Jadpro 12 810

REVIEW
Premedications for Cancer

Therapies: A Primer for the
Hematology/Oncology Provider
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial Non-Derivative License, which permits unrestricted
non-commercial and non-derivative use, distribution, and reproduction in any medium, provided the original work is properly cited.
AMBER CLEMMONS,1,2 PharmD, BCOP, ARPITA GANDHI, 3 PharmD, BCOP,

ANDREA CLARKE, 2 PharmD, SARAH JIMENEZ, 2 APN-BC, AGACNP, AOCNP®, THUY LE, 2 MD,
and GERMAME AJEBO, 2 MD
From 1University of Georgia College of Pharmacy,

Abstract
Augusta, Georgia; 2Augusta University Medical
Center, Augusta, Georgia; 3Emory Healthcare, Chemotherapeutic agents and radiation therapy are associated with
Atlanta, Georgia numerous potential adverse events (AEs). Many of these common AEs,
Authors’ disclosures of conflicts of interest are namely chemotherapy- or radiation-induced nausea and vomiting, hy-
found at the end of this article. persensitivity reactions, and edema, can lead to deleterious outcomes
Correspondence to: Amber B. Clemmons, (such as treatment nonadherence or cessation, or poor clinical out-
PharmD, BCOP, University of Georgia College of comes) if not prevented appropriately. The occurrence and severity of
Pharmacy, 914 New Bailie Street, Augusta, GA
30912. E-mail: [email protected]
these AEs can be prevented with the correct prescribing of prophy-
lactic medications, often called “premedications.” The advanced prac-
https://doi.org/10.6004/jadpro.2021.12.8.4
titioner in hematology/oncology should have a good understanding
© 2021 Harborside™ of which chemotherapeutic agents are known to place patients at risk
for these adverse events as well as be able to determine appropriate
prophylactic medications to employ in the prevention of these adverse
events. While several guidelines and literature exist regarding best
practices for prophylaxis strategies, differences among guidelines and
quality of data should be explored in order to accurately implement
patient-specific recommendations. Herein, we review the existing lit-
erature for prophylaxis and summarize best practices.
V
irtually all anticancer ed that all hematology/oncology
regimens have potential practitioners be well versed in these
adverse events. Often, potential adverse events and the
some of these adverse premedications necessary to mini-
events, such as chemotherapy- and mize their occurrence and severity
radiation-induced nausea and vom- (Roeland et al., 2020).
iting (CINV; RINV), infusion re- Chemotherapy-induced nausea
actions (IRs), and edema, can be and vomiting is one of the most dis-
prevented or ameliorated by the tressing and frequent side effects of
administration of premedications. cancer treatment and can have a sig-
J Adv Pract Oncol 2021;12(8):810–832 Therefore, it is highly recommend- nificant impact on a patient’s quality
J Adv Pract Oncol 810 AdvancedPractitioner.com

PREMEDICATIONS REVIEW
of life. Unless adequately prevented and treated, guidelines and evaluate their limitations in order
CINV can lead to adverse outcomes such as meta- to optimally tailor CINV prophylaxis for each pa-
bolic derangements, nutritional depletion and an- tient. Herein, only recommendations for adult pa-
orexia, esophageal tears, premature withdrawal of tients are discussed.
antineoplastic treatment, and/or degeneration of Guidelines divide anticancer therapies into
self-care and functional ability (National Compre- four risk categories: highly emetogenic chemo-
hensive Cancer Network [NCCN], 2021). therapy (HEC), moderately emetogenic chemo-
Infusion reactions (often referred to as “hy- therapy (MEC), low emetogenic chemotherapy
persensitivity reactions”) are defined as unexpect- (LEC), and minimally emetogenic, which causes
ed reactions that cannot be explained by a drug’s CINV in > 90%, 30% to 90%, 10% to 30%, and ≤ 10%
known toxicity profile. These are either allergic of patients, respectively (NCCN, 2021). Guidelines
reactions to foreign proteins (generally immuno- also delineate recommended prophylaxis regi-
globulin E [IgE]-mediated) or non–immune-me- mens needed in acute (within first 24 hours) vs.
diated reactions (Chung, 2008). Infusion reactions delayed (> 24 hours after chemotherapy) phases.
can range from mild (e.g., flushing, itching, fever, Chemotherapy-induced nausea and vomiting can
and/or shaking chills) to severe and even fatal re- also be classified as anticipatory (conditioned re-
actions (e.g., dyspnea, throat tightening, hypoxia, sponse and occurs before chemotherapy begins),
and/or seizures). Identifying and treating IRs is breakthrough (occurs within 5 days of prophy-
critical, as failure to do so can lead to potentially lactic antiemetics and requires rescue therapy),
avoidable morbidities and mortalities, particularly refractory, and chronic (Grunberg et al., 2005;
upon reexposure. Hesketh, 2008; Kris et al., 2011). Chronic CINV
Fluid retention is an adverse event associated in advanced cancer patients is associated with a
with the taxoid group of drugs and can occasion- variety of poorly understood potential etiologies
ally lead to discontinuation of treatment (Lagrue (Schwartzberg et al., 2006).
et al., 1979; Taylor, 1984; Vayssairat et al., 1993). Existing guidelines differ in their scope and
Patients typically present with peripheral edema, frequency of updates (i.e., evidence-based vs.
which starts at the lower extremities (ankles) but consensus-based). The NCCN (2021) produces
can progress to generalized anasarca. Corticoste- consensus-based antiemetic guidelines with sup-
roid premedication has been effective for this par- porting evidence that are updated as frequently
ticular adverse effect. as panel members determine necessary, while
In this review, we present concise evidence- American Society of Clinical Oncology (ASCO)
based recommendations for use of premedica- antiemetic evidence-based guidelines were last
tions aimed at assisting clinicians in their ev- updated and published in 2020 (Hesketh et al.,
eryday decision-making for commonly used 2020). The Multinational Association of Support-
anticancer regimens. ive Care in Cancer/European Society of Medical
Oncology (MASCC/ESMO) antiemetic guidelines
PROPHYLAXIS FOR CINV are evidence based and were recently updated in
Intravenous Chemotherapy July 2019 (slide deck version), although the most
Current management of CINV remains subopti- recent peer-reviewed publication is from 2016
mal despite the availability of effective antiemet- (Roila et al., 2016). Within these guidelines, con-
ics and existence of several guidelines (Hesketh sensus exists on a few key principles, as shown in
et al., 2020; NCCN, 2021; Razvi et al., 2019; Roila Table 1.
et al., 2016). Reasons may include poor adherence While these guidelines agree on key prin-
to existing antiemetic guidelines, patient-specific ciples, numerous differences are worth noting;
characteristics and factors not included in current however, it is important to highlight that some of
CINV guidelines, antiemetic regimen not tailored the variations reflect the information available at
to individual risk for CINV, and others (Clemons, the time of guideline publication. Therefore, prac-
2018; Roeland et al., 2020). A need exists for practitioners should consider this point when choos-
titioners to compare recommendations among ing a guideline recommendation to implement for
AdvancedPractitioner.com 811 Vol 12  No 8  Nov/Dec 2021

