Management of infusion-related reactions in cancer therapy: strategies and challenges

Abstract

Several anticancer therapies have the potential to cause infusion-related reactions (IRRs) in the form of adverse events that typically occur within minutes to hours after drug infusion. IRRs can range in severity from mild to severe anaphylaxis-like reactions. Careful monitoring at infusion initiation, prompt recognition, and appropriate clinical assessment of the IRR and its severity, followed by immediate management, are required to ensure patient safety and optimal outcomes. Lack of standardization in the prevention, management, and reporting of IRRs across cancer-treating institutions represents not only a quality and safety gap but also a disparity in cancer care. The present article, supported by recently published data, was developed to standardize these procedures across institutions and provide a useful tool for health care providers in clinical practice to recognize early signs and symptoms of an IRR and promptly and appropriately manage the event.

Highlights

• •Several anticancer therapies can cause IRRs minutes to hours after the infusion.
• •Prompt recognition and appropriate clinical assessment and management of the IRR are crucial for patient safety.
• •Lack of standardization in the prevention, management, and reporting of IRRs across institutions is an unmet need.
• •This article seeks to help clinicians recognize early signs of an IRR and promptly manage the event.
• •It also aims to standardize procedures across institutions.

Introduction

According to the National Cancer Institute (NCI), an infusion-related reaction (IRR) is a condition characterized by an adverse reaction to the infusion of pharmacological or biological substances.¹ Several anticancer therapies administered by the parenteral route [intravenously (i.v.) or subcutaneously (s.c.)] carry a risk for IRRs, including chemotherapy and monoclonal antibodies (mAbs).2, 3, 4 Typically, IRRs are mild to moderate, develop during the infusion or several hours afterward,^3,5 and can be effectively managed, normally followed by reintroduction of the anticancer agent at a reduced infusion rate and with additional support medication.³ Less frequently, IRRs can be life-threatening without appropriate intervention.^3,5, 6, 7 It is therefore crucial that clinicians and health care professionals involved in the administration of these drugs, especially nurses, are able to recognize the signs and symptoms of an IRR and act promptly to prevent severe outcomes. Furthermore, educating patients about IRRs before administering these drugs is crucial. In addition, understanding the pathophysiology underlying each IRR may guide the decision for an eventual restart, potentially improving treatment outcomes.

The incidence of IRRs has been difficult to ascertain due to historical inconsistencies and discrepancies in the terminology, grading, and reporting of these events.² Although the literature is sparse regarding the subject, studies available show that the incidence of IRRs fluctuates according to anticancer therapy, cancer type, and administration practices.^2,8 In a systematic review from 2012, the incidence of IRRs associated with chemotherapy ranged between 0% and 71% for all-grade and 0% and 15% for grade 3-4 reactions.⁹ For mAbs, the incidence of IRRs was more heterogeneous and varied according to the molecule considered: 0%-4% and 0%-1% of all-grade and grade 3-4 IRRs with panitumumab, 1.6%-11% and 0%-4% with bevacizumab, and 7.6%-33% and 0%-22% with cetuximab, respectively.⁹ For rituximab, an overall incidence of 77% has been reported with the first infusion.⁵ Single-institution reports have also shown disparate results. Among 597 patients receiving anticancer therapies in early-phase clinical trials at the Department of Investigational Cancer Therapeutics of MD Anderson Cancer Center from January to November 2013, 1.5% (n = 9) experienced an IRR of grade ≤ 2.¹⁰ All IRRs were reversible with appropriate symptomatic treatment, and seven of the nine patients who experienced an IRR were able to complete treatment after temporary cessation of infusion. A retrospective chart review of 197 breast cancer patients who received trastuzumab showed an incidence of IRRs corresponding to 16.2% of patients and 1.8% of administered doses.⁸ All IRRs were mild to moderate and successfully managed with temporary infusion interruption and/or supportive medication.⁸ Nonetheless, according to the evidence, 20%-40% of IRRs are anticipated on the first trastuzumab infusion, with only 1% corresponding to severe reactions.11, 12, 13 In a recent prospective real-world study in an oncology outpatient clinic, 85 (0.53%) IRRs were reported among 75 of 1604 patients receiving anticancer therapies during 2017, of which 48.2% were moderate or severe (grade 2-3) and none was life-threatening or fatal (grade 4-5).¹⁴ When looking at individual anticancer agents, carboplatin was the drug with more IRRs in this study (n = 23), followed by oxaliplatin (n = 21), docetaxel (n = 11), and cetuximab and paclitaxel (n = 8 each). These agents have also been associated with the highest incidence of IRRs in the literature, respectively, 12%, 0.5%-25%, 21%, 22%, and 2%-45%, with pegylated liposomal doxorubicin also associated with a relevant 7%-11% incidence of IRRs.¹⁴

The importance of accurate and standardized definitions

The term IRR is a broad designation, and standardized definitions of the concepts associated with IRRs are required for accurate documentation of reactions and guidance on treatment and restart decisions. Terminology standardization is also crucial for consistency in the definition of treatment-related toxicities in clinical trials. However, there has been a lack of consensus in the literature in both the terminology used to define an IRR and the grading used to determine the severity of reactions.^2,15

According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (CTCAE v5.0), an adverse event (AE) is any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be related to the medical treatment or procedure.¹

CTCAE defines an IRR as a disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances.¹ It is non-dose related, unpredictable, generally unrelated to the drug’s pharmacological activity, and usually resolves when infusion is paused.^16,17 After resolution of all symptoms, treatment can be resumed at a slower rate, unless severe reactions occur.

IRRs can occur by one of two mechanisms, immune-mediated or non-immune-mediated, and be broadly classified as non-immune-mediated (or non-allergic) reactions or immune [generally immunoglobulin E (IgE)]-mediated (or true allergic) reactions to foreign proteins.^3,5 The symptoms of both types of IRRs overlap, but their timing is typically different. Non-immune-mediated reactions usually occur during or immediately after the first infusion and are most commonly seen with mAbs and taxane chemotherapies.^2,3,5,18 Conversely, true allergic responses typically manifest in subsequent exposures and are most commonly observed with chemotherapy, particularly platinums.^2,3,5

Non-immune-mediated, or non-allergic, reactions include cytokine-release syndrome (CRS; a cytokine-mediated hypersensitivity reaction occurring within the first hours after infusion and characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia),^1,19 idiosyncratic reactions (uncommon and unpredictable reactions unrelated to the drug’s pharmacological action), and intolerances.³ CRS is also termed an anaphylactoid reaction, i.e. a reaction that resembles anaphylaxis but arises from non-immunological causes,³ with symptoms that can include fever, hypotension, and/or hypoxia, according to CTCAE v5.0.¹ Tarlatamab (AMG 757), a first-in-class DLL3-targeted bispecific T-cell engager, showed a 53% rate of CRS in the DELLphi-201 trial.²⁰

