therapy. Surgical interventions combined with medical treatments have been associated with higher survival rates in patients with mucormycosis when compared to pharmacologic therapy alone [28].

Cancer patients are commonly on numerous medications and chemotherapies that may interact with concomitant azole therapy. Azoles are potent inhibitors and substrates of cytochrome p450 enzymes; therefore, clinicians must be diligent about evaluating for drug-drug interactions (DDIs). In addition, azoles can cause QTc prolongation. Clinicians should monitor closely and optimize electrolytes, particularly in patients on multiple QTc prolonging medications.

Pneumocystis Jiroveci Pneumonia

Prophylaxis and treatment for pneumocystis jiroveci pneumonia (PJP) should be considered in patients with risk factors (neutropenic, immunosuppressed, long-term or high-dose steroids) who are not improving on standard antimicrobial therapy. Prophylactic therapy is usually given to oncologic patients receiving certain types of chemotherapy (i.e., alemtuzumab, purine analogs), HCT patients, or patients on immunosuppression with chronic and/or high-dose steroids. The choice of prophylaxis (e.g., sulfamethoxazole-trimethoprim [SMZ-TMP], pentamidine) is typically based on patient- and/or disease-specific factors (Table 5). Prophylaxis is usually continued until immunosuppression therapy has been discontinued and counts have recovered (absolute neutrophil count [ANC] >1000), CD4 > 200, or according to the specific chemotherapy regimens as noted on the package insert or protocol [32].

Table 5.

Oncologic considerations for Pneumocystis jiroveci pneumonia (PJP)

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Sulfamethoxazole/Trimethoprim [24, 32]	Drug of choice for treatment and prophylaxis of PJP	Dosing Prophylaxis: PO/PT: 80 mg TMP daily or 160 mg TMP three times weekly Treatment: IV/PO/PT: 15–20 mg/kg TMP given in divided doses 3–4x/day (usually 5 mg/kg q8h or q6h)	Monitoring CBC, LFTs, SCr/BUN AE/toxicities Agranulocytosis, hyperkalemia, nephrotoxicity, Stevens-Johnson syndrome, QTc prolongation	Inhibitor of CYP2C8 Substrate of P-gp	• PJP prophylaxis usually given for 3–12 months after last chemotherapy treatment • PJP prophylaxis in HCT starts at day +30 and continues for 6–12 months (or longer if still receiving immunosuppressive therapy) • IV formulation requires large volume of D5W as diluent (caution in fluid overload and/or hyponatremia) • High sorbitol content of oral suspension may contribute to diarrhea • Although treatment of choice for PJP, in hematologic malignancy/HCT, alternative therapy may need to be considered given bone marrow suppressive effects and concomitant use with other nephrotoxic medications (risk vs. benefit analysis)
Clindamycin/ Primaquine [32]	Preferred alternative PJP treatment	Dosing Treatment: Clindamycin IV (600 mg q6h or 900 mg q8h) plus Primaquine 30 mg (base) PO/PT daily	Monitoring CBC, visual color check of urine, glucose, electrolytes AE/toxicities Primaquine- hemolytic anemia, methemoglobinemia, QTc prolongation Clindamycin – diarrhea (C difficile infection)	Clindamycin: Substrate CYP3A4 (minor) Primaquine: Substrate of CYP2D6 (major) and CYP3A4 (major)	• Primaquine is contraindicated in patients with known G6PD deficiency. • Primaquine can be compounded into a suspension for administration via a feeding tube • Preferred alternative therapy for patients unable to receive SMZ-TMP
Pentamidine [32, 37]	Alternative PJP therapy	Dosing Prophylaxis: Nebulized pentamidine 300 mg every 28 days IV (limited data): 300 mg q21 days until patient able to tolerate oral alternative therapy Treatment: IV: 4 mg/kg every 24 h infused over at least 60 min for 21 days. May reduce dose to 3 mg/kg due to toxicities	Monitoring Glucose, CBC, EKG, LFTs AE/toxicities Bronchospasm, cough, fatigue, dizziness, fever, leukopenia, QTc prolongation, cardiac dysrhythmia
Atovaquone [32]	Alternative PJP prophylaxis or treatment	Dosing Prophylaxis: PO/PT: 1500 mg daily with food Treatment: PO/PT: 750 mg BID with food Administer with high fat meal to enhance oral absorption	AE/toxicities Diarrhea, transaminase elevations	Do not co-administer with rifampin	• Substantially more expensive than alternative oral regimens • Not recommended for severe PJP infections • Only available as an oral suspension
Dapsone [32]	Alternative PJP prophylaxis	Dosing Prophylaxis: PO/PT: 100 mg daily or 50 mg BID	Monitoring CBC, LFTs, reticulocyte AE/toxicities Hemolytic anemia, methemoglobinemia, rash, serious dermatologic reactions (rare)		• Use with caution in patients with known G6PD deficiency • Use with caution with patients with hypersensitivity to sulfonamides