REVIEW CLEMMONS et al.
Table 1. Key Principles of Antiemetics for CINV

• First and foremost, CINV prophylaxis should be initiated prior to chemotherapy with > 10% risk of CINV
(i.e., LEC, MEC, and HEC).
• Antiemetic(s) (either as monotherapy or in combination) should be continued for long enough to cover the duration
of emetic risk.
• For combination chemotherapy regimens, the agent with the highest emetogenic potential should guide selection of
antiemetic prophylaxis.
• For breakthrough CINV, general consensus is to reevaluate emetic risk, disease status, concurrent illnesses, and
medications, and ascertain that the best regimen is being administered for the emetic risk. It is also a general
consensus to add an antiemetic with a different mechanism of action than that of those used in the previous cycle of
chemotherapy.
» Olanzapine is the first-line agent for management of breakthrough CINV.
Note. CINV = chemotherapy-induced nausea and vomiting; LEC = low emetogenic chemotherapy;
MEC = moderately emetogenic chemotherapy; HEC = highly emetogenic chemotherapy.
individual patients. Antiemetic recommendations CINV based on trial data (Chiu et al., 2016; Na-
for IV chemotherapy are summarized in Table 2, vari et al., 2016), while MASCC considers addi-
while specific dosing information is provided in tion of olanzapine (Zyprexa) to NK1-RA–based
Table 3. triplet therapy as optional. The recommenda-
tion is based on a trial by Navari and colleagues
Differences Among CINV Guidelines (2016) which found olanzapine-based quadru-
Classification of Emetic Risk. Several differences plet therapy led to superior complete response
exist among the guidelines. Namely, carboplatin (CR) rate (no emesis, no rescue) for acute (86%
(Paraplatin) AUC ≥ 4, doxorubicin (Adriamycin) ≥ vs. 65%, p < .001), delayed (67% vs. 52%, p =
60 mg/m2, ifosfamide (Ifex) ≥ 2 gm/m2/dose, and .007), and overall time periods (64% vs. 41%, p <
epirubicin (Ellence) > 90 mg/m2 are classified as .001) when compared with NK1-RA–based trip-
HEC per NCCN, but as MEC per ASCO and MAS- let therapy.
CC/ESMO; carmustine (BiCNU) > 250 mg/m2 is For prevention of delayed CINV, ASCO no
HEC per NCCN while ASCO and MASCC/ESMO longer recommends administration of dexameth-
classify it as HEC without any dose limit; thiotepa asone on days 2 to 4 following doxorubicin and
(Thioplex) and romidepsin (Istodax) are classi- cyclophosphamide (Cytoxan) chemotherapy (AC
fied as LEC per NCCN, but MEC per ASCO and regimen for breast cancer), whereas MASCC/
MASCC/ESMO; alemtuzumab (Campath) is mini- ESMO and NCCN state that administration can
mal per NCCN, but MEC per ASCO and MASCC/ continue (Hesketh et al., 2020; NCCN, 2021; Roila
ESMO. Further, as NCCN is updated more fre- et al., 2016). ASCO’s recommendations are based
quently, novel agents are incorporated that are not on two randomized controlled trials, which evalu-
listed in previously published ASCO or MASCC/ ated the safety and efficacy of NK1-RA in patients
ESMO guidelines (Hesketh et al., 2020; NCCN, on AC regimens in which dexamethasone was only
2021; Roila et al., 2016). administered on day 1 (Aapro et al., 2014; Warr et
Choice of 5-HT3 Receptor Antagonist (RA). al., 2005).
ASCO states no 5-HT3-RA is preferred while Carboplatin Classification and Recommenda-
MASCC/ESMO does not comment; however, tions. NCCN classifies carboplatin when dosed at
NCCN recommends either palonosetron (Aloxi) AUC ≥ 4 as HEC, while ASCO and MASCC/ESMO
or subcutaneous (SC) granisetron extended-re- classify this as MEC. For these patients, ASCO and
lease injection (Sustol) as preferred 5-HT3-RA for MASCC/ESMO recommend NK1-RA–based trip-
MEC when used with dexamethasone (Decadron) let therapy, while NCCN recommends quadruplet
two-drug antiemetic regimens (i.e., no neuroki- therapy (Hesketh et al., 2020; NCCN, 2021; Roila
nin-1 [NK1] RA; Gralla et al., 2003; Hesketh et al., et al., 2016; Yahata et al., 2016). NCCN changed the
2020; NCCN, 2021; Roila et al., 2016). emetogenic classification for carboplatin when
Prophylaxis of HEC. NCCN and ASCO rec- dosed at AUC ≥ 4 to HEC a few years ago because
ommend a four-drug combination for acute its emetogenicity is on the higher end within the

Table 2. CINV Prophylaxis Recommendations for IV Chemotherapy

ASCO MASCC/ESMO NCCN
HEC Acute 5-HT3-RA + dex + NK1-RA + 5-HT3-RA + dex + NK1-RA Option 1: 5-HT3-RA + dex
phase olanzapine +/- olanzapine + NK1-RA + olanzapine
(preferred)
Option 2: Any 5-HT3-RA +
dex + NK1-RA
Option 3: palonosetron + dex
+ olanzapine
Delayed Non-AC: dex days 2-4 + oral Non-AC: dex days 2–4 Olanzapine days 2–4 +
phase aprepitant (if used on day 1) aprepitant po days 2–3 (if
AC: aprepitant (if used on
days 2–3 + olanzapine days used on day 1) + dex days 2–4
day 1) or dex days 2–3 +/-
2–4 olanzapine. Note: no further Olanzapine days 2–4
AC: aprepitant (if given on prophylaxis if fosaprepitant Aprepitant po days 2–3 (if
day 1) + olanzapine (Emend for injection), used on day 1) + dex days 2–4
netupitant (Akynzeo), or
rolapitant used on day 1
Carboplatin Acute 5-HT3-RA + dex + NK1-RA, 5-HT3-RA + dex + NK1-RA Same as HEC above
phase when dosed at AUC ≥ 4
Delayed No prophylaxis Aprepitant days 2 and 3 if Same as HEC above
phase used on day 1
MEC Acute 5-HT3-RA + dex 5-HT3-RA + dex Option 1: 5-HT3-RA + NK1-RA
phase + dex
Option 2: 5-HT3-RA + dex
Option 3: Olanzapine +
palonosetron + dex
Delayed Dex only if patients Dex only if patients receiving 5-HT3-RA or dex or
phase receiving therapies therapies with known olanzapine (on days 2 and 3
with known potential potential for delayed CINV only if given on day 1)
for delayed CINV (i.e., (i.e., oxaliplatin, anthracycline,
Aprepitant (if given on day 1)
oxaliplatin, anthracycline, cyclophosphamide)
+/- dex on days 2 and 3
cyclophosphamide)
LEC Acute 5-HT3-RA or dex Dex or 5-HT3-RA or Dex or metoclopramide or
phase dopamine RA prochlorperazine or 5-HT3-RA
Delayed None None None
phase
Minimal Acute None None None
phase
Delayed None None None
Note. ASCO = American Society of Clinical Oncology; MASCC = Multinational Association of Supportive Care in
Cancer; ESMO = European Society for Medical Oncology; NCCN = National Comprehensive Cancer Network; RA =
receptor antagonist; dex = dexamethasone; AUC = area under the curve; LEC = low emetogenic chemotherapy; MEC
= moderately emetogenic chemotherapy; HEC = highly emetogenic chemotherapy. Information from Hesketh et al.
(2020); NCCN (2021); Roila et al. (2016).
MEC group (i.e., potential to cause CINV is closer triplet or olanzapine-based triplet for select pa-
to 90%). While NCCN classifies carboplatin AUC tients with additional risk factors. Notably, most
≥ 4 as HEC, no trial data exists for the four-drug evidence for olanzapine in CINV prophylaxis is
combination regimen for this specific population for patients receiving HEC, and methodologi-
(NCCN, 2021). cal flaws exist in the limited data available for
Prophylaxis of MEC. ASCO, MASCC/ESMO, MEC (Hesketh et al., 2020; NCCN, 2021; Roila
and NCCN recommend the 5-HT3-RA doublet. et al., 2016). In a meta-analysis by Chiu and col-
Only NCCN also recommends NK1-RA–based leagues (2016), none of the studies included trials