Immune-mediated, or allergic, reactions include anaphylactic reactions (or anaphylaxis), a subtype of IgE-mediated systemic hypersensitivity reactions (HSRs) that are severe, rapid in onset, and life-threatening.^3,21 As defined by CTCAE v5.0, symptoms can include breathing difficulty, dizziness, hypotension, cyanosis, and loss of consciousness.¹

HSRs can be broadly defined as a subset of IRRs that occur by exposure to a defined stimulus at doses normally tolerated by the majority of patients and with objectively reproducible signs or symptoms.³ Besides anaphylactic reactions, they also comprise reactions mediated by IgG and IgM antibodies (such as hemolytic anemia and thrombocytopenia), reactions mediated by immune complexes (such as serum sickness and vasculitis), and delayed reactions mediated by T cells (such as allergic contact dermatitis, erythema multiforme and Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms).³

When an IRR occurs, the severity of the reaction will determine whether treatment can be subsequently restarted. To ensure a common understanding when discussing the treatment with molecules that can cause IRRs, the authors propose consensus definitions for rechallenge and restart. Rechallenge should be defined as ‘repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment’. Restart refers to ‘resuming the infusion, usually at a reduced rate and with additional premedication, once symptoms of the IRR have resolved’.²²

Based on this, the authors suggest the use of restart to support the clinical decision and management of IRRs. The term restart will be adopted throughout the manuscript.

Signs and symptoms of infusion reactions

Clinical manifestations of IRRs vary from patient to patient and among therapeutic agents, can have varying severities, and may involve different body systems (Figure 1).

Figure 1.

Signs and symptoms of infusion reactions.

The most frequent signs and symptoms of an IRR include mucocutaneous manifestations—like pruritus, urticaria, and skin flushing—in up to 90% of patients, respiratory manifestations—like wheezing and dyspnea—in around 40%, and circulatory manifestations—like hypotension—in 30%-35%.23, 24, 25 Abdominal symptoms, such as diarrhea, cramps, nausea, and vomiting, have also been reported.^24,25 Most symptoms occur within minutes to hours after drug administration,23, 24, 25 with a direct relation between how quickly the reaction manifests and its severity.³ Additional less common manifestations can occur in other body systems, such as cardiovascular, central nervous system, endocrine, gastrointestinal, genitourinary, musculoskeletal, psychiatric, or dermatologic.²

In addition, some therapeutic agents are associated with specific symptoms. For example, oxaliplatin has been associated with acute laryngopharyngeal dysesthesia, jaw tightness, difficulty in talking or swallowing, and strange sensations in the tongue and/or pharynx during or after the infusion.³ Irinotecan has been associated with diarrhea, diaphoresis, abdominal cramping, emesis, and, less commonly, hyperlacrimation and rhinorrhea occurring within the first 24 h of administration, a group of symptoms globally known as irinotecan-related cholinergic syndrome.²⁶ Among the patients (safety population, n = 114) receiving amivantamab in the cohort D of the CHRYSALIS trial, IRRs were reported in 66% of the patients (all-grade reactions but only 3% grade >3) and were characterized by dyspnea, flushing, chills, and nausea occurring almost exclusively on day 1 of cycle 1.²⁷

Several risk factors for IRRs have been identified.²² Some drug classes are more likely to cause IRRs, such as taxanes, platinum compounds, and mAbs.^22,28 The route of administration (i.v. versus subcutaneous), rate of infusion (slower rates are typically associated with lower risk of an IRR), interval between treatments, and drug formulation [certain excipients are associated with a higher incidence of an IRR than the drug itself (for example, Polysorbate 80)], have all been implicated in the development of IRRs.^22,28,29 Patient factors may also contribute to the risk of developing an IRR (including history of mild dermal reactions in previous courses, respiratory dysfunction, and obesity, among others).^22,30,31

Prophylaxis of infusion reactions

Given the potentially detrimental impact of IRRs on patients’ safety and treatment, strategies should be implemented to minimize the risk of an IRR when using anticancer therapies with potential to elicit this type of reaction. Possible strategies include the assessment of patients’ risk factors for IRRs, the use of graduated infusion rates when administering treatments, and the use of recommended premedication.^3,22

Agents used as premedication vary depending on the anticancer therapy, but typically involve corticosteroids (e.g. dexamethasone), antihistamines (e.g. diphenhydramine), and antipyretics. These agents target the mechanisms of IRRs, which include the release of leukotrienes, prostaglandins, and histamines, among other factors, and are thereby capable of preventing and mitigating the reaction.^5,32,33

Corticosteroids cause immunosuppression, inhibiting the expression and action of cytokines, prostaglandins, and leukotrienes, among other actions,³² and at commonly used antiemetic doses, may prevent non-IgE-mediated infusion or inflammatory reactions.⁵ Corticosteroids have been shown to be effective in lowering the risk of IRRs, as reported in one study where overall IRRs were reduced from 25.6% to 9.6% and severe IRRs from 4.7% to 1% with the use of premedication with an antihistamine plus corticosteroid compared to an antihistamine alone.³⁴ Antihistamines prevent the release of histamine from mast cells, with histamine 2 blockers potentiating the effects of histamine 1 blockers.^33,35 The feasibility and safety of omitting antihistamine premedication after the first two cetuximab infusions has been demonstrated, based on the recognition that most IRRs occur with the first cetuximab infusion and that antihistamines are not expected to be effective in preventing non-IgE-mediated events.³⁶ Of note, anaphylactoid reactions or pseudoallergic reactions are immediate systemic reactions that mimic anaphylaxis but are caused by non-IgE-mediated release of mediators from mast cells and basophils. For instance, as montelukast inhibits the mast cell-mediated release of leukotrienes, it can be used to reduce inflammation and bronchoconstriction.^32,37 Thus, the addition of montelukast could be a potential therapeutic option to mitigate the risk of IRRs.³⁸ Indeed, the SKIPPirr trial (NCT05663866) is separately assessing the potential of dexamethasone, montelukast, and methotrexate administration, before amivantamab infusion given through a needle in the vein, to decrease the incidence and/or severity of first-dose IRRs associated with amivantamab.

Management of infusion reactions associated with anticancer therapies

Despite IRRs being a composite of many different signs and symptoms, the ability to recognize and treat these reactions is essential for quality cancer care.