SMZ-TMP sulfamethoxazole-trimethoprim, PJP Pneumocystis jiroveci pneumonia, PO oral, TMP trimethoprim, IV intravenously, CBC complete blood count, LFTs liver function tests, SCr serum creatinine, BUN blood urea nitrogen, AE adverse effects, P-gp P-glycoprotein, D5W 5% dextrose in water, HCT hematopoietic cell transplant, BID twice daily, G6PD glucose-6-phosphate dehydrogenase, NG nasogastric, EKG electrocardiogram

For treatment of PJP infection, sulfamethoxazole-trimethoprim (SMZ-TMP) remains the drug of choice (Table 5). However, certain circumstances preclude use of SMZ-TMP, such as an allergy to sulfa medications, the desire to avoid agents that may suppress the bone marrow (e.g., HCT patients pre-engraftment), or persistent SMZ-TMP-related hyperkalemia. In such situations, alternative agents such as clindamycin/primaquine should be considered.

Antiepileptics

Seizures are a common neurologic complication in oncologic patients, secondary to primary brain tumors, metastases, radiation toxicity, and metabolic abnormalities [57]. Selection of an antiepileptic drug (AED) warrants special consideration in the oncologic patient due to interactions with chemotherapy, side effects, and unique mechanisms of certain brain tumors. Enzyme inducing anticonvulsants such as phenytoin may lead to insufficient serum levels of concomitantly administered chemotherapy. Conversely, enzyme inhibiting anticonvulsants such as valproate may lead to toxic levels of chemotherapy [17]. AEDs that are substrates for P-gp (phenobarbital, carbamazepine, lamotrigine, topiramate, and felbamate) may result in insufficient intraparenchymal levels [88].

Patients with brain tumors are more prone to refractory epilepsy, requiring the use of multiple AEDs with different mechanisms. With the introduction of more well-tolerated AEDs, many practitioners are avoiding enzyme inducers as first-line agents [88]. While non-CYP-450 enzyme-inducing AEDs such as levetiracetam, gabapentin, and lamotrigine may be preferable in cancer patients receiving chemotherapy, levetiracetam may be preferred as an initial option in the ICU as it is available for IV administration, does not appear to be affected by P-gp expression, and has favorable pharmacokinetic properties (Table 6) [57, 142].

Table 6.

Oncologic considerations for seizures

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Levetiracetam [19, 138]	Prophylaxis or treatment of seizures	Dosing IV or PO/PT (immediate release tablet): 1000–3000 mg/day, divided doses q12h *max 4500 mg/day PO/PT: administer without regard to food Administration IV: 15 min, for SE, max 2–5 mg/kg/min	AE/toxicities CNS depression, toxic epidermal necrolysis, Stevens-Johnson syndrome, and aggression		• Dosing may be limited by somnolence • Prophylaxis may be warranted in patients receiving CAR T-cell therapy

IV intravenously, PO oral, SE status epilepticus, AE adverse events, CNS central nervous system, CAR chimeric antigen receptor

Immunosuppressants

Recipients of a HCT, particularly allogeneic HCT, require immunosuppression to prevent GVHD [149]. Tacrolimus, sirolimus, or cyclosporine are often utilized for GVHD prophylaxis (Table 7). Similar to the approach in solid organ transplant patients, these medications are managed within a narrow therapeutic window in attempt to decrease both the risk of GVHD as well as toxicities of therapy. Additionally, practitioners should remain cognizant of DDIs with these agents [1].

Table 7.