Table 3. Antiemetic Dosing for Prophylaxis With IV Chemotherapy Regimensa

Agent Dosing
NK1-RA
Aprepitant (po) 125 mg on day 1, 80 mg on days 2 and 3
Aprepitant emulsion (Cinvanti; IV) 130 mg on day 1
Fosaprepitant (IV) 150 mg on day 1
Rolapitant (Varubi; po) 180 mg on day 1
5-HT3-RA
Ondansetron (po) 16–24 mg on day 1; 8 mg twice daily or 16 mg daily on
subsequent daysb
Ondansetron (IV) 8–16 mg on day 1 and subsequent daysc
Palonosetron (IV) 0.25 mg on day 1
Granisetron SQ 10 mg on day 1
Granisetron po (Kytril) 2 mg on day 1
Granisetron IV (Kytril) 10 μg/kg (max 1 mg) on day 1
Granisetron patch (Sancuso) 3.1 mg/24-hour transdermal patch applied 24–48
hours prior to first dose of chemotherapy
Dolasetron (Anzemet; po) 100 mg on day 1
Combination products
Netupitant palonosetron (NK1-RA/5-HT3-RA; po) 300 mg/0.5 mg
Fosnetupitant palonosetron (Akynzeo; NK1-RA/5-HT3-RA; IV) 235 mg/0.25 mg
Other agents
Olanzapine (po) 5–10 mg on day 1 and subsequent days
Dexamethasone (po or IV) 12 mg on day 1d; 8 mg on subsequent dayse
Lorazepam (Ativan; po/IV/SL) 0.5–2 mg every 6 hours
Prochlorperazine (oral/IV) 10 mg every 6 hours
Prochlorperazine (pr) 25 mg every 12 hours
Promethazine (Phenergan; po) 12.5–25 mg every 4 to 6 hr
Promethazine (pr) 25 mg every 12 hours
Metoclopramide (po, IV) 10–20 mg every 4 to 6 hr
Scopolamine (Transderm Scop; transdermal) 1.5 mg (1 patch) every 72 hr
Note. aAlways consult up-to-date drug information resources when prescribing any antiemetic agent.
b
ASCO includes 8 mg oral twice daily as an option for day 1.
MASCC guideline does not distinguish dosing between day 1 and subsequent days. Recommendation is 8 mg or 0.15
c
mg/kg IV and 16 mg po. ASCO recommends ondansetron 0.15 mg/kg IV. Notably, FDA recommends a maximum of 16
mg for a single dose of IV ondansetron to prevent prolongation of the QT interval of the ECG.
ASCO recommends dexamethasone 20 mg oral or IV if used concomitantly with rolapitant for CINV prophylaxis from
d
MEC or HEC. MASCC/ESMO recommends dexamethasone 20 mg oral or IV for prevention of acute emesis from HEC
except when used in combination with fosaprepitant or netupitant, in which case 12 mg oral or IV is recommended. In
addition, MASCC/ESMO recommends 8 mg oral or IV on day 1, followed by 8 mg oral or IV daily on days 2–3.
ASCO includes dexamethasone 8 mg oral or IV twice daily as an option for day 3 and 4. MASCC/ESMO recommends
e
dexamethasone 8 mg oral or IV twice daily on days 3 and 4.
assessing only MEC. Results from another small limited in scope because only 50% of those classi-
trial that evaluated olanzapine, palonosetron, and fied as MEC received non-AC chemotherapy (Na-
dexamethasone in patients receiving MEC were vari et al., 2007).

Duration of Dexamethasone for MEC. NCCN added a caveat that olanzapine 2.5 mg may be
recommends dexamethasone continue through considered in patients who have excessive seda-
the entire risk period, which is 2 days after the last tion with a 5-mg dose, although no clinical trial
dose of MEC, whereas ASCO does not endorse data were cited.
routine use beyond day 1 due to absence of high- Prophylaxis for Hematopoietic Cell Transplan-
quality evidence for dexamethasone in delayed tation (HCT). ASCO and MASCC/ESMO support
emesis prophylaxis for all MEC agents (Hesketh the use of a three-drug combination (NK1-RA,
et al., 2020; NCCN, 2021). Adult patients who are 5-HT3-RA, dexamethasone) in patients receiving
treated with cyclophosphamide, doxorubicin, ox- high-dose chemotherapy for HCT (Hesketh et al.,
aliplatin (Eloxatin), and other MECs known to 2020; Roila et al., 2016). This recommendation is
cause delayed nausea and vomiting may be offered based on three randomized, placebo-controlled
dexamethasone on days 2 and 3. Similarly, MAS- trials finding that the addition of aprepitant to
CC/ESMO recommends continuing dexametha- 5-HT3-RA and dexamethasone resulted in sig-
sone for delayed CINV prevention only if patients nificantly improved nausea control (Schmitt et
are receiving therapies with known potential for al., 2014; Stiff et al., 2013; Svanberg & Birgegård,
delayed CINV (oxaliplatin, anthracycline, and cy- 2015). NCCN does not provide specific recom-
clophosphamide; Roila et al., 2016). mendations for this population; however, it cites
Prophylaxis for Multiday Chemotherapy. Mul- a study of four-drug combination therapy (NK1-
tiday chemotherapy presents a uniquely compli- RA, 5-HT3-RA, dexamethasone, olanzapine) in
cated scenario since overlap of acute and delayed patients receiving HEC for HCT (NCCN, 2021).
CINV exists after the first day of chemotherapy. In this phase III randomized trial, CR rate for
Guidelines offer general recommendations to those receiving the four-drug olanzapine regimen
tailor therapy based on practical issues, such as vs. those receiving the three-drug regimen was
inpatient vs. outpatient setting, preferred route 55% vs. 26% in the overall phase (p = .003) and
of administration, tolerability of daily antiemet- 60.8% vs. 30% (p = .001) in the delayed phase, re-
ics, adherence/compliance issues, and individual spectively (Clemmons et al., 2018). Additionally,
patient risk factors. Further, ASCO and NCCN based off this same study, ASCO now includes the
recommend offering antiemetics that are appro- option of adding olanzapine to the three-drug
priate for the emetic risk of the anticancer agent combination for the adult HCT population (Hes-
administered on each day of the treatment and for keth et al., 2020).
2 days after the completion of the anticancer ther- Breakthrough CINV. Both ASCO and NCCN
apy (Hesketh et al., 2020; NCCN, 2021). MASCC/ recommend adding olanzapine to standard an-
ESMO makes a specific recommendation for meta- tiemetic therapy if patients experience break-
static germ cell tumor patients receiving multiday through CINV despite optimal prophylaxis if
cisplatin (Platinol) to receive aprepitant (Emend), prophylaxis did not originally include olanzapine
5-HT3-RA, and dexamethasone for prevention of (Hesketh et al., 2020; Navari et al., 2013; NCCN,
acute CINV with aprepitant and dexamethasone 2021). MASCC/ESMO does not comment on pre-
for prevention of delayed CINV (Roila et al., 2016). ferred breakthrough antiemetic (Roila et al., 2016).
Olanzapine Dose. Both NCCN and MASCC/ Adjunctive Agents. Only NCCN specifically
ESMO guidelines acknowledge sedation as a con- recommends considering histamine-2 receptor
cern related to 10-mg doses and suggest a lower antagonists (H2RAs) or proton pump inhibitors in
dose in certain populations (i.e., elderly or overse- patients with dyspepsia, as this may mimic nausea
dated) based on a phase II trial (Roila et al., 2016; (NCCN, 2021).
Zhou et al., 2020). The option for a lower dose (5
mg) is included in the updated ASCO guideline Oral Chemotherapy
dosing table (Hesketh et al., 2020). A phase III Recommendations are severely limited for CINV
trial found efficacy with 5 mg olanzapine added prevention in patients receiving oral chemothera-
to standard NK1-based triplet regimen (Hashi- py. Nearly all clinical trials for CINV prophylaxis
moto et al., 2020). In the 2020 update, NCCN focus on patients who are receiving IV chemo-