Before administering an anticancer therapy with the potential to elicit an IRR, the need for premedication should be assessed in the context of the agent to be administered and the comorbidities of the patient. The management protocol for IRRs and medical equipment required for resuscitation should be at hand, and drug administration should comply with a course of sequential steps detailed in Figure 2. Importantly, all staff (physicians and nurses) should be trained to act quickly and effectively.

Figure 2.

Workflow for the management of infusion reactions related to anticancer therapies in clinical practice (adapted from Roselló et al. 2017³and Cancer Care Ontario 2019²²). BSA, body surface area; IRR, infusion-related reaction; i.v., intravenous; LOC, level of consciousness; PO, oral administration; PRN, as the situation demands; SOB, shortness of breath.

In short, health care providers should monitor the patient closely during the infusion, being alert to the occurrence of an IRR and prepared to act promptly according to the established institutional procedures and protocols.

The resolution of IRRs varies according to the IRR. Most IRR signs and symptoms abate when the infusion is held. The management protocol of these reactions foresees the interruption of the infusion at the first sign of an IRR and the administration of additional supportive medication (e.g. glucocorticoids, antihistamines, antipyretics, antiemetics, supplemental oxygen) as clinically indicated.^3,22 Physicians should follow their institution’s guidelines and monitor the patient’s vital signs as clinically indicated until resolution of the IRR and recovery from symptoms. Moreover, they should follow any guidance provided in the product information of the respective agent [e.g. the Summary of Product Characteristics (SmPC)]. The patient should be monitored until the physician is confident that symptoms will not recur. The patient’s vital signs should be monitored as clinically indicated and, depending on the severity of symptoms and type of reaction, the infusion may be restarted at a slower rate on the same day or on the following day (according to the manufacturer’s instructions) or permanently discontinued if the severity of symptoms justifies so.^3,22

For more severe IRRs, particularly those involving respiratory symptoms (e.g. bronchospasm) or severe hypotension, more aggressive measures should be initiated. If anaphylaxis is suspected, treatment may include epinephrine, an antihistamine, anti-hypotensive or hypertensive agents, a beta-blocker, or corticosteroids.^3,22 If CRS or other hypersensitivity reactions are suspected, treatment may include antihistamines and corticosteroids.^3,22

• 1.
  Preparation for the infusion (based and adapted from Roselló et al. 2017³ and Cancer Care Ontario 2019²²)

  • •
    Assess the patient’s baseline vital signs, medical history, atopic status, past allergic disorders, and concomitant medications to establish if any risk factors are present.^3,22
  • •
    Ensure that the patient has taken the appropriate premedication at the recommended timing.^3,22

    • −
      Patients with a history of non-compliance to oral premedication should receive i.v. alternatives.^3,22,39
  • •
    Ensure that an updated management protocol for IRRs as well as medical equipment necessary for resuscitation are in place and readily available. The room should have enough space for resuscitation maneuvers if necessary.^3,22
  • •
    Educate the patient and caregiver(s) about signs and symptoms of IRRs. Unless contraindicated, an anxiolytic or other intervention for reducing anxiety may be considered.^3,22
• 2.
  Administration of the anticancer therapy

  • •
    Monitor the patient closely.^3,22
  • •
    Assess the patient’s vital signs.^3,22
  • •
    Measure blood pressure and pulse rate in patients who feel odd or uncomfortable or express the need to urinate or defecate, as these symptoms have been associated with acute anaphylactic reactions.^3,22,23
• 3.
  Prompt recognition of the IRR and assessment of reaction severity

  • •
    Follow the four ‘R’ rule^3,22:

    • −
      Realize the risk.
    • −
      Recognize the signs/symptoms.
    • −
      Respond calmly and quickly.
    • −
      Review the situation to prevent a recurrence.
  • •
    Call for medical assistance immediately.^3,22
  • •
    Assess the severity of the IRR.^3,22
• 4.
  Management of the IRR

  • •
    Stop the infusion.^3,22
  • •
    Maintain i.v. access.^3,22
  • •
    Assess ‘ABCs’ (airway, breathing, and circulation) and the patient’s level of consciousness.^3,22
  • •
    Assess the patient’s vital signs.^3,22
  • •
    Adjust the patient’s position, if one of the following is observed^3,22:

    • −
      Hypotension → place the patient in the Trendelenburg position
    • −
      Respiratory distress → place the patient in a sitting position
    • −
      Unconsciousness → place the patient in a recovery position
  • •
    Provide oxygen, if needed.^3,22
  • •
    Assess if the patient fulfils any of the three criteria of anaphylaxis (acute onset of symptoms, respiratory compromise, and/or hypotension).^3,22 Please refer to Table 1 for more details.
• 5.
  Post-reaction assessment

  • •
    Monitor the patient’s vital signs until resolution.^3,22
  • •
    Monitor recurrence symptoms.^3,22
  • •
    Keep 24-h observation for patients who experienced a severe IRR.^3,22
  • •
    Optional: Collect and measure serum tryptase within 15 min to 3 h after symptom onset.^3,22
  • •
    Inform the patient and caregiver(s) of potential signs of recurrence after leaving the hospital.^3,22

Table 1.

Suggested guidance for the management of anaphylaxis (based and adapted from Roselló et al. 2017³ and Cancer Care Ontario 2019²²)