Oncologic considerations for immunosuppressants

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Tacrolimus [9, 104, 147, 148]	GVHD prevention	Dosing Starting dose CIVI: 0.03 mg/kg/day (age ≤50 y/o, no interacting medications) 0.015 mg/kg/day if one or more criteria met: age >50 y/o, renal dysfunction, interacting medication(e.g., voriconazole) Starting dose PO (in two divided doses): 0.12 mg/kg (age ≤50, no interacting medications) 0.06 mg/kg (age >50, renal dysfunction, interacting medication (e.g., voriconazole))	Monitoring Serum level: 5–15 ng/mL With continuous IV infusion can draw random level With PO dosing, should draw a trough 30 min prior to dose Wait at least 24–36 h after starting/adjusting dose for steady state AE/toxicities Neurotoxicity, PRES, nephrotoxicity, hypertension, diabetes, TMA-TTP, electrolyte imbalance (hypomagnesemia, hyper/ hypokalemia), infection	Substrate of CYP3A4 (Major) Drug-food interaction: Avoid grapefruit and pomegranate	• IV to PO conversion is 1:3 or 1:4 • Dose based on IBW • Minimal renal excretion – no dose modification needed • Clearance lowered in patients with severe hepatic dysfunction – likely dose modifications needed • Dose reductions 50–75% required when used concomitantly with voriconazole or posaconazole • If unable to swallow capsules, content of capsule may be mixed with water and flushed through feeding tube • SL administration may be used by opening the contents of the capsule under the tongue – decrease dose in half if switching from PO to SL
Cyclosporine [93, 148]	GVHD prevention	Dosing Starting dose CIVI: 3 mg/kg/day Starting dose PO-in two divided doses: 10 mg/kg/day Administration Neoral®/Gengraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably	Monitoring Goal: 200–400 ng/mL With continuous IV infusion can draw random level With PO dosing, should draw a trough 30 min prior to dose Wait at least 24–36 h after starting / adjusting dose for steady state AE/toxicities Neurotoxicity, PRES, nephrotoxicity, hypertension, hepatotoxicity, TMA-TTP, electrolyte imbalance (hypomagnesemia, hyperkalemia), hyperuricemia, infection, gingival hyperplasia, malignancy	Substrate of CYP3A4 (Major) Drug-food interaction: Avoid grapefruit and pomegranate	• IV to PO is 1:2–3 or 1:4 conversion dependent upon formulation • Dose based on IBW • Minimal renal excretion – no dose modification needed • Clearance lowered in patients with severe hepatic dysfunction – likely dose modifications needed • Dose reductions 25–50% required when used concomitantly with voriconazole or posaconazole • Suspension is available for administration via feeding tube
Sirolimus [1, 35, 108]	GVHD prevention	Dosing PO: 12 mg LD x1, then 4 mg daily OR 6 mg LD x1, then 2 mg daily	Monitoring Goal: 3–12 ng/mL Trough drawn 30 min prior to dose Due to long half-life, recommended to wait 3–4 days to check level after loading dose and reasonable to wait 1 week after dose adjustment AE/toxicities Hyperlipidemia, hypertriglyceridemia, hypertension, nephrotoxicity, hepatotoxicity (VOD), TMA-TTP	Substrate of CYP3A4 (Major) Drug-food interaction: Avoid grapefruit and pomegranate	• No IV formulation available • Suspension is commercially available for administration via feeding tube • Dose reductions 50–90% required when used concomitantly with voriconazole or posaconazole
Corticosteroids [2, 44, 45, 70, 79, 81, 85, 87, 106, 112, 113, 129, 135, 140, 141, 143]	GVHD treatment DAH IPS SCC	Dosing GVHD treatment Methylprednisolone 2 mg/kg IV in two divided doses followed by slow taper DAH/IPS Methylprednisolone 2 mg/kg IV in two to four divided doses followed by slow taper Other dosing strategy for DAH Methylprednisolone 500–1000 mg IV/day (in one to two divided doses) x 3–4 days, then taper to 1 mg/kg/day x 3 days followed by slow taper over 2–4 weeks SCC Dexamethasone 4–10 mg IV q6 h (doses range from 16 mg/day to 96 mg/day in four divided doses)	Monitoring Blood pressure, blood glucose, electrolytes, body weight, HPA axis suppression; IOP and bone mineral density (with long term use) AE/toxicities Hypertension, hyperglycemia, increased infection risk, steroid psychosis, myopathy, adrenal suppression, edema / fluid retention, electrolyte disturbances, visual impairment, increased IOP osteoporosis (Long term use)	Dexamethasone major CYP3A4 substrate and weak inducer of CYP3A4	• Concomitant use in patients receiving immune or cellular therapy should be avoided unless specifically treating toxicity related to treatment

GVHD graft vs host disease, CIVI continuous intravenous infusion, PO by mouth, AE adverse effects, PRES posterior reversible encephalopathy syndrome, TMA-TTP thrombotic microangiopathy-thrombotic thrombocytopenic purpura, IBW Ideal body weight, NG nasogastric, SL sublingual, LD loading dose, IV intravenous, VOD veno-occlusive disease, DAH Diffuse alveolar hemorrhage, IPS Idiopathic pulmonary syndrome, SCC Spinal cord compression, IOP intraocular pressure

Corticosteroids are universally utilized immunosuppressants in oncology patients. Often times, corticosteroids are included in different chemotherapy regimens, especially to treat diseases such as diffuse large b-cell lymphoma or acute lymphoid leukemia. High-dose corticosteroids are also utilized to treat a wide range of complications in cancer patients, including but not limited to GVHD, diffuse alveolar hemorrhage (DAH), idiopathic pulmonary syndrome (IPS), and spinal cord compression (SCC) (Table 7). Collaboration between the oncology and critical care teams is recommended when initiating or stopping corticosteroids in the ICU to avoid untoward interactions with ongoing oncologic treatments.