therapy or radiation. Neither NCCN, ASCO, nor of high-quality data (Hesketh et al., 2020; Roila
MASCC/ESMO guidelines provide primary ref- et al., 2016).
erence citations for prophylaxis of oral chemo- In addition to the lack of available studies, sev-
therapeutics (Hesketh et al., 2020; NCCN, 2021; eral other challenges exist with determining opti-
Roila et al., 2016). Cancer Care Ontario (CCO) mal prophylaxis regimens in practice. First, many
provides antiemetic guidelines from a work- oral chemotherapeutics are administered over
ing group (Salama et al., 2019). These authors several days, falling into the “multiday” regimen
state a paucity of data exists, citing only three category where there may be overlap of acute and
small studies assessing antiemetic regimens for delayed nausea. However, multiday dosing of oral
oral chemotherapy, specifically temozolomide chemotherapeutics may have lower emetic risk
(Temodar). These studies are limited by phase over time; therefore, some advocate for the use of
II nonrandomized design with fewer than forty antiemetics on an “as needed” (prn) basis instead of
participants each and concomitant radiation ex- routine scheduled prophylaxis (MD Anderson Can-
posure, which can also be emetogenic (Affronti et cer Center, 2020). Second, oral chemotherapeutics
al., 2016; Matsuda et al., 2016; Rozzi et al., 2011). are often given in conjunction with IV chemothera-
Further, the primary outcome measure in these py and/or radiation; therefore, overlap of toxicities
studies did not include nausea assessment, which can confound assessment. Lastly, practical issues
is the gold standard for contemporary CINV stud- must be taken into consideration when choosing a
ies. High-quality studies are needed to elucidate CINV prophylaxis regimen: inpatient vs. outpatient
optimal CINV prophylaxis for patients receiving setting, route of administration, duration of risk
oral chemotherapeutic agents. period, and antiemetic duration of efficacy, adher-
Based on the paucity of data available, existing ence, tolerability of prolonged antiemetic use, etc.
antiemesis guidelines provide limited details on
recommendations for oral chemotherapy CINV Radiation Treatment
prophylaxis. NCCN divides oral chemotherapeu- Guideline recommendations for prevention of
tics into two categories: moderate to high risk vs. RINV are based on emetogenic risk (high, moder-
minimal to low risk, providing consensus-based ate, low, and minimal), which is dependent on the
antiemetic recommendations for each (Table 4; anatomic site of radiation therapy (RT; Table 5). No
NCCN, 2021). Comparatively, both ASCO and other patient-, tumor-, or treatment-related factors
MASCC/ESMO evidence-based guidelines divide (i.e., radiation dose, fractionation, technique, and
oral chemotherapeutics into high, moderate, low, field size) are accounted for in the risk classifica-
and minimal emetogenicity categories; however, tion (Hesketh et al., 2020; Roila et al., 2016).
these guidelines do not provide prophylaxis rec- While all guidelines recommend 5-HT3-RAs
ommendations by these risk levels due to a lack as the preferred agent for preventing RINV from
Table 4. CINV Prophylaxis Recommendations for Oral Chemotherapy

Moderate Recommendation: Start 5-HT3 receptor antagonist before chemotherapy and continue daily
to high Prophylaxis options:
emetic risk • Dolasetron 100 mg po daily
• Granisetron 1–2 mg po daily
• Granisetron 3.1 mg/24-hr transdermal patch every 7 days
• Ondansetron 8–16 mg po daily
Minimal to Recommendation: Provide patient with an as needed (prn) antiemetic agent; if CINV occurs, begin
low emetic scheduled antiemetic before chemotherapy and continue daily.
risk Prophylaxis options:
• Metoclopramide 10–20 mg po and then every 6 hr prn (maximum 40 mg/day)
• One of the 5-HT3 receptor antagonists:
» Dolasetron 100 mg po daily prn
» Granisetron 1–2 mg po daily prn
» Ondansetron 8–16 mg po daily prn

high and moderate emetic risk RT, the guidelines Table 5. Emetic Risk by Site of Radiation
differ in recommendations regarding dexametha- Emetic risk level Site
sone due to inconsistent trial data (Table 6). Fur-
High (> 90%) Total body irradiation
ther, while NCCN does not provide recommen-
dations regarding antiemetic prophylaxis for low Moderate (30%–90%) Upper abdomen
Craniospinal irradiationa
and minimal emetic risk RT, ASCO and MASCC/ Localized sitesb
ESMO provide recommendations primarily based Low (10%–30%) Brain/Craniumc
on expert consensus (Hesketh et al., 2020; NCCN, Head and neck, thorax, pelvis
2021; Roila et al., 2016). Minimal (< 10%) Extremities, breast
Evidence-based recommendations for RINV
Note. Per ASCO and MASCC/ESMO only (Hesketh et al.,
a
prevention are limited due to the paucity of ran- 2020; Roila et al., 2016).
domized clinical trials investigating optimal b
Per NCCN only (NCCN, 2021).
medication, dosing, and duration of prophylaxis
c
Per MASCC/ESMO only (Roila et al., 2016).
regimens. While some studies address RINV pro-

phylaxis in high and moderate emetic risk, limited prevention of emesis from RT (Salvo et al., 2012).
data exist regarding low and minimal emetic risk. The optimal dose, duration, and specific 5-HT3-
A systematic review of nine trials found 5-HT3- RA is unclear due to significant heterogeneity
RAs to be superior to placebo or other antiemet- among studies (Dennis et al., 2013; Roila et al.,
ics (metoclopramide [Reglan], prochlorperazine 2016; Salvo et al., 2012). Further, few studies have
[Compazine], chlorpromazine [Thorazine]) in the assessed dexamethasone for prevention of RINV.
Table 6. RINV Prophylaxis Recommendations

ASCO MASCC/ESMO NCCN
High emetic risk 5-HT3-RAa (IV or po) + 5-HT3-RA + dex 5-HT3-RA (po)a +/- dex po
(TBI) dex (IV or po) Route of administration and Start pretreatment for each
Before each fraction and on timing not specified. day of RT treatment.
the day after each fraction if
RT is not planned for that day
Moderate emetic risk Upper abdomen and Upper abdomen and craniospinal: Upper abdomen/localized
craniospinal: 5-HT3-RA + dex sites:
5-HT3-RAb (IV or po) (optimal short course) 5-HT3-RA (po)a +/- dex po
before each fraction +/- Route of administration and Start pretreatment for each
dex (IV or po) timing not specified. day of RT treatment.
before the first 5 fractions
Low emetic risk Brain (previously cranium): Cranium: –
Dex rescue (IV or po) Prophylaxis or rescue with dex
Head and neck, thorax, pelvis: Head and neck, thorax, pelvis:
Rescue therapy with a 5-HT3- Prophylaxis or rescue with a
RAa, dex, or a dopamine 5-HT3-RA, dex, or a dopamine
receptor antagonist c receptor antagonist c
(IV or po) Route of administration not
specified.
Minimal emetic risk Rescue therapy with a 5-HT3- Rescue therapy with a 5-HT3- –
(extremities, breast) RAa, dex, or a dopamine RA, dex, or a dopamine receptor
receptor antagonistc (IV or PO) antagonist c
Route of administration not
specified.
Note. RINV = radiation-induced nausea and vomiting; TBI = total body irradiation; dex = dexamethasone.
Information from Hesketh et al. (2020); NCCN (2021); Roila et al. (2016).
a
5-HT3-RAs: granisetron OR ondansetron.
b
Granisetron OR ondansetron preferred; alternative is tropisetron (not available in US).
c
Dopamine receptor antagonists: metoclopramide OR chlorpromazine.

