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Guidelines update Guidelines for Pharmacy Services for Antineoplastic Drugs

 Last Update: 2022-11-25
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Summary

Antibody drugs are drugs prepared by using antibody engineering technology mainly based on cell and genetic engineering technology, and are widely used
in the treatment of malignant tumors.
At present, the antibody antitumor drugs on the market can be divided into monoclonal antibody drugs, bispecific antibody drugs and antibody conjugates according to the structural characteristics of drugs
.
As of June 1, 2022, 39 antibody anti-tumor drugs have been approved for marketing
in China.
Because the pharmaceutical properties, efficacy and pharmacokinetic characteristics are different from traditional small molecule drugs, antibody antitumor drugs have distinctive characteristics
in clinical applications 。 In order to standardize the rational use of antibody antitumor drugs, under the guidance of the National Cancer Center, the Cancer Specialist Pharmacist Branch of the Chinese Pharmacists Association, together with multidisciplinary experts across the country, based on clinical evidence-based evidence, relevant regulations on pharmaceutical affairs management and pharmaceutical service practices, using Delphi method and expert interviews and discussions, formulated a pharmaceutical service guide for antibody antitumor drugs, which covers the whole process of chemical pharmacy service system before, during and after medication, and provides a scientific basis for pharmacists to carry out pharmaceutical services of antibody antitumor drugs
。

【Keywords】malignant tumor; antineoplastic drugs; pharmacy services; Guide

One

Introduction

In recent years, with the development of biotechnology and people's in-depth research on tumor biology, antibody anti-tumor drugs have sprung up and played an important role
in the treatment of malignant tumors.
At present, the antibody anti-tumor drugs approved for marketing in China mainly include monoclonal antibodies, bispecific antibodies and antibody-drug conjuate (ADC) drugs
that act on tumor signaling pathways.
Compared with traditional chemotherapy drugs, antibody antitumor drugs have the characteristics of
high specificity, relatively low adverse reactions, long half-life, and high storage and transportation conditions.
At the same time, the production process and pharmaceutical characteristics of antibody antitumor drugs make them easy to cause immunogenic adverse reactions, allergies, off-target and other problems in clinical application, and improper clinical application directly affects their safety and effectiveness, requiring pharmacists to participate in the clinical treatment team to provide full chemical pharmacy services
for clinical and patients.

There are guidelines, guidelines, consensus and other relevant standards for the clinical application of antibody antitumor drugs, but the content is mostly focused on clinical diagnosis and application, and the pharmaceutical service content in use is relatively small, and there is still a lack of unified pharmaceutical service standards
that effectively guide the clinical rational use of antibody antitumor drugs 。 To this end, under the guidance of the Chinese Pharmacists Association and the National Cancer Center, the Cancer Specialty Pharmacist Branch of the Chinese Pharmacists Association formulated this guideline based on clinical evidence-based evidence, with its own professional expertise and practical experience in pharmaceutical services, and with multidisciplinary experts across the country, in order to provide reference
for the pharmaceutical services of antibody antitumor drugs.

One

Guide formation methodology

1.
Guidelines initiators and expert group members: Entrusted by the Chinese Pharmacists Association, this guideline was initiated and organized by the Oncology Specialty Pharmacists Branch of the Chinese Pharmacists Association, and jointly formulated
by multidisciplinary experts under the guidance of the Chinese Pharmacists Association and the National Cancer Center, based on clinical evidence-based evidence, pharmaceutical service practices and expert interviews.

2.
Guidelines Working Group and Expert Group: This guideline has established a multidisciplinary working group and expert group, mainly covering experts
in oncology pharmacy, medical oncology, oncology surgery, epidemiology, evidence-based medicine, health economics and oncology nursing.
All Working Group members completed a Conflict of Interest Declaration Form and there is no direct conflict of interest
with this guide.

3
.
Guidelines for users and application target groups: This guide is suitable for use in pharmaceutical services of antibody antitumor drugs in medical institutions at all levels.
The guidelines are used by pharmacy and clinical workers (including physicians, nurses and other related staff)
in medical institutions at all levels.
The guideline recommendations are intended for oncology patients
using antibody-based antineoplastic drugs.

4.
Selection and determination of clinical problems: Through systematic search of published guidelines, systematic reviews and related studies in the field of clinical application and evaluation of antibody antitumor drugs at home and abroad, as well as interviews with some tumor pharmacy, medical and nursing experts who often use antibody antitumor drugs in clinical practice, the working group has preliminarily formulated a framework for 7 categories of key issues, covering 7 categories 24 clinical questions, investigated and scored
on the importance of clinical questions in the form of an online questionnaire.
A total of 74 people were collected in 2 rounds (23 in the first round and 51 in the second round Feedback) expert letter feedback, and finally selected the 24 clinical questions
to be solved by this guideline.

5.
Search, evaluation and grading of evidence: The guideline development working group searched the key questions for final inclusion by population, intervention, control and outcome principles, including PubMed, Embase, and specific search databases Clinicaltrial, Cochrane Library, Web of Science, CNKI, Wanfang Data Knowledge Service Platform and China Biomedical Literature Database
.
The grading of recommendations assessment, deve-lopment and evaluation (GRADE) method was used to grade the quality of evidence and recommendations, as shown in Table 1
。

6.
Formation of recommendations: Based on the retrieved clinical evidence at home and abroad, combined with the pharmaceutical service process of medical institutions in China, the guideline working group preliminarily formed the drug information and pharmaceutical monitoring content required for the pharmaceutical service of antibody antitumor drugs, and formed recommendations for clinical problems
.
The guideline working group has twice solicited opinions from the members of the project expert group through an online questionnaire using the Delphi method, and further revised the recommendations to form recommendations
.
For administrative clinical issues, A-level evidence and strong recommendations are formed in accordance with relevant pharmaceutical regulations, guiding principles and drug labels
.