Antifibrinolytic/Antihemophilic Agents

Diffuse Alveolar Hemorrhage (DAH)

Prognosis in patients with DAH secondary to cancer therapy or sepsis is poor [39]. Pulse dose corticosteroids (methylprednisolone 1–2 mg/kg/day) with or without antifibrinolytic therapy has been used in practice but has not been consistently associated with reductions in ICU or hospital mortality, ventilator days, or ICU and hospital length of stay in the literature [77, 113, 143]. Treatment with steroids or antifibrinolytic therapy can be considered in patients at high risk of rapid clinical deterioration or death (Table 8). Agents such as recombinant factor VIIa have been used to achieve hemostasis in non-hemophiliac patients with DAH [100]. Additionally, a case series of six patients successfully used intrapulmonary factor VII as adjunctive treatment for DAH with doses ranging from 30 to 60 mcg/kg [12]. The potential benefit of antifibrinolytic and antihemophilic therapies must be weighed against the risk of thrombotic events [150].

Table 8.

Oncologic considerations for bleeding in the ICU

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Aminocaproic acid [64, 113]	DAH, oral bleeding with thrombocytopenia	Dosing DAH: IV: 4 g over 1 h, followed by continuous infusion at 1 g/h Topical for oral bleeding with thrombocytopenia: Rinse with hydrogen peroxide, then rinse with saline, followed by a third rinse with 5 ml (1.25 g) aminocaproic acid syrup for 30 sec. Repeat q4h until bleeding controlled Administration Rapid IV administration can result in hypotension, bradycardia, and/or arrhythmias	Monitoring CPK, heart rate agranulocytosis, signs and symptoms of VTE AE/toxicities Bradycardia, arrhythmias, VTE		• May accumulate in renal failure. Specific guidelines for dosage adjustments are unavailable; dose should be modified based on clinical response and degree of renal impairment
Tranexamic acid [62, 105, 123]	DAH, thrombocytopenia-related bleeding	Dosing Minimal dosing recommendations We recommend IV/PO/PT: TXA 10–15 mg/kg q8-12 h Alternate dosing regimens: Hemoptysis: 250–500 mg TXA in 500 mg/5 mL solution nebulized via facemask over 15 min Administration Hypotension can occur when infusion rates exceed 100 mg/min	AE/toxicities VTE, abdominal pain, back pain, musculoskeletal pain, myalgia		• Accumulates in renal failure. Dose adjustment needed. See package insert.
Factor VIIa, recombinant [12, 63, 95, 100, 133]	Refractory bleeding	Dosing Life-threatening bleeding: IV: 35–120 mcg/kg q2h up to 4 doses per day. Usual starting dose was 75 mcg/kg	Monitoring aPTT, DIC AE/toxicities Thromboembolism

DAH diffuse alveolar hemorrhage, IV intravenous, PO oral, CPK creatinine protein kinase, VTE venous thromboembolism, TXA tranexamic acid, aPTT activated partial thromboplastin time, PTT partial thromboplastin time, DIC disseminated intravascular coagulation, PT Prothrombin time

Thrombocytopenia

Spontaneous bleeding complications due to thrombocytopenia are common in the critically ill oncologic patient population [75]. Most patients can be managed by observation and supportive care alone. Use of antifibrinolytic agents have been used in emergency treatment of severe thrombocytopenia-associated bleeding to reduce transfusion requirements without increased risk in thromboembolic events (Table 8) but have not been shown to decrease mortality [7].

Disseminated Intravascular Coagulation (DIC)

Routine use of aminocaproic acid, tranexamic acid and recombinant FVIIa in patients with cancer-related DIC is not recommended. Practitioners may consider use of tranexamic acid in patients with therapy-resistant hyperfibrinolytic DIC bleeding (Table 8). Platelet transfusion to maintain platelets >50 × 10³/L, and transfusion of fresh frozen plasma (15–30 ml/kg) with careful monitoring, is the primary therapy in patients with DIC and active bleeding [134].

Gastrointestinal (GI) Bleeding

A large randomized control trial (RCT) is currently underway to examine the use of tranexamic acid for the treatment of GI bleeding [118].