A study evaluating dexamethasone vs. placebo istration. Symptoms range from mild (flushing,
reported significant improvement in emesis for chills, pruritus) to severe (anaphylaxis, cardiac
patients receiving moderate-risk RT (Kirkbride arrest). Incidence of IR varies by agent and re-
et al., 2000). One study comparing ondansetron ported rates may vary over time due to improve-
(Zofran) monotherapy with dexamethasone plus ments in administration and premedication prac-
chlorpromazine in patients receiving lower hemi- tices. While severe IRs are rare with an overall
body RT concluded that ondansetron was sig- incidence of < 5%, they can greatly impact patient
nificantly better at controlling emesis and nausea outcomes. Appropriate prophylactic medications
on day 1 of RT (Sykes et al., 1997). In a placebo- can reduce the need for prolonged infusion times,
controlled study, the addition of dexamethasone dose reductions, delays, and discontinuations, and
to 5-HT3-RA for patients receiving moderate hospitalizations. Knowledge of IR risk and ap-
emetic risk RT significantly improved complete propriate prevention strategies are therefore key
control of emesis and lowered average nausea to optimizing patient care (McBride et al., 2010).
scores (Wong et al., 2006). The overall paucity of Herein we describe common strategies to prevent
data demonstates the need for further studies to IRs; acute management of IRs and desensitization
determine ideal evidence-based regimens for pro- strategies is beyond the scope of this article and is
phylaxis of RINV. discussed elsewhere (Crespo et al., 2019; Roselló
Regarding those receiving concomitant radia- et al., 2017).
tion and chemotherapy, guidelines recommend
antiemetic prophylaxis be determined based on Classification of Infusion Reactions
the emetogenic risk of the chemotherapy regimen, The nomenclature of IRs is not standardized and
unless the emetogenic risk level of RT is higher may vary based on the resource, with “hypersen-
(Hesketh et al., 2020; NCCN, 2021; Roila et al., sitivity reaction” (HSR) sometimes used inter-
2016). Additionally, if a patient continues RT after changeably with “infusion reaction.” Hypersensi-
CINV prophylaxis for chemotherapy is discontin- tivity reactions are a subset of IRs that are immune
ued, ASCO guidelines recommend antiemetic pro- mediated (true allergic responses) and can be fur-
phylaxis appropriate for the emetic risk of RT be ther divided into Types I to IV based on the Gell
used until the next period of chemotherapy (Hes- and Coombs classification (Table 7). Nonimmune
keth et al., 2020). All patients receiving RT alone (nonallergic) IRs include pseudoallergic reactions
or in combination with chemotherapy should be such as anaphylactoid-appearing cytokine release
prescribed prn antiemetics for breakthrough nau- syndrome (CRS), idiosyncratic reactions, and in-
sea and vomiting. tolerances. Cytokine release syndrome is char-
acterized by fever, tachycardia, hypotension, or
PROPHYLAXIS FOR hypoxia caused by the release of cytokines and is
HYPERSENSITIVITY REACTIONS frequently seen after treatment with MoAbs and
An IR is an adverse reaction to IV- or SC-admin- T-cell engaging agents. Symptoms of immune-
istered medications, including chemotherapy and mediated and nonimmune-mediated IRs greatly
monoclonal antibodies (MoAbs). Reactions usual- overlap and may be identical, making clinical dif-
ly occur during infusion or within a day of admin- ferentiation difficult (Joerger, 2012; Roselló et al.,
Table 7. Gell and Coombs Classification of Hypersensitivity Reactions

Type I Immunoglobulin E (IgE) antibody-mediated reactions; onset typically within 1 to 6 hours after administration
(anaphylaxis)
Type II Antibody-mediated cytotoxic reactions (hemolytic anemia, thrombocytopenia, blood transfusion reactions)
Type III Immune complex-mediated hypersensitivity (serum sickness, vasculitis)
Type IV Delayed T cell-mediated responses; onset from 1 hour to days after administration (allergic contact
dermatitis, psoriasis, maculopapular exanthema, erythema multiforme, toxic epidermal necrolysis)
Note. Information from Roselló et al. (2017).

2017). The Common Terminology Criteria for cific risk factors, individual anticancer agent IR
Adverse Events (CTCAE) system for classifying risk, drug formulation, concomitant medications,
adverse events distinguishes between infusion- route and rate of administration, and optimiza-
related reactions, CRS, and anaphylaxis (Table 8), tion of prophylactic medications (Crespo et al.,
but the similarity in these presentations limits its 2019). Patient-specific risk factors for severe and
usefulness (National Institutes of Health, 2017). fatal immune-related IRs include older age, use
When reviewing drug monographs and primary of β-adrenergic blockers or angiotensin-convert-
literature for IR data, determining how IRs were ing enzyme inhibitors, and certain comorbidities
defined aids with analysis. For example, in the (e.g., respiratory or cardiovascular disease, aller-
blinatumomab (Blincyto) monograph, incidence gic rhinitis, mastocytosis; Simons et al., 2011). Tu-
of any-grade IR is reported as 30% and any-grade mor burden is an important patient risk factor for
CRS as 14%, but notably, their definition of IR in- pseudoallergic IRs, such as CRS; therefore, pseu-
cluded CRS and therefore are not additive (Amgen doallergic IRs are often most severe and frequent
Inc., 2018). with the first dose as commonly seen with MoAbs
and T cell–engaging agents (Asselin, 2016; Maude
Prevention et al., 2014; Winkler et al., 1999). While any IV
Due to possible negative consequences of IRs on or SC anticancer agent has the potential for IRs,
patient safety and treatment continuation, it is certain agents are associated with higher rates, as
important to implement strategies to minimize IR detailed in the following pages. Additionally, ex-
risk. Strategies may include assessing patient-spe- cipients rather than the drug itself can cause IRs.
Table 8. CTCAE Grading for Infusion-Related Reactions, Cytokine Release Syndrome, and Anaphylaxis
CTCAE term Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Infusion-related Mild transient Therapy or infusion Prolonged (e.g., not Life-threatening Death
reactiona reaction; infusion interruption indicated rapidly responsive to consequences;
interruption but responds promptly symptomatic medication urgent
not indicated; to symptomatic and/or brief interruption intervention
intervention not treatment (e.g., of infusion); recurrence indicated
indicated antihistamines, of symptoms following
NSAIDS, narcotics, IV initial improvement;
fluids); prophylactic hospitalization indicated
medications indicated for clinical sequelae
for ≤ 24 hr
Cytokine Fever with or Hypotension Hypotension managed Life-threatening Death
release without responding to with one pressor; consequences;
syndromeb constitutional fluids; hypoxia hypoxia requiring urgent
symptoms responding to ≥ 40% O2 intervention
< 40% O2 indicated
Anaphylaxisc – – Symptomatic Life-threatening Death
bronchospasm, with consequences;
or without urticaria; urgent
parenteral intervention intervention
indicated; allergy-related indicated
edema/angioedema;
hypotension
Note. CTCAE = Common Terminology Criteria for Adverse Events; NSAID = nonsteroidal anti-inflammatory drug.
Information from National Institutes of Health (2017).
Infusion-related reaction is a disorder characterized by adverse reaction to the infusion of pharmacological or
a
biological substances.
Cytokine release syndrome is characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or
b
hypoxia caused by the release of cytokines.

Anaphylaxis is characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
c
like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing
difficulty, dizziness, hypotension, cyanosis, and loss of consciousness, and may lead to death.