If yes → suspected anaphylaxis	If no → suspected cytokine-release syndrome/hypersensitivity reaction
1.Immediately administer epinephrine (adrenaline) at a dose of 0.01 mg/kg (1 mg/ml dilution, to a maximum total dose of 0.5 ml) intramuscularly into the lateral thigh muscle.	1.Assess the grade of the reaction: If grade 1—slow down the infusion rate If grade 2—slow down the infusion rate or suspend the infusion for short term
2.Repeat every 5-15 min, if necessary.	2.Treat with: Antihistamines: 50 mg of i.v. diphenhydramine plus 50 mg of i.v. ranitidine (clemastine can also be also an option) Corticosteroids: equivalent dose to 1-2 mg/kg of i.v. (methyl)prednisolone every 6 h After symptom resolution, restart the infusion at half the rate and titrate until tolerated
3.Administer i.v. epinephrine in cases of failure of a prompt response, with severe hypotension or cardiac arrest.	If grade 3/4—stop the infusion
4.Provide fluid resuscitation in the form of a rapid infusion of 1-2 l of normal saline at a rate of 5-10 ml/kg in the first 5 min. Provide crystalloids or colloids in boluses of 20 ml/kg, followed by slow infusion.	Treat with: Antihistamines: 50 mg of i.v. diphenhydramine plus 50 mg of i.v. ranitidine Corticosteroids dose equivalent to 1-2 mg/kg of i.v. (methyl)prednisolone every 6 h
5.Administer diphenhydramine (1-2 mg/kg or 25-50 mg) slowly via i.v. infusion in combination with ranitidine (50 mg diluted in 5% dextrose water to a total volume of 20 ml) injected i.v. over 5 min.	Do not restart (not recommended in severe reactions)
6.Treat bradycardia with 600 mg of i.v. atropine.
7.Treat refractory cardiovascular effects in patients receiving β-blockers with 1-5 mg of i.v. glucagon infusion over 5 min, followed by an infusion (5-15 mg/min) titrated to clinical response.
8.Treat hypotension that is unresponsive to epinephrine and fluid resuscitation with:
a.Dopamine (400 mg in 500 ml of 5% dextrose water) administered at 2-20 mg/kg/min and titrated to increase systolic blood pressure.
b.Vasopressin 25 units (U) in 250 ml of 5% dextrose water or normal saline (0.1 U/ml), with a dose range of 0.01-0.04 U/min.
9.Provide corticosteroids for preventing biphasic reactions in the equivalent to 1-2 mg/kg of i.v. (methyl)prednisolone every 6 h (note that methylprednisolone is slightly stronger than prednisone, so caution should be exercised about the dose to use)

i.v., intravenous.

Reporting of infusion reactions

Accurate and detailed documentation of IRRs is crucial to guide treatment and restart decisions, to share data among institutions, and for research purposes. In addition, clear communication among health care providers is crucial to identify patients at risk for future IRRs and ensure that patients have a safe restart. IRRs should be reported as AEs to the product manufacturer.

As shown by the experience of the Memorial Sloan-Kettering Cancer Center, the use of a standardized protocol for the management and documentation of IRRs secondary to the administration of chemotherapy and biologic agents developed at the institution resulted in improvements and in an 88% increase in the reporting of this type of events, both to the institution’s adverse drug reaction reporting program and to the Food and Drug Administration (FDA).⁴⁰

IRRs should be documented in the patient’s clinical chart following a standardized procedure. The documentation of the IRR should include pre-infusion assessments carried out, the description and grading of the reaction according to a standardized classification system such as CTCAE, and the description of how the IRR was managed.^3,41 Table 2 provides an example of how to document an IRR (based on Roselló et al. 2017³).

Table 2.

Template for reporting IRRs

Pre-infusion assessment	Drug
	Number of cycles
	Treatment reintroduction (yes/no)
	Relevant medical history/allergy/atopy
	Concomitant medication(s)
	Oral premedication correctly taken
Description and grading of the IRR	Infusion rate
	Premedication
	Timing of symptom onset
	Vital signs
	Signs/symptoms
	Standard grading (CTCAE)
Management	Intervention
	Time to symptom resolution
	Patient response
	Treatment reintroduction (yes/no)
	Rate reintroduction

CTCAE, Common Terminology Criteria for Adverse Events; IRR, infusion-related reaction.

Restart

Most patients who experience an IRR, particularly when symptoms are mild to moderate, can safely resume treatment with proper medication and close monitoring (normally on the same day, but if necessary, restart can be delayed to the next day).^15,42,43 There should be a careful assessment of the risk of a serious recurrent reaction and the potential clinical benefit and risks of further treatment, while simultaneously considering patient factors, the severity and nature of the IRR, and the mechanism of action of the drug.^3,15,22 Patient education regarding the risks of the procedure is also recommended.

Restart should be carefully initiated after all symptoms of the IRR have resolved, at a reduced infusion rate (e.g. at 50% of the administration rate at which the IRR occurred and titrated to tolerance), and with additional premedication (e.g. corticosteroids and antihistamines).^3,22

However, restart is usually discouraged after severe IRRs, i.e. those with CTCAE grade 3-4, and in cases of true anaphylactic reactions.^3,22 The Cancer Care Ontario guidelines for the management of cancer medication-related infusion reactions propose considering restart if no vital signs are affected during the IRR (i.e. absence of respiratory distress, hypotension, etc.).²² Ultimately, the timing for restart will depend on the drug in question.

If clinically necessary and no alternative treatment is available, restart with intensified premedication and extended infusion duration can be considered.²² A desensitization protocol may be required to safely re-administer the medication.^3,15,22,39 Successful desensitization with mAbs is also possible, as previously reported.⁴⁴ A multidisciplinary approach to manage these events may require a close collaboration with immuno-allergology.

For patients with recurrent IRRs despite premedication, therapy switch, treatment discontinuation, or the use of a desensitization protocol before each subsequent administration are options to consider.^3,22 Drug desensitization consists of the administration of small amounts of the suspected therapeutic agent with prolonged infusion time and gradual dose escalation until tolerance to the desired total dose is achieved.^3,22,45 Desensitization induces only temporary tolerance to the drug and is dependent on continuous exposure, with the state of tolerance being lost once the drug is cleared.^3,46

Management of IRRs associated with anticancer therapies

Most anticancer therapies cause a risk for IRRs, but some agents are more prone to causing these reactions. These include, but are not limited to, taxanes, platinum compounds, and mAbs (Table 3).

Table 3.