Thrombolytics

Hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD), is a potentially life-threatening complication with a wide-ranging incidence. Severe SOS is associated with a mortality rate greater than 80% [27]. SOS is characterized by a prothrombotic, hypofibrinolytic state as a result of endothelial damage and hepatocellular injury to sinusoidal endothelial cells. Hallmark symptoms include weight gain, painful hepatomegaly, fluid retention/ascites, and hyperbilirubinemia; the reported incidence varies in part due to variable definitions and evaluated populations [36]. SOS is a complication that occurs typically within 3 weeks of a myeloablative HCT but can also be observed in patients with risk factors of pre-existing liver disease, total body irradiation or abdominal/liver radiation, or exposure to certain hepatotoxic drugs, such as inotuzumab or gemtuzumab (list of VOD/SOS risk factors is not all-inclusive) [27, 36]. Defibrotide was FDA approved in the United States in 2016 for the treatment of severe hepatic SOS after publication of a pivotal phase III trial [117]. Its proposed mechanism of action is to reduce endothelial cell activation and injury and promote restoration of the thrombo-fibrinolytic balance [116]. Due to the severity of illness associated with SOS, many patients are transferred to the ICU for continued management and administration of defibrotide (Table 9).

Table 9.

Oncologic considerations for thrombolytics

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Defibrotide [69, 117]	Hepatic SOS (VOD)	Dosing IV: 6.25 mg/kg q6h for at least 21 days and a maximum of 60 days (until SOS resolution or hospital discharge) Utilize baseline (dry) weight prior to stem cell transplant or initiation of chemotherapy Administration Administer over 2 h using 0.2 micron in-line filter via a dedicated line	Monitoring Platelets, INR, Fibrinogen AE/Toxicities Hemorrhage, Hypersensitivity reaction CI Active bleeding, hemodynamic instability requiring vasopressor support	Co-administration with systemic anticoagulation or fibrinolytic therapy is contraindicated	• For invasive procedures – discontinue defibrotide at least 2 h prior to procedure; resume treatment once the procedure-related risk of bleeding is resolved • Maintain platelets >30,000, INR <1.5, Fibrinogen >150 to decrease bleeding risk

SOS Sinusoidal obstruction syndrome, VOD Veno-occlusive disease, IV intravenous, INR International normalized ratio, AE: adverse effects, CI Contraindications

Uric Acid Reducing Agents

Over 50% of oncologic patients with high-risk for tumor lysis syndrome (TLS) require ICU admission, and nearly 1/3 of those will present with acute kidney injury (AKI). Clinicians should be familiar with the management of hyperuricemia to help preserve renal function. Hyperuricemia results from the rapid release and catabolism of intracellular nucleic acids either spontaneously or in response to chemotherapy in patients with a high tumor burden. Patients who are considered high risk for TLS should receive rasburicase over allopurinol (Table 10) [25].

Table 10.

Oncologic considerations for uric acid reduction

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Allopurinol [144]	Prevention of hyperuricemia in TLS	Dosing PO/PT: 600–800 mg daily in one to three divided doses. IV: 200–400 mg/m2 daily Administration Initiate 1–2 days before chemotherapy	Monitoring Serum uric acid levels, BUN, SCr HLA-B*5801 testing in high-risk patients (not typically feasible in acute setting) AE/Toxicities Dermatologic toxicities Hepatotoxicity (increased alkaline phosphatase) Nephrotoxicity	6-mercaptopurine, azathioprine, cyclophosphamide, thiazide, and loop diuretics, warfarin	• Preferred in patients with known G6PD deficiency • Does not lower existing uric acid levels • May require up to 72 h to effectively decrease uric acid levels • Does not warrant dose reductions in acute management of TLS • Caution in hypoxanthine/xanthine nephropathy
Rasburicase [20, 121]	Hyperuricemia associated with malignancy	Dosing IV: 3–6 mg x 1, may repeat Administration Infuse over 30 min to avoid reaction, dose 4 h prior to chemotherapy if possible	Monitoring Serum uric acid levels AE/toxicities Anaphylaxis CI: Patients with known hemolytic anemia, methemoglobinemia, and G6PD deficiency* *due to time sensitive administration, G6PD screening should not preclude administration of rasburicase acutely	N/A	• Initiate in patients with pre-existing hyperuricemia (Uric acid >7.5 mg/dL) or high-risk patients regardless of baseline uric acid levels • Achieves target uric acid lowering in ~ 4 h in most patients • Enzymatic degradation of uric acid in blood specimen will occur if left at room temperature; collect samples on ice and assay within 4 h

TLS tumor lysis syndrome, PO oral, IV intravenous, AE adverse events, G6PD glucose-6 phosphate dehydrogenase deficiency, CI contraindicated in, N/A not available

Hypercalcemia of Malignancy/Hypercalcemia Management

All patients presenting with hypercalcemia of malignancy should be given IV crystalloids at 1–2 ml/kg/h to restore intravascular volume and promote calciuresis. For patients that are fluid restricted due to other co-morbidities (e.g., heart failure), consider concomitant diuresis with a loop diuretic if necessary. Symptomatic patients presenting with abdominal pain, confusion, weakness, and electrocardiogram (EKG) changes may require a bisphosphonate +/− calcitonin. Critical care practitioners should be cognizant of all prior therapy given in order to avoid duplicating therapy and the potential development of hypocalcemia (e.g., recent bisphosphonate or denosumab administration) (Table 11).