Modifiable risk factors for IRs include route and start of infusion. With paclitaxel, the compounded
rate of administration, with SC administration and product needs to be thoroughly mixed, as incom-
slower infusion rates being associated with lower plete mixing can lead to excessive complement
reaction rates for some agents. activation and IRs. No benefit from extended du-
Commonly used agents to prevent IRs include ration (3-hour vs. 24-hour) or lower dose (175 vs.
acetaminophen, corticosteroids, and histamine-1 135 mg/m2) has been identified (Picard & Castells,
(H1) and H2RAs. These agents are used in various 2014). For patients on weekly paclitaxel, some
combinations, doses, routes, and administration institutions choose to reduce the steroid dose or
times as directed by drug monographs. For some omit it and other premedications entirely if a pa-
anticancer agents, current premedication practic- tient does not experience a reaction to the first
es may differ from the monograph recommenda- two doses, with safety demonstrated in a few
tions based on subsequently published data. How retrospective studies of breast cancer patients
strictly practitioners need to follow monograph (Berger et al., 2015; de Castro Baccarin et al., 2019;
recommendations regarding route (i.e., IV vs. oral) Parinyanitikul et al., 2018; Picard & Castells, 2014).
and timing (i.e., 30 vs. 60 minutes) is controversial,
with practice frequently differing by institution Platinum Agents
based on experience and subsequent literature Infusion reactions associated with the platinum
(Crespo et al., 2019). Table 9 describes premedica- agents (cisplatin, carboplatin, and oxaliplatin) are
tion strategies and considerations for prophylaxis typically consistent with IgE-mediated Type 1 re-
of agents commonly associated with IRs. actions, resulting in increasing IR risk with subse-
quent cycles. Incidence of IR peaks around cycles
Taxanes seven through ten for carboplatin and oxaliplatin
Despite premedication, incidence of IRs associ- and around cycles four through eight for cispla-
ated with taxanes has been reported as 10% for tin, with cisplatin-induced IRs typically milder
paclitaxel (Taxol) and 5% for docetaxel (Taxotere; than those seen with carboplatin and oxaliplatin
Picard & Castells, 2014). Taxane IRs may be due to (Makrilia et al., 2010). Routine premedication is
IgE-mediated reactions to the drug or excipient, not recommended since it has not been effective.
or due to complement activation by the excipients: In select cases, such as high-risk gynecologic ma-
Cremophor EL in paclitaxel and polysorbate 80 in lignancy patients receiving a seventh cycle of car-
cabazitaxel (Jevtana) and docetaxel (Crespo et al., boplatin, premedication with corticosteroids and
2019). Cross-reactivity rates between paclitaxel H1RAs without or without H2RAs may be consid-
and docetaxel are as high as 41% to 90%, suggest- ered (Crespo et al., 2019; O’Cearbhaill et al., 2010).
ing IRs are frequently related to drug rather than
excipient (Sánchez-Muñoz et al., 2011; Dizon et al., Monoclonal Antibodies
2006). Albumin-bound paclitaxel (Abraxane) does Incidence of MoAb-induced IRs is variable, and
not contain Cremophor EL and has an IR rate of the mechanism is not fully elucidated. Infusion
< 2% with no premedication required (Abraxis Bio- reactions may be related to mast cell or basophil
Science LLC., 2019). Case reports exist describing activation, antibody-antigen interactions, or im-
successful treatment with albumin-bound pacli- munogenicity of each specific agent based on its
taxel after experiencing severe IRs with docetaxel ability to induce human antichimeric, human an-
or paclitaxel; however, such a switch should be tihuman, or human antimouse antibodies. Mono-
carefully considered as efficacy data may not be clonal antibody–related IRs are most frequently
available, so caution should be exercised and the attributed to the direct activity of the MoAb on the
switch should be guided based on clinical data as target cell (antibody-antigen interaction), leading
these agents are not necessarily therapeutically to CRS; therefore, the highest risk of MoAb-relat-
equivalent (de Leon et al., 2013; Fader & Rose, 2009; ed IRs is seen with the first one to two doses.
Pellegrino et al., 2017; Picard & Castells, 2014). To reduce the incidence and severity of these
Taxane IRs most commonly occur during the IRs, common practice is to start the first infusion
first or second dose within 10 minutes from the at a slower rate and titrate up for subsequent doses

Table 9. Summary of Guideline and Manufacturer Recommendations and Considerations for Prophylaxis
of Infusion Reactions in Chemotherapeutics and Monoclonal Antibodies
Drug Prophylaxis Comment
Anthracyclines, • No routine premedication –
liposomal • Infusion rate: limit initial infusion rate to
≤ 1 mg/min
Asparaginase • No routine premedication per manufacturer • MASCC/ESMO guidelines recommend and
(erwinia recommendations CCO guidelines recommend considering:
chrysanthemi » Antihistamines
asparaginase, » Corticosteroids
pegaspargase, • Universal premedication can be considered
calaspargase) due to availability of therapeutic drug
monitoring to assess for drug-inactivating
antibodies
• Agents (see references for specific
regimens):
» +/- acetaminophen 650 mg po
» +/- diphenhydramine (Benadryl) 50 mg
IV/po
» +/- famotidine (Pepcid) 20 mg IV/po
» +/- hydrocortisone (Solu-Cortef) 100 mg IV
• Onset of IR usually after several doses
• Consider administering asparaginase via
intramuscular or SC route to reduce rate
of IRs
• Pegylated formulations are least
immunogenic
Carfilzomib For cycle 1 of carfilzomib monotherapy • Combination regimens incorporate
(Kyprolis) • Timing: 30 minutes to 4 hours prior dexamethasone; therefore, premedication is
• Agents: unnecessary
» Dex 4 mg IV/po when carfilzomib given
over 10 minutes
» Dex 8 mg IV/po when carfilzomib given
over 30 minutes
Platinum agents • No routine premedication • Caution in carboplatin patients approaching
(carboplatin, 7th cycle of treatment or a retreatment
cisplatin, oxaliplatin) interval of > 2 years and with oxaliplatin
patients approaching 7th cycle
Taxane: Cabazitaxel • Timing: 30 minutes prior –
• Agents:
» Diphenhydramine 25 mg IV
» H2RA IV
» Dex 8 mg IV
Note. Some drug monographs do not recommend a specific agent within a class or a specific dose). IR = infusion
reaction; dex = dexamethasone. MRD = minimal residual disease; ALL = acute lymphoblastic lymphoma. Information
from Amgen, Inc. (2017, 2018); Barr et al. (2018); Berger et al. (2015); Biogen and Genentech USA, Inc. (2020a, 2020b);
Bristol-Myers Squibb Company (2018); Chouhan & Herrington (2011); Cooper et al. (2019); Crespo et al. (2019); Daiichi
Sankyo, Inc. (2019); de Castro Baccarin et al. (2019); Eli Lilly and Company, 2020); EMD Serono, Inc. and Pfizer, Inc.
(2019); Genentech, Inc. (2018, 2019a, 2019b, 2020a, 2020b, 2020c); Genzyme Corporation (2019); Hamadeh et al. (2020);
Hofmeister & Lonial (2016); Hospira, Inc. (2018, 2019); ImClone LLC (2019); Janssen Biotech, Inc. (2019, 2020); Jazz
Pharmaceuticals, Inc. (2019); Lenz (2007); Marini et al. (2019); Markman et al. (1999); Montoya et al. (2007); Nooka et
al. (2018); Novartis Pharmaceuticals Corporation (2016); Onyx Pharmaceuticals, Inc. (2019); Parinyanitikul et al. (2018);
Roselló et al. (2017); Sanofi-Aventis U.S. LLC (2020); Servier Pharmaceuticals LLC (2019a, 2019b); Shah et al. (2013); Siena
et al. (2007); Stock et al. (2011); Wyeth Pharmaceuticals LLC (2018, 2020); Yanaranop & Chaithongwongwatthana (2016).
Continued on following page