Characteristics of IRRs associated with major anticancer therapies

Drug	Incidence of IRRs	Onset of IRRs	Signs/symptoms of IRRs	Prophylaxis	Management
Chemotherapy
Paclitaxel3,30,31,39,47, 48, 49, 50, 51, 52, 53	Albumin-bound: 4% without premedication. Cremophor-bound: 10% despite premedication.	On first exposure during cycle 1 or 2, within the first 10 min of infusion.	Nausea, vomiting, diarrhea, dyspnea, chest tightness, wheezing, throat tightness, bronchospasm, skin reactions, angioedema, urticaria, hypotension, tachycardia.	One dose of i.v. dexamethasone plus diphenhydramine (50 mg i.v.) and a H2 receptor antagonist (ranitidine 50 mg or cimetidine 300 mg i.v.) 30 min before the infusion.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Docetaxel3,15,30,39,46, 47, 48,52	5% (2% severe) despite premedication. 30% without Premedication.	On first exposure during cycle 1 or 2, within the first 10 min of infusion.	Flushing, hypotension, dyspnea, bronchospasm, skin reactions, urticaria, pruritus, angioedema, tachycardia, chest or back pain, fluid retention.	Oral dexamethasone 8 mg bid for 3 days (starting 1 day before docetaxel administration) or 12, 3, and 1 h before the infusion.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Cabazitaxel15,39,47,54, 55, 56, 57	Between <1% with concomitant prednisone and 6%.	Within minutes of the infusion, especially during the first and second infusions.	Flushing, rash, urticaria, dyspnea, drug-induced fever, bronchospasm with or without urticaria, allergy-related edema, angioedema, hypotension, erythema, anaphylaxis (in severe cases).	Antihistamines (diphenhydramine 25 mg or equivalent), corticosteroids (e.g. dexamethasone 8 mg or equivalent), or histamines (H2)-receptor antagonist (e.g. ranitidine 50 mg or equivalent) at least 30 min before administration.	Supportive care measures, such as antihistamines, corticosteroids, i.v. fluids, oxygen, and bronchodilators.
Carboplatin15,39,49,53,58, 59, 60, 61, 62, 63	8%-16% Incidence increases from 1% with ≤6 infusions to 27% with ≥7 infusions, to up to 46% with >15 infusions. Highest incidence with the eighth or ninth exposure.	Variable (minutes to hours). Risk increases with cumulative doses. Highest incidence at the eighth exposure. First IRR typically around the second and third re-exposure during the second line of therapy (eighth and ninth courses overall).	Nausea, vomiting, diarrhea, pruritus, urticaria, rash, erythema on palms and soles, abdominal cramps, facial edema, bronchospasm, wheezing, hypotension, tachycardia, dyspnea, chest pain, facial swelling, or anaphylaxis.	Corticosteroids and H1/H2 antagonists not routinely recommended. Can be considered in high-risk patients. Premedication may not prevent IRRs.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Oxaliplatin15,39,48,50,64, 65, 66, 67, 68, 69	7%-24% 0.5%-2% severe	Within 60 min (typically 5-10 min) after infusion start, but the first IRR can also occur throughout the treatment course. Incidence increases with the number of cycles; up to 20% after cycle 6.	Flushing, pruritus, urticaria, rash, palmar erythema, angioedema, hypertension, hypotension, sweating, watering, fever, dyspnea, back or chest pain, cough, throat tightness, nausea, diarrhea, laryngospasm, bronchospasm.	Corticosteroids and H1/H2 antagonists not routinely recommended. Can be considered in high-risk patients. Premedication may not prevent IRRs.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization. Administer treatment over 6 h.
Cisplatin68,70, 71, 72, 73	5%-20% Incidence increases with the number of cycles and with concomitant radiation therapy. Higher incidence after cycle 6.	First IRR typically around the second and third re-exposure during the second line of therapy (eighth and ninth courses overall).	Urticaria, pruritus, respiratory distress, hypotension.	Adequate hydration and antiemetics to prevent nausea and vomiting.	Extravasation: stop the infusion immediately, aspirate any fluid collection, and administer sodium thiosulfate.
Procarbazine30,39,53,74,75	6%-18% Higher with concomitant use of anticonvulsants. 2% severe	Mostly in the first treatment courses.	Rash, urticaria, angioedema, toxic epidermal necrolysis, fever.	Steroid and diphenhydramine. Premedication with oral corticosteroids usually not successful once the IRR occurs, requiring treatment interruption.	Grade 1/2: symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment.
Nab-paclitaxel15,30,39,48,49,53,76, 77, 78	30% without premedication. 2%-4% severe anaphylactic reactions.	First or second dose, within the first 10 min of infusion. 1%-2% severe hypersensitivity reactions after an IRR despite adequate premedication.	Dyspnea, hypotension, tachycardia, flushing, skin reactions, bronchospasm, angioedema, urticaria.	No premedication with corticosteroids, prolonged infusions, or special i.v. infusion sets required. Limit the infusion to 30 min to reduce the likelihood of IRRs. One dose of i.v. dexamethasone + diphenhydramine (50 mg i.v.) and a H2 receptor antagonist (ranitidine 50 mg or cimetidine 300 mg i.v.) 30 min before the infusion.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Asparaginase15,53,79, 80, 81	60% hypersensitivity reactions. 10% severe reactions.	Mostly within the first hour of infusion, with incidence and severity increasing with continued dosing.	Pruritus, rash, urticaria, abdominal pain, dyspnea, bronchospasm, laryngospasm, hypotension, angioedema.	Antihistamines and/or corticosteroids.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic therapy switch to PEGasparaginase.
Anthracyclines30,39,46,82	Rarely cause IRRs and most reactions are mild. 7%-11% with PEGylated liposomal doxorubicin and daunorubicin.	Mostly in the first infusion.	Fever, flushing, chills, angioedema, rash, urticaria, pruritus, tachycardia, syncope, dyspnea, hypotension, nausea, vomiting, headache, and back and chest pain.	Not routinely recommended. Reduced infusion rate can be considered.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Etoposide30,39,53,83, 84, 85, 86, 87	1%-3% anaphylactic-like reactions. Case reports described in the literature.		Chills, fever, tachycardia, bronchospasm, dyspnea, hypotension.	Corticosteroids and antihistamines. Slow the infusion over 30-60 min.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Consider desensitization.
Bleomycin88	1%	Immediate or delayed for several hours, usually after the first or second dose.	Fever, chills, mental confusion, hypotension, wheezing. Sudden onset of acute chest pain syndrome suggestive of pleuropericarditis during infusion.	≤2 units for the first two doses in lymphoma patients, due to the possibility of anaphylactoid reactions. If no IRR, follow the regular dosage schedule.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment.
Monoclonal antibodies