Table 11.

Oncologic considerations for hypercalcemia of malignancy

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Calcitonin [55, 90, 132]	Acute treatment for hypercalcemia of malignancy	Dosing SQ: 4–8 units/kg q12h Skin test should be performed in patients with sensitivity to salmon calcitonin	AE/toxicities Hypocalcemia, facial flushing, local injection site edema		• Onset within 2–4 h. Tachyphylaxis develops within 48–72 h • Not to be used as single agent • Bisphosphonate therapy can be prescribed on day 1 of calcitonin (overlap therapy to compensate for slow onset of bisphosphonate)
Pamidronate [13, 26, 55, 132]	Hypercalcemia of malignancy	Dosing IVPB: 60–90 mg x1 Dose can be repeated x1 after 7 days if inadequate response to initial treatment, then do not give more than once every 28 days due to risk of renal failure Administration Infuse over 2–24 h	AE/toxicities Hypocalcemia, nephrotoxicity Flu-like symptoms (fever, chills) Bone pain Osteonecrosis of the jaw (rare)		• Onset of action 2–4 days with response duration of 1–3 weeks • Not recommended in renal dysfunction. Dosage should be modified depending on degree of renal impairment and response, but no quantitative recommendations are available. Dose reduction generally not warranted unless SCr severely elevated >4.5 mg/dL
Zoledronic acid [26, 55, 94, 132]	Hypercalcemia of malignancy	Dosing 4 mg IVPB x1 Dose can be repeated x1 after 7 days if inadequate response to initial treatment, then do not give more than once every 28 days due to risk of renal failure Administration Can be infused over 15–30 min	AE/toxicities Hypocalcemia, nephrotoxicity Flu-like symptoms (fever, chills) Bone pain Osteonecrosis of the jaw (rare)		• Convenience of administration (IVPB over 15–30 min) for outpatients • Onset of action 2–4 days with response duration of 1–3 weeks • Not recommended in renal dysfunction. Dosage should be modified depending on degree of renal impairment, but no quantitative recommendations are available. Dose reduction generally not warranted unless SCr severely elevated >4.5 mg/dL
Denosumab [4, 55, 132]	Hypercalcemia refractory to bisphosphonates	Dosing 120 mg SQ weekly x4 weeks, then every 28 days Administration Denosumab should only be administered via the SQ route. Do not administer IV, IM, or ID	AE/toxicities Hypocalcemia Osteonecrosis of the jaw		• Onset of action 2–4 days. Terminal half-life of 25.4 days after single-dose administration

SQ subcutaneous, AE adverse effects, IVPB intravenous piggy back, SCr serum creatinine, IV intravenous, IM intramuscular, ID intradermal

Interleukin-6 Receptor Antagonists

Chimeric antigen receptor (CAR) T-cell therapy induces rapid and durable clinical responses in many types of cancer but is associated with unique, acute toxicities that can be fatal. This includes both cytokine release syndrome (CRS) and cytokine-related encephalopathy syndrome (CRES). IL-6 therapy may be warranted in patients exhibiting signs and symptoms of toxicity, particularly those requiring ICU care. IL-6 receptor antagonists are indicated in patients with grade 2 and greater CRES and grade 3 and 4 CRS, and may be considered in those with grade 1 CRES and/or persistent grade 1 or 2 CRS [91].See Table 12 for considerations for IL-6 therapy for CRS or CRES.

Table 12.

Oncologic considerations for treatment of cytokine release syndrome or cytokine related encephalopathy syndrome

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Tocilizumab [48]	CRS CRES	Dosing IV: 8 mg/kg for up to 3 doses in a 24-h period (max 800 mg/dose) Administration Infuse over 1 h No premedications needed Have emergency medications immediately available in the event of hypersensitivity reaction	Monitoring prior to therapy Latent TB,CBC with diff, LFTs, lipid panel AE/Toxicities Infection, infusion reaction, anaphylaxis, GI perforation, CNS demyelinating disorders, increased cholesterol, increased LFTs, infusion reactions, neutropenia, thrombocytopenia	Theoretical increased metabolism of CYP 450 substrates	• May consider re-dosing in patients not responding or with worsening grade toxicities within 4 h.
Siltuximab [68]	CRS CRES	Dosing IV: 11 mg/kg once Administration Infuse over 1 h; complete infusion within 4 h of reconstitution No premedications needed Have emergency medications immediately available in the event of hypersensitivity reaction	Monitoring prior to therapy CBC prior to first dose AE/Toxicities Infection, infusion reaction, anaphylaxis, GI perforation, peripheral edema, fatigue (long-term exposure), pruritus, skin rash, weight gain, hyperuricemia, diarrhea, abdominal pain, arthralgia, URI, thrombocytopenia, hypertriglyceridemia	Theoretical increased metabolism of CYP 450 substrates	• Do not re-dose within 21 days • Consider in patients who fail to respond to 1–2 doses of tocilizumab