of Infusion Reactions in Chemotherapeutics and Monoclonal Antibodies (cont.)
Taxane: Docetaxel • Timing: 1 day prior • If adherence to po regimen is questionable,
• Agents: consider administering dex 10–20 mg IV 30
» Dex 8 mg po bid × 3 days starting 1 day min prior to dose
before dose
» For metastatic castration-resistant
prostate cancer on concurrent prednisone,
dex 8 mg po at 12, 3, and 1 hour prior to
dose
Taxane: Paclitaxel • Timing: 30 minutes prior • If no IR with the first 2 doses, consider
(see below for dex po timing) decreasing or omitting premedications
• Agents:
» Diphenhydramine 50 mg IV/po
» H2RA IV
» Dex 20 mg po 12 and 6 hours prior OR
dex 20 mg (10 mg if weekly regimen) IV
Alemtuzumab • Dose: escalate per drug monograph • Consider SC administration of Campath
(Campath, • Timing: 30 min prior formulation to reduce risk of IRs
Lemtrada) • Agents:
» Acetaminophen 650 mg po
» +/- methylprednisolone (Solu-Medrol)
1,000 mg IV × 3 days (use for Lemtrada
formulation; consider for Campath
formulation)
Atezolizumab • No routine premedication –
(Tecentriq) • Infusion rate:
» First dose: over 60 minutes
» Subsequent doses: over 30 minutes if first
dose well-tolerated
Avelumab First 4 doses –
(Bavencio) • Timing: Not specified
• Agents:
» Acetaminophen
» Antihistamine
Bevacizumab • No routine premedication –
(Avastin) • Infusion rate:
» First dose: over 90 minutes
» Second dose: over 60 minutes
» Subsequent doses: over 30 minutes
» All longer infusions tolerated: consider
rapid infusion over 10 to 15 minutes (0.5
mg/kg/minute) for doses up to 7.5 mg/kg

Blinatumomab MRD ALL indication • Median time to onset of CRS of 2 days, with
(Blincyto) • Timing: 1 hour prior IRs occurring in 44%–67% of patients
• Agents:
» Dex 16 mg IV OR prednisone 100 mg po
Relapsed/refractory ALL indication
• Timing: 1 hour prior to infusion start, dose
increase, and restart after interruption ≥ 4
hours
• Agent:
» Dex 20 mg IV
Cetuximab (Erbitux) • Infusion rate: • MASCC/ESMO and CCO guidelines
» First dose: over 2 hours recommend addition of IV corticosteroid
» Subsequent doses: over 1 hour premedication to reduce IR rate
• Consider discontinuing premedication after
First 2 doses
2nd infusion based on clinical judgment if no
• Timing: 30–60 min prior
IR experienced
• Agents:
» +/- corticosteroid IV
Daratumumab • Timing: 1 to 3 hours prior • Consider administering premedications
(Darzalex) • Agents: 30 min prior based on expert opinion
Daratumumab/ » Acetaminophen 650–1,000 mg po and retrospective chart reviews of rapid
hyaluronidase » Diphenhydramine 25–50 mg IV/po infusion daratumumab with premedications
(Darzalex Faspro) » Corticosteroid administered 30 min prior to infusion
- Monotherapy: Methylprednisolone 100 • Consider splitting first daratumumab dose
mg IV or equivalent. Third dose onward: over 2 days in clinics with limited hours, with
methylprednisolone 60 mg IV/po or premedications given on both days
equivalent • Consider rapid infusion if no IRs seen with
- Combination therapy: Dex 20 mg IV. first 2 doses at standard infusion rates
Second dose onward: Dex 20 mg IV/po.
If dex is part of regimen, it will serve as
premedication
» Montelukast (Singulair) 10 mg po (first 1 to
3 doses; only data with IV daratumumab)
» Famotidine 20 mg IV (first 1 to 3 doses;
only data with IV daratumumab)
• Post-medications:
» Corticosteroid starting day after infusion
- Monotherapy: Methylprednisolone 20
mg or equivalent po daily × 2 days
- Combination therapy:
Methylprednisolone ≤ 20 mg or
equivalent daily × 1 day.
- If dex or prednisone is part of regimen,
additional post-medication may not be
necessary
» Consider bronchodilators in patients with
chronic obstructive pulmonary disorder

Elotuzumab • Timing: 45–90 min prior • Most IRs (70%) occur with first dose
(Empliciti) • Agents:
» Acetaminophen 650–1,000 mg po
» Diphenhydramine 25–50 mg IV/po
» Famotidine 20 mg IV
» Dexamethasone 8 mg IV
• Timing: 3–24 hours prior

• Agents:
» Dex 28 mg po for patients ≤ 75 years
on pomalidomide-based regimen or all
patients on lenalidomide-based regimen
» Dex 8 mg po for patients > 75 on
pomalidomide-based regimen
Gemtuzumab • Timing: 1 hr prior • In patients with high disease burden,
ozogamicin • Agents: consider cytoreduction to reduce the
(Mylotarg) » Acetaminophen 650 mg po incidence of IRs
» Diphenhydramine 50 mg IV/po
• Timing: 30 min prior

• Agents:
» Methylprednisolone 1 mg/kg or equivalent
Inotuzumab • Timing: Not specified • IRs generally occur during cycle 1 shortly
ozogamicin • Agents: after the end of infusion
(Besponsa) » Acetaminophen • In patients with high disease burden,
» Antihistamine consider cytoreduction to reduce the
» Corticosteroid incidence of IRs
Obinutuzumab • Timing: 1 hour prior • IRs reported in 65% of CLL patients with
(Gazyva) • Agents: first 1,000 mg and in 37%–60% of non-
» Dex 20 mg IV or methylprednisolone 80 Hodgkin lymphoma patients with first dose,
mg IV. First dose AND any subsequent with > 10% of IRs being grade 3–4
dose if grade 3 IR with prior dose or • Consider holding antihypertensives on day
lymphocyte > 25,000/mm3 of infusion due to risk of hypotension
• Timing: 30 min prior

• Agents:
» Acetaminophen 650-1000 mg po.
All doses.
» Diphenhydramine 50 mg IV/po. First dose
AND any subsequent dose if had any-
grade IR with prior dose or lymphocyte
> 25,000/mm3

Ofatumumab • Timing: 30 minutes to 2 hours prior • IRs most common with first 2 doses
(Arzerra, Kesimpta) • Agents:
» Acetaminophen 1000 mg po
» Diphenhydramine 50 mg po/IV or
cetirizine 10 mg po or equivalent
» Prednisolone IV or equivalent
- Previously untreated CLL: doses 1–2:
50 mg IV; doses ≥ 3: consider reducing
or omitting after 2nd dose if no grade
3 or 4 IR
- Refractory CLL: use full corticosteroid
dose for doses 1, 2, and 9. Doses 1,
2, and 9: 100 mg IV. Doses 3-8: may
reduce dose or omit. Doses 10-12: may
reduce dose to 50% if no grade 3 or 4
IR with dose 9
Panitumumab • No routine premedication –
(Vectibix) • Infusion rate:
» First dose: over 1 hour if ≤ 1000 mg
» Subsequent doses: over 30 min if
tolerated
» Doses > 1000 mg: infuse over 90 min
Polatuzumab • Infusion rate: • Approved for use in combination with
vedotin (Polivy) » First dose: over 90 min bendamustine and rituximab, so patients
» Subsequent doses: over 30 min should already be premedicated for
• Timing: 30–60 min prior if not already rituximab regardless of polatuzumab
premedicated for other drugs administration
• Agents:
» Acetaminophen
» Antihistamine
Ramucirumab • Timing: Not specified • Most IRs reported during or following first or
(Cyramza) • Agents: second dose
» Diphenhydramine IV
» If grade 1 or 2 IR with prior dose, dex/
equivalent or acetaminophen