Rituximab2,5,17,39,89, 90, 91, 92, 93	77% on the first infusion. 10% severe.	Mostly in the first 2 h of the first infusion. Less likely in subsequent infusions. 63% in the first infusion, 9% in the second infusion, 15% in cycles 3-10, 7% in cycles 11-20, 6% in cycles 20-53.	Fever, chills, rash, pruritus, angioedema, dyspnea, hypotension, nausea, rhinitis, urticaria, asthenia, bronchospasm. Symptoms of tumor lysis syndrome and CRS observed.	Antipyretics and antihistamines (e.g. paracetamol and diphenhydramine). Slow the initial infusion rate. Corticosteroids may be considered if not given with chemotherapy. If high tumor burden, reduce the infusion rate for the first infusion or split dosing over 2 days.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment with antihistamines, acetaminophen, and methylprednisolone before dosing. Grade 3/4: stop treatment + aggressive symptomatic treatment. Treatment can be resumed at half the previous rate after resolution of all symptoms, except if severe reaction.
Cetuximab5,15,17,89,94, 95, 96	12%-19%, depending on the investigational area. 15%-21% grade 1/2. 2%-5% grade 3/4 despite premedication.	During or after the first and subsequent infusions (>90% in the first infusion). Most severe reactions during the first infusion. Time of onset depends on the type of reaction, varying between the first minute of infusion (e.g. anaphylactic reaction) and after 1 h (e.g. CRS-induced).	Flushing, nausea, vomiting, rash, fever, urticaria, chills, bronchospasm, dyspnea, angina, myocardial infarction, blood pressure changes.	Corticosteroids plus antihistamines before the first dose. Premedication optional for subsequent infusions if no reaction during the first cycle. Administer the first dose slowly while closely monitoring vital signs for at least 2 h.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Treatment can be resumed at a slower rate after resolution of all symptoms, except if severe reaction.
Daratumumab89,97, 98, 99, 100, 101	42%-48% in the drug’s phase III trials.	Median of 1.4 h to onset of a reaction. >90% during the first infusion. 7% during the second or third infusion. 5% in more than one cycle.	Nasal congestion, nausea, vomiting, cough, throat irritation, chills (grade 1-2 in 90%-95% of cases). Dyspnea, bronchospasms, laryngeal and pulmonary edema, hypoxia, hypertension (grade 3 in 5%-10% of cases).	1 h before every infusion: i.v. corticosteroid [(methyl)-prednisolone 100 mg or equivalent], oral antipyretics (paracetamol 650-1000 mg) and oral or i.v. antihistamine (diphenhydramine 25-50 mg or equivalent) 1 h before every infusion. After the second infusion: i.v. corticosteroid dose can be reduced [(methyl)prednisolone 60 mg].	Grade 1/2: stop or slow the infusion rate + standard symptomatic treatment (e.g. antihistamines, bronchodilators). Resume the infusion at half the rate when the patient is stable and titrate to tolerance. Grade 3: stop the infusion + aggressive symptomatic treatment. Resume treatment at half the rate if the reaction improves to grade ≤2 and titrate to tolerance. Permanently discontinue if grade ≥3 reaction at the subsequent infusion. Grade 4: permanently discontinue.
Alemtuzumab39,102, 103, 104, 105, 106, 107, 108	Up to 90%. 3% severe.	More frequent in the first infusion, decreasing with each infusion thereafter. More frequent during the first course (84.7% with 12 mg and 96.3% with 24 mg during the first course versus 68.6% with 12 mg and 81.9% with 24 mg during the second course).	Predominantly skin reactions, but also fever, nausea, headache, insomnia, chills, flushing, fatigue, dyspnea, dysgeusia, chest discomfort, tachycardia, dizziness, pain, atrial fibrillation, nausea, chest discomfort, or hypotension.	Corticosteroids [(methyl)prednisolone 1 g] on the first 3 days. Consider antihistamines and/or antipyretics. Monitor and document the body temperature every half hour for early detection of an IRR, as well as heart rate and blood pressure every hour.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment (e.g. antihistamines or antipyretics/anti-inflammatory agents). Grade 3/4: stop the infusion + aggressive symptomatic treatment. Resume treatment at a slower rate after symptom resolution, except if severe reaction.
Bevacizumab39,89,109	Up to 5%. <3% in the first Infusion. <1% severe.	Mostly in the first infusion.	Hypertension, dyspnea, rigor, flushing, rash, blood pressure changes, chest pain, nausea, vomiting.	No systematic premedication recommended before treatment. Regardless of dose, first infusion should be given in 90 min, and if tolerated second infusion in 60 min and subsequent infusions in 30 min.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: stop treatment + aggressive symptomatic treatment. Resume treatment at a slower rate after symptom resolution, except if severe reaction (e.g. anaphylactic shock), where treatment should be discontinued.
Trastuzumab5,8,46,110, 111, 112, 113, 114, 115, 116, 117	16.2%-40%, mostly grade 1-2. 6.5% grade 2. 0.6%-5% severe (usually after multiple exposures). Some reports of fatal cases.	Mostly during the first infusion and decreasing in frequency thereafter: 45%-91% in the first infusion, 29% in the second infusion, 20% in the third Infusion. When the reaction occurs in the first hour, greater probability of subsequent serious reaction.	Chills, fever, dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, respiratory distress, rash, nausea, vomiting, headache. Respiratory symptoms (65%) and chills/rigors (32%) in patients with severe IRRs.	Premedication not recommended but can be used to reduce the risk of IRRs. Antihistamines and corticosteroids together with a very low infusion rate (3 and 5 h instead of 90 min) successfully used.	Grade 1/2: stop or slow the infusion rate + monitor the patient until symptom resolution + treatment with analgesics/antipyretics (e.g. meperidine or paracetamol) or antihistamines (e.g. diphenhydramine). Treatment can be resumed at a slower rate if all symptoms resolve. Grade 3/4: stop the infusion + supportive therapy (e.g. oxygen, beta-agonists, corticosteroids). Observe the patient for 6 h after the first infusion and for at least 2 h after all subsequent ones.
Trastuzumab deruxtecan118, 119, 120	2.2% any grade. 1.7%-2% across multiple tumor types, all grade 1/2. 0.3% leading to dose interruptions.		Fever, chills, hypersensitivity, flushing, injection site reactions, hypotension, infusion site extravasation, rash, wheezing.	A combination regimen of two or three medicinal products (e.g. dexamethasone with a 5-HT3 receptor antagonist and/or an NK1 receptor antagonist, as well as other medicinal products as indicated) before infusion to prevent nausea and/or vomiting.	Monitor the patient during and after the infusion for signs such as fever and chills. Slow or stop the infusion if the patient develops infusion-related symptoms. Grade 3/4: permanently discontinue treatment.
Ramucirumab121, 122, 123	1.4% (grade 2 and 3) despite antihistamine and steroid premedication.	Mostly during or following the first or second infusion.	Rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, paresthesia. In severe cases, bronchospasm, supraventricular tachycardia, hypotension, acute hypertension.	Histamine H1 antagonist (e.g. diphenhydramine) before infusion. If grade 1/2 IRR, antihistamine before all subsequent infusions. If second grade 1/2 IRR, dexamethasone (or equivalent) and an i.v. histamine H1 antagonist (e.g. diphenhydramine hydrochloride), paracetamol, and dexamethasone for subsequent infusions.	Grade 1/2: reduce the infusion rate by 50% for the duration of the infusion and all subsequent infusions. Grade 3/4: immediately and permanently discontinue treatment. Monitor the patient during infusion for signs of IRRs, ensuring availability of appropriate resuscitation equipment.