CRS cytokine release syndrome, CRES cytokine related encephalopathy syndrome, IV intravenous, TB tuberculosis, CBC complete blood count, diff differential, LFTs liver function tests, AE adverse effects, GI gastrointestinal, CNS cerebral nervous system, CBC: complete blood count, URI upper respiratory infection

Growth Factors

Colony stimulating factors (CSF) are recommended to be administered in a prophylactic manner when the risk of febrile neutropenia (FN) with a given chemotherapy regimen is 20% or higher [127]. The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommend primary prophylaxis for FN with CSFs based on factors associated with the disease, chemotherapy regimen, patient risk, and treatment intent (curative vs. palliative). Secondary prophylaxis may be warranted in patients who have FN or a dose-limiting neutropenic event [31, 127]. Additionally, CSFs may be used to reduce the length of hospitalization and time to neutrophil recovery, for HCT mobilization, and to reduce the risk of infection in patients with intermittent/persistent neutropenia status post HCT. Of note, the medical record of oncology patients admitted to the ICU should be evaluated for prior CSF administration as such therapy my confound interpretation of leukocytosis (Table 13).

Table 13.

Oncologic considerations for growth factors in the ICU

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Filgrastim [6]	Increase WBC	Dosing 5 mcg/kg/day IV/SQ	Monitoring CBC with differential AE/toxicities Common: fatigue, bone/joint pain, peripheral edema/capillary leak syndrome, thrombocytopenia, headache, splenomegaly Serious: ARDS, pulmonary infiltrates, splenic rupture	N/A	• Higher doses may be used during mobilization for HCT • Onset of action, 24 h • Duration: Counts return to baseline within 4 days • Do not administer within 24 h (before or after) of cytotoxic chemotherapy
Pegfilgrastim [5]	Increase WBC	Dosing 6 mg SQ once per chemotherapy cycle, beginning at least 24 h after completion of chemotherapy	Monitoring CBC with differential AE/toxicities Common: bone/joint/muscle pain Serious: ARDS, pulmonary infiltrates, splenic rupture	N/A	• Onset of action is 96 h(delayed compared to filgrastim) • Pegylated formulation allows for prolonged duration of action (half-life 15–80 h) • Do not administer within 14 days before or 24 h after cytotoxic chemotherapy
Romiplostim [3]	Increase platelets in chronic ITP	Dosing 1 mcg/kg SQ once weekly; increasing by 1 mcg/kg/week increments to achieve platelet count ≥50,000/mm3 (Max dose: 10 mcg/kg/week)	Monitoring CBC with differential AE/toxicities Common: headache, dizziness, abdominal pain, arthralgia, myalgia, increased circulating myeloblasts (MDA patients) Serious: angioedema, marrow fibrosis, VTE, hematology malignancy risk		• Onset of action between 4–9 days • Should be discontinued after 4 weeks if no response • Upon discontinuation of therapy, may see rebound thrombocytopenia and increased bleeding risk • May be used off label to increase platelet count if high risk for bleeding or for CIT

WBC white blood cell, IV intravenous, SQ subcutaneous, CBC complete blood count, AE adverse effects, ARDS acute respiratory distress syndrome, ITP idiopathic thrombocytopenia purpura, VTE venous thromboembolism, CIT chemotherapy-induced thrombocytopenia

Thrombopoietin and thrombopoietin mimetics are FDA approved for the treatment of chronic immune thrombocytopenia; these agents may also be helpful off label to increase the platelet count in patients with thrombocytopenic disorders [66, 74, 76]. The management of thrombocytopenia in patients with increased bleeding risk (e.g., post-surgical), chemotherapy-induce thrombocytopenia, and/or promotion of platelet engraftment after HCT are some examples of off-label uses for thrombopoietin agents, such as romiplostim (Table 13) [83, 86, 96, 128].

Antidotes

The toxicity profiles of chemotherapy regimens are often severe and adversely affect patients’ quality of life. Although most symptoms can be managed with supportive care (see Table 1 in 10.1007/978-3-319-74588-6_21), there are times when treatment interruptions or reversal are necessary.