Rituximab (Rituxan) • Infusion rate: titrate per package insert • Consider addition of corticosteroid to
Rituximab/ • Timing: 30 min prior premedication for IV rituximab if high-bulk
hyaluronidase • Agents: disease, non-Hodgkin lymphoma, or CLL
(Rituxan Hycela) » Acetaminophen • For previously untreated follicular lymphoma
» Antihistamine and diffuse large B-cell lymphoma patients,
» +/- corticosteroid if high-bulk disease, if no grade 3 or 4 IR occurred with first
non-Hodgkin lymphoma, or CLL (consider cycle, 90-min infusion (rapid) can be
for IV rituximab only) considered with a glucocorticoid-containing
regimen; not recommended for patients with
clinically significant cardiovascular disease
or with circulating lymphocyte count ≥
5000/mm3
• Rapid administration is also frequently used
off-label for other indications
• For patients with bulky disease or high
lymphocyte count > 25–50 × 109/L, consider
using reduced infusion rate, splitting dose
over two days, or deferring rituximab until
chemotherapy has debulked disease
• Before use of rituximab/hyaluronidase
SC formulation, patient must tolerate IV
rituximab without IRs
Trastuzumab • No routine premedication –
(Herceptin) • Infusion rate:
» First dose: over 90 min
Trastuzumab
» Subsequent doses: over 30 min
emtansine (Kadcyla)
Trastuzumab
deruxtecan
(Enhertu)

as tolerated (Crespo et al., 2019). To facilitate ad- premedication with acetaminophen, antihista-
ministration, the first dose of daratumumab (Dar- mines, and corticosteroids; similarly, daratumum-
zalex) can be split over 2 days as the initial infu- ab also requires extensive premedication (Table
sion duration is frequently prolonged due to high 9). In the absence of additional data supporting al-
IR rates (Janssen Biotech, Inc., 2019). Split-day ternative premedication strategies, manufacturer
administration and slower infusion rate of ritux- recommendations should be followed (Crespo et
imab (Rituxan) can also be considered for patients al., 2019).
with high lymphocyte counts greater than 25 to 50
× 109/L (Crespo et al., 2019). PROPHYLAXIS FOR EDEMA
Subcutaneous formulations of rituximab Fluid retention is a common side effect following
(Rituxan Hycela) and daratumumab (Darzalex infusion with taxoid agents, docetaxel, and pacli-
Faspro) in combination with hyaluronidase have taxel. The exact mechanism by which fluid reten-
recently been approved, but notably only for some tion occurs is unknown; however, it has been pro-
indications (Biogen and Genentech USA, Inc., posed that docetaxel increases the permeability of
2020a, 2020b; Janssen Biotech, Inc., 2019, 2020). capillaries leading to capillary leak syndrome (Ho
Before use of rituximab/hyaluronidase SC, a full & Mackey, 2014). This leakage can lead to pleural
dose of IV rituximab must be tolerated without se- or pericardial effusions, ascites, and peripheral
vere adverse reaction (Biogen and Genentech USA, edema (Baker et al., 2009). Severity of fluid reten-
Inc. 2020b). Daratumumab/hyaluronidase SC can tion is directly related to cumulative dose adminis-
be used in daratumumab-naive patients. The SC tered; therefore, even if the first doses of docetaxel
formulation is associated with lower rates of IR on are well tolerated, prophylaxis against fluid reten-
first dose with 10% vs. 37% for SC and IV formu- tion should be continued (Ho & Mackey, 2014). To
lations, respectively. Time to onset of IR with the reduce the incidence and severity of fluid reten-
first dose is slower with SC, with median 3.7 hours tion reactions, the manufacturer of docetaxel rec-
(range: 9 minutes–3.5 days) vs. 1.5 hours (range: 0 ommends premedication with oral corticosteroids
to 3 days) for IV, so observation time with the first such as dexamethasone 16 mg daily in split dos-
dose of the SC formulation should be carefully con- ing for 3 days starting one day prior to docetaxel
sidered (Janssen Biotech, Inc., 2019, 2020). administration. For patients with prostate cancer
Prevalence of IRs with cetuximab (Erbitux), a who are receiving concomitant prednisone, the
chimeric human/mouse MoAb, has a strong geo- recommended dexamethasone dosing is 8 mg giv-
graphical association. While the drug monograph en 12 hours, 3 hours, and 1 hour prior to chemo-
reports severe IR rates of approximately 3%, high- therapy (Hospira, Inc., 2019).
er rates of up to 22% have been reported in the Although effective as prophylaxis, dexameth-
middle southeastern United States (Chung et al., asone is associated with various side effects and
2008; ImClone LLC, 2019). This has been deemed the potential for nonadherence. Therefore, some
to be due to IgE-mediated anaphylaxis, with the studies have evaluated the effectiveness of single-
majority of patients who experienced severe reac- dose dexamethasone vs. the standard 3-day regi-
tions having preexisting antibodies to galactose-α- men. These studies found a lower incidence of flu-
1,3-galactose, a component of cetuximab (Chung id retention with single-dose dexamethasone 20
et al., 2008). Evidence suggests that this antibody mg po/IV premedication compared to previously
may develop as a result of tick bites, as the cetux- published data with the standard 3-day dexameth-
imab reaction distribution mimics the distribution asone (Chouhan & Herrington, 2011; Montoya et
of the Lone Star tick species (Steinke et al., 2015). al., 2007). As these studies were retrospective in
Many MoAbs do not require prophylaxis due nature and used historical data as a comparator,
to the low incidence of IRs, while some MoAbs the results should ideally be confirmed by pro-
only require extended infusion times with initial spective studies. A preferred regimen is not yet
doses. In general, MoAbs that target the CD20 an- established, but single-dose dexamethasone pre-
tigen (rituximab, ofatumumab [Arzerra, Kesimp- medication should be considered if a patient has
ta], obinutuzumab [Gazyva]) require extensive been nonadherent to the 3-day regimen.

CONCLUSION ejon.2008.03.006
This article summarizes available evidence-based Barr, H., Dempsey, J., Waller, A., Huang, Y., Williams, N.,
Sharma, N.,...Hofmeister, C. C. (2018). Ninety-minute da-
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Disclosure nausea and vomiting (CINV): A systematic review and
The authors have no conflicts of interest to disclose. meta-analysis. Supportive Care in Cancer, 24(5), 2381–
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REVIEW

Premedications for Cancer

AMBER CLEMMONS,1,2 PharmD, BCOP, ARPITA GANDHI, 3 PharmD, BCOP,

From 1University of Georgia College of Pharmacy,

J Adv Pract Oncol 810 AdvancedPractitioner.com

AdvancedPractitioner.com 811 Vol 12  No 8  Nov/Dec 2021

Table 1. Key Principles of Antiemetics for CINV

J Adv Pract Oncol 812 AdvancedPractitioner.com

Table 2. CINV Prophylaxis Recommendations for IV Chemotherapy

AdvancedPractitioner.com 813 Vol 12  No 8  Nov/Dec 2021

Table 3. Antiemetic Dosing for Prophylaxis With IV Chemotherapy Regimensa

dexamethasone 8 mg oral or IV twice daily on days 3 and 4.

J Adv Pract Oncol 814 AdvancedPractitioner.com

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Table 4. CINV Prophylaxis Recommendations for Oral Chemotherapy

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regimens. While some studies address RINV pro-

Table 6. RINV Prophylaxis Recommendations

AdvancedPractitioner.com 817 Vol 12  No 8  Nov/Dec 2021

Table 7. Gell and Coombs Classification of Hypersensitivity Reactions

J Adv Pract Oncol 818 AdvancedPractitioner.com

hypoxia caused by the release of cytokines.

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J Adv Pract Oncol 820 AdvancedPractitioner.com

Continued on following page

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Continued on following page

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• Timing: 3–24 hours prior

• Timing: 30 min prior

• Timing: 30 min prior

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Continued on following page

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of Canada Clinical Trials Group phase III study. Jour- ctep.cancer.gov/protocolDevelopment/electronic_appli-

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J Adv Pract Oncol 832 AdvancedPractitioner.com

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