Amivantamab27	66% (8% grade 1, 55% grade 2, and 3% grade 3)	Almost exclusively on cycle 1, day 1 (93%) or day 2 (4%); first dose is split over 2 days, and rarely recurred with subsequent dosing [one event was reported after cycle 2 (0.09%) of doses administered]. Most IRRs occur within 2 h of infusion start.	Dyspnea, flushing, chills, nausea, chest discomfort, vomiting, mild hypotension.	Antihistamines, antipyretics, and glucocorticoids before infusion (week 1, days 1 and 2). Antihistamines and antipyretics for subsequent doses. Initial infusion in split doses on week 1, days 1 and 2. Antiemetics as needed.	Interrupt the infusion at the first sign of an IRR of any grade. Administer additional supportive medication (e.g. additional glucocorticoids, antihistamines, antipyretics, antiemetics) as clinically indicated. Grade 1/3: upon symptom recovery, resume infusion at 50% of the previous rate. If no additional symptoms, the rate may be increased per recommended infusion rate. Administer concomitant medications at the next dose. Recurrent grade 3/4: permanently discontinue treatment.
Sacituzumab govitecan124,125	35% within 24 h of dosing. 2% grade 3/4. 0.2% leading to permanent discontinuation. 0.2% anaphylactic reactions. 3% grade ≥3	During or within 24 h of the infusion and for up to 30 min after.	During or within 24 h following the infusion: facial, lip, tongue, or throat swelling, urticaria, difficulty breathing, lightheadedness, dizziness, chills, rigors, wheezing, pruritus, flushing, rash, hypotension, fever. Severe: cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, skin reactions, life-threatening anaphylactic reactions.	Antipyretics, H1 and H2 blockers before infusion. Corticosteroids (e.g. 50 mg hydrocortisone or equivalent orally or intravenously) may be used for patients with prior infusion reactions. Two or three drug combination regimens (e.g. dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist, as well as other drugs as indicated).	Closely monitor the patient during the infusion and for at least 30 min after infusion completion. Slow or interrupt the infusion in case of signs of an IRR. Permanently discontinue treatment if the patient develops life-threatening IRRs. Have medications and emergency equipment available to immediately treat IRRs, including anaphylaxis, during administration.
Blinatumomab126	33.4%	Mostly within 48 h after infusion start. Some reports of delayed reactions or reactions in later cycles.	Pyrexia, CRS, hypotension, myalgia, acute kidney injury, hypertension, rash, tachypnea, swelling face, face edema, rash erythematous.	Dexamethasone 20 mg i.v. 1 h before infusion. Antipyretics (e.g. paracetamol) to reduce pyrexia during the first 48 h of each cycle.	Observe the patient closely, especially during the start of the first and second treatment cycles + provide appropriate treatment. Administer antipyretics (e.g. paracetamol) to reduce pyrexia during the first 48 h of each cycle.
Panitumumab127, 128, 129, 130	1.5%-5% 0.2%-1% grade 3-4	Mostly (61.7%) in the first infusion. 14.9% in the second infusion. One report of latest reaction at the 21st administration. One report of fatal angioedema >24 h after the infusion.	Headache, rashes, itching or hives, flushing, swelling (face, lips, mouth, around the eyes, and throat area), rapid and irregular heartbeat, fast pulse, sweating, nausea, vomiting, dizziness, difficulty breathing or swallowing, or a decrease in blood pressure that may be severe or life-threatening and, very rarely, lead to death.		Grade 1/2: reduce the infusion rate during the current and all subsequent infusions. Grade 3/4 during or at any time after the infusion (e.g. bronchospasm, angioedema, hypotension, need for parenteral treatment, anaphylaxis): permanently discontinue treatment.
Immunotherapy
Pembrolizumab131, 132, 133, 134, 135	3% <1% grade ≥3 0.2% (of 2799 patients) severe or life-threatening (hypersensitivity, anaphylaxis).		Pyrexia, chills.	Antipyretics and antihistamines can be considered.	Grade 1/2: stop or slow the infusion rate with close monitoring + symptomatic treatment. Grade 3/4: stop and permanently discontinue treatment.
Nivolumab136, 137, 138, 139, 140	2%-5%, including grade 3/4. <1% grade 3/4 leading to treatment discontinuation.		Facial flushing, hives, angioedema.	Infusion time of 30 min safe. Premedication advised in case of grade 1/2 reactions. Antipyretics and antihistamines can be considered in case of a reaction.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Grade 3/4: permanently stop the infusion + aggressive symptomatic treatment.
Ipilimumab141, 142, 143, 144, 145, 146	0.6%-5.8%, mostly grade 2	More frequent with the second dose, suggesting that the first dose is a sensitizing one.	Cough, shortness of breath, chills, rigors, pruritus, maculopapular rash, facial flushing, chest, abdominal, and back pain.	Antipyretics and antihistamines can be considered. Patient observation for a short period of time after the infusion recommended to monitor the occurrence of IRRs.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment (diphenhydramine and/or corticosteroids). Restart the infusion with close monitoring. Grade 3/4: stop the infusion + aggressive symptomatic treatment (including corticosteroids). Permanently discontinue treatment.
Durvalumab147	1.6% any grade 0.2% grade 3		Chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, fever.	Premedication for prophylaxis of subsequent infusion reactions can be considered.	Grade 1/2: stop or slow the infusion rate. Grade 3/4: permanently discontinue treatment. Monitor patients for signs and symptoms of IRRs.
Atezolizumab148, 149, 150, 151, 152, 153	1%-2% 1.3%-1.7% severe	Only reports of single cases: 10 min into the first infusion; after second lifetime exposure.	Dizziness, numbness, lack of consciousness, severe hypotension, chills, itching or rash, swelling of face or lips, flushing, shortness of breath, swelling, dyspnea or wheezing, fever, back or neck pain, anaphylaxis.	Antipyretics and antihistamines can be considered.	Grade 1/2: stop or slow the infusion rate + symptomatic treatment. Treatment may be resumed with close monitoring when the event is resolved. Grade 3/4: stop the infusion + aggressive symptomatic treatment. Permanently discontinue treatment.
Sintilimab154,155	2.3%-13% 0.8% grade ≥3 Pyrexia most frequent: 9% May cause severe or life-threatening IRRs, including severe hypersensitivity or anaphylactic reactions.	During or shortly after the infusion. Usually resolve completely within 24 h after completing the infusion. Pyrexia within 24 h of the first infusion, resolving on the same day and not reoccurring with subsequent infusions.	Infusion site pain and swelling, pyrexia, hypersensitivity, blood pressure increase, rash.