For reversal of toxicities or overdose, infusion of antidote should be started as soon as possible (Table 14).

Table 14.

Antidotes for critically Ill oncologic patients

Drug	Primary role in therapy	Dosing and administration	Monitoring, adverse events, and toxicities	Drug-drug interactions	Clinical pearls
Sodium bicarbonate or sodium acetate [65]	Urinary alkalinization for methotrexate toxicity	Dosing Dose: IV: 50 meq/L to maximally tolerated rate (≥3 L/m2 per day) to maximize urine output and keep urine pH > 7	AE/Toxicities Metabolic alkalosis		• Limited compatibility with many other IV medications
Amifostine [122]	Cisplatin toxicity	Dosing Dose: IV: 910 mg/m2 over 15 min once daily given 30 min prior to chemotherapy. Chemotherapy should be started 15 min after completion of amifostine infusion.	Monitoring BP every 3–5 min during infusion and decrease dose for severe decrease in SBP (see dosage adjustments from package insert). If full dose cannot be administered prior to cisplatin therapy, reduce amifostine dose to 740 mg/m2 for subsequent cycles AE/Toxicities Hypotension, N/V	Patients should have antihypertensive therapy interrupted 24 h before receiving amifostine	• Cytoprotective detoxicant. Reduces ototoxicity, nephrotoxicity, and possible decrease in severity of peripheral neuropathy • Premedicate with antiemetics including dexamethasone and a serotonin 5HT3 receptor antagonist
Dexrazoxane [107]	Extravasation Doxorubicin toxicity	Dosing First infusion should be started within 6 h after extravasation IV: Day 1: 1,000 mg/m2 (max 2000 mg/day) Day 2: 1,000 mg/m2 (Max: 2000 mg) Day 3: 500 mg/m2 (Max 1000 mg) Infusions on day 2 and 3 should start at the same hour (± 3 h) as on the first day	AE/Toxicities myelosuppression		• Remove cooling procedures (e.g., ice packs) from area at least 15 min prior to administration to allow sufficient blood flow to area
Leucovorin [65]	Primary therapy for MTX toxicity	Dosing IV, IM, or PO: Initially 15 mg (10 mg/m2), then 15 mg (10 mg/m2) q6h until serum MTX <0.05 uM/L. Subsequent dosing based on follow-up MTX levels [65] If SCr ≥ 50% baseline 24 h post MTX, or if serum MTX > 5 uM/L, increase leucovorin to 100 mg/m2 IV or q3h until serum MTX < 0.05 uM/L.	AE/Toxicities Dehydration, diarrhea		• Do not administer within 2 h before or after glucarpidase • Do not exceed infusion rate of 160 mg of leucovorin per minute due to calcium content of solution
Glucarpidase [65]	MTX toxicity in patients with renal dysfunction	Dosing IV: 50 U/g over 5 min	Monitoring Serum MTX reduced by ≥97% within 15 min of dose administration		• MTX TDM is unreliable for at least 48 h following glucarpidase administration • No effect on intracellular MTX concentrations. Must be administered with high-dose leucovorin
Levocarnitine [15]	Pegaspargase-induced hepatotoxicity	Dosing IV LD: 50 mg/kg, followed by 50 mg/kg/day divided in six daily doses	AE/Toxicities Diarrhea, hypertension	Patients who are on antidiabetic agents may need dose adjustments for hypoglycemia	• Use with caution in patients with history of seizures
Methylene blue [103, 115]	Ifosfamide-induced neurotoxicity	Dosing IV: 50 mg infused up to six times daily	AE/Toxicities Contraindicated in patients with G6PD deficiency Dysgeusia, hot flashes	Avoid concomitant use with SSRIs, SNRIs, and MAOI therapy due to risk of serotonin syndrome	• Urine discoloration (blue or green) can occur due to oxidation when exposed to air
Thiamine [46, 61, 73, 131]	Ifosfamide toxicity Beriberi Wernicke’s Encephalopathy	Dosing Limited data: IV: Ifosfamide toxicity: 100 mg q4h Beriberi: IV: 100 mg/day x7 days, followed by 10 mg/day orally until complete recovery Wernicke’s Encephalopathy: IV: 200 mg TID x 5–7 days or until no further improvement in symptoms			• Consider thiamine for Wernicke in the malnourished and confused oncologic patient

IV intravenous, AE adverse effects, BP blood pressure, SBP systolic blood pressure, N/V nausea and vomiting, MTX methotrexate, IM intramuscular, PO by mouth, q3h every three hours, TDM therapeutic drug monitoring, LD loading dose, TID three times daily