5-HT3, 5-Hydroxytryptamine (serotonin) receptors; CRS, cytokine-release syndrome; IRR, infusion-related reaction; i.v., intravenous; NK1, Neurokinin 1 receptor.

IRRs associated with taxanes may occur through IgE-mediated mast cell and/or basophil activation, direct action on basophils with histamine release, or IgG-mediated complement activation with release of anaphylatoxins by the taxane and/or through IgE-mediated mast cell activation or direct complement activation induced by its excipients (such as Polysorbate 80 with docetaxel or Cremophor EL with paclitaxel).^47,156, 157, 158 They most commonly occur within minutes during the first or second infusion,^3,15,158, 159, 160 and prophylaxis with premedication before taxane infusion is the standard of care.^3,22

IRRs to platinum compounds are typically associated with IgE-mediated type 1 reactions, cytokine-release reactions, and mixed reactions.^15,58,64,161 The timing of reactions is variable, with some being immediate and occurring during or within hours after infusion,^70,162 and others typically manifesting with increased and repeated drug exposure.^70,163 Routine prophylaxis with premedication is not recommended to prevent IRRs with platinum compounds due to insufficient efficacy evidence, with strategies like extending the infusion duration and using skin testing to predict patients at risk of experiencing an IRR preferred.²²

Although the exact mechanism of IRRs to mAbs is not clear, they are mostly thought to be caused by the release of cytokines into circulation due to binding of the mAb to the target cell.^17,164 In addition, rituximab, trastuzumab, and cetuximab are also able to induce IgE-mediated allergic reactions, inducing the release of vasoactive mediators from mast cells and basophil cells.⁸⁹ Most IRRs occur during the first infusion, starting within 30-120 min after the start of mAb administration, but delayed reactions have been observed.^2,165,166 Strategies to prevent the incidence and severity of IRRs with mAbs include premedication with antihistamines, acetaminophen, and corticosteroids, incremental escalation of the infusion rate in the first and sometimes second treatment cycle, and dose reductions in the first cycle for some agents.^2,5,15,89

Practical aspects in the management of IRRs in clinical practice

A standardized approach to the management of IRRs associated with anticancer therapies has the potential to reduce the impact of these reactions on patients’ safety and on the quality of treatment provided and should be adopted in oncology clinical practice.

Preventing IRRs (through the use of premedication and/or infusion of the anticancer medication at a graduated rate) is a key factor for reducing their incidence and improving patient management. Therefore, when clinical manifestations of IRRs arise, their accurate assessment and prompt management by trained health care providers are imperative to avoid severe AEs, including fatality.

Patients experiencing IRRs may be erroneously labelled as having an allergy to the medication in question, restricting the use of first-line therapies.^47,167 Therefore, providing training in the recognition and management of IRRs to health care providers involved in the i.v. administration of anticancer medications, especially oncology nurses, is crucial to optimize the procedure and should be implemented in hospitals and oncology centers. A knowledgeable and trained medical team is also a reassuring factor for patients.

Variability in the prevention and management of IRRs across health institutions is a quality and safety gap in cancer care. In this context, the implementation of a standardized protocol for the management of IRRs common to all hospitals administering i.v. cancer medications and readily available at the day hospital is key to ensure that patients receive the best and most equitable standards of care. The development and implementation of a standardized reporting procedure for documenting IRRs that is also in place at day hospitals and is systematically used when reporting an IRR is also a valuable tool toward this goal, as well as for data sharing among institutions and research purposes.

Treatment completion after an IRR

IRRs manifest during the infusion process or shortly after the start of therapy, presenting with a range of symptoms across different body systems and varying severity levels among patients.⁸⁹ IRRs are usually safely managed with pre- and post-infusion medications.⁸⁹ However, after an IRR episode, it is crucial that the clinician evaluates the characteristics of the precipitating drug and event to identify preventive measures against future episodes.³ A period of observation may be advisable.³ Observation periods should be tailored to the individual patient, based on factors such as the severity of the reaction, the patient’s status, and the proximity of emergency facilities. Severe or refractory symptoms may require prolonged observation (up to 24 h) or hospitalization.³ If the reaction strongly suggests an anaphylactic reaction, consultation with an allergist/immunologist is recommended.¹⁶⁸ It is important to offer psychological support and have a detailed, informative discussion with the patient about the advantages and disadvantages of continuing the medication, with emphasis on the possibility of a recurrence of the IRR.¹⁶⁹ Although not limited to them, the following aspects should be considered when developing a strategy for completing treatment after an IRR:

• 1.The severity and nature of the IRR play a key role in the decision to restart treatment. Therefore, clinical factors such as the risk of a serious recurrent reaction and the potential clinical benefit of further treatment should be carefully assessed when considering whether to resume treatment.³
• 2.Consider the drug’s mechanism of action and the patient’s compliance with the recommendations described in the SmPC. These factors contribute significantly to the overall understanding of the drug’s pharmacological properties and intended use, guiding its appropriate and effective use in clinical practice.
• 3.After complete resolution of all symptoms, restarting treatment with an adjusted (usually reduced) infusion rate and additional premedication (such as corticosteroids and antihistamines) is generally successful and may be considered. Permanent discontinuation may be considered depending on the severity of symptoms.³
• 4.The infusion rate plays a critical role in drug administration. It is a critical factor that requires careful consideration to ensure safe and effective drug perfusion and should be adjusted/managed accordingly.⁸⁹ Once all symptoms have resolved, restarting treatment with a reduced infusion rate and additional premedication (such as corticosteroids and antihistamines) is usually successful.³
• 5.Restarting treatment after an IRR with CTCAE grade 3 or higher or true anaphylaxis should not be attempted.³
• 6.The presence of an allergist in the multidisciplinary team is key and should be encouraged. Allergists can contribute to a deeper understanding of the identified IRR and assist in the drug desensitization process if needed.¹⁷⁰
• 7.Treatment alternatives (such as nab-paclitaxel and paclitaxel) should be available in case a switch is needed.
• 8.The medical team should feel confident about restarting treatment.

Conclusion

IRRs are a group of heterogeneous AEs that can occur after drug infusions, and anticancer therapies are no exception. Patient education, awareness, prompt recognition and health care team intervention, as well as treatment with rapid access to the intensive care unit if needed, are crucial to prevent further complications. Although some molecules have a higher incidence of IRRs, having a well-trained team of health care professionals and following the IRR management protocol is critical to mitigate the risk of additional incidents after an IRR and optimize treatment benefits for patients.