One

Key questions and recommendations

(1) Relevant pharmaceutical information and parameters required for pharmaceutical services of antibody antitumor drugs

Clinical Question 1

Classification and basic information of antibody antitumor drugs marketed in China

At present, the antibody anti-tumor drugs on the market can be divided into monoclonal antibody drugs, bispecific antibody drugs and ADC drugs according to the structural characteristics of drugs
.
As of June 1, 2022, the NMPA has approved 39 anti-tumor drugs (including biosimilars See Table 2
for details.

Clinical Question 2

Pharmaceutical properties of antineoplastic antineoplastic drugs

At present, antibody antitumor drugs are mainly immunoglobulin G (IgG), and the pharmaceutical properties of this class of drugs are closely related to
their IgG subtype and humanization.

There are 4 subtypes of IgG, namely IgG1, IgG2, IgG3, IgG4, though The spatial structure of the four subtypes is similar, but the content, half-life and immunogenicity in the human body are different
.
According to the degree of humanization, it can be divided into murine monoclonal antibody, human-mouse chimeric monoclonal antibody, humanized monoclonal antibody and fully humanized monoclonal antibody
.
The degree of humanization of IgG has a certain correlation
with the strength of immunogenicity.

The distribution of antibody antitumor drugs in vivo is mainly through blood and interstitial fluid convection, endocytosis, phagocytosis, pinocytosis, etc.
, and receptor-mediated endocytosis is an important mechanism
for the distribution of antibody drugs in vivo.
The molecular weight of antibody antitumor drugs is large, and they are not metabolized by liver enzymes, nor can they be excreted by the kidneys as prototypes, and their main metabolic mode is intracellular enzyme degradation
.
Antibody antitumor drugs are exogenous protein drugs, which may cause the formation of anti-drug antibodies (ADA), which in turn affects the safety and efficacy of drugs, and even triggers different degrees of immunogenic reactions
.
Therefore, it is important
to grasp the IgG subtype, degree of humanization, pharmacokinetic characteristics, and incidence of ADA of antibody antitumor drugs.
In order to accurately carry out the whole process of chemical pharmaceutical services, this guide summarizes the information related to the pharmaceutical properties of antibody antitumor drugs, as shown in Table 3
.

Clinical Question 3

Suggestions for antibody-based antitumor drug pharmacovigilance work

Pharmacovigilance is an indispensable scientific means for the safe use of drugs and prevention of drug risks, and it is also an important content of
pharmaceutical services.
Suggestions: (1) Medical institutions should formulate and establish their own pharmacovigilance monitoring system, and actively carry out drug safety evaluation; (2) Pharmacists should formulate pharmacovigilance plans for antibody antitumor drugs, participate in the clinical treatment process, monitor all aspects of drug use, timely detect pharmacovigilance signals, report adverse drug reactions, and prevent drug harm incidents; (3) According to the monitoring dynamics of adverse drug events at home and abroad, issue and update adverse drug reaction information, and timely start early warning of adverse drug events occurring in the hospital; (4) Do a good job in patient medication education, improve patients' initiative to self-report adverse drug reactions; (5) Long-term follow-up and regular follow-up of key patients, and do a good job in home pharmacy services
.

This guide collects the global pharmacovigilance content of antibody antitumor drugs marketed in China to provide reference for pharmacists to carry out pharmacovigilance work, as shown in Table 4
.

(2) Prescription management of antibody antitumor drugs

Clinical Question 4

Indications management and extended clinical application

The indications in the drug label are the legal basis
for the clinical application of antibody antitumor drugs.
Due to the rapid progress of clinical research of antibody antitumor drugs, based on expert consensus, it is recommended that the recommended level for the extended clinical application of antibody antitumor drugs is divided into two levels: level 1 is the indication or treatment recommendation approved by foreign drug inserts or domestic and foreign guidelines based on large randomized controlled studies, 2 Grade is foreign instructions or domestic and foreign guidelines based on other types of research approved indications or treatment recommendations
.
Extended use should be with informed patient consent
.

1.
Indications for immune checkpoint inhibitors (ICIs): The ICIs currently marketed in China mainly involve the target of programmed death receptor 1 (programmed cell death-1, PD-1), programmed cell death-ligand 1 (PD-L1), and CTLA-4
。 As of June 1, 2022, 14 ICIs have been approved for listing in China, among which Five are imported drugs and nine are domestically produced drugs
.
The 5 imported ICIs listed in China have about 50 indications approved by the Food and Drug Administration (FDA).
Remainder
.
In addition to tumors approved by the National Medical Products Administration (NMPA), it also involves endometrial cancer, B-cell lymphoma, Merck cell tumor, cervical cancer, kidney cancer, breast cancer, skin squamous cell carcinoma and other tumors, as well as "high tumor mutation burden.
" See Table 5 for the indications for pan-neoplasia.

All ICIs listed in China, NMPA approved nearly 50 indications, involving non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, nasopharyngeal carcinoma, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, colorectal cancer, malignant melanoma, head and neck squamous cell carcinoma, gastric cancer and other tumors, Among them, 18 indications are conditionally approved, which must be further confirmed by subsequent clinical study data
.
In the guidelines of the Chinese Society of Clinical Oncology (CSCO), most of the conditionally approved indications are at the first-class recommended level
.
It is recommended that pharmacists continue to pay attention to the results of follow-up clinical trials of conditionally listed drugs in clinical pharmacy services, and provide timely, effective and correct clinical use information
for clinical drugs.
The indications for conditional approval of immune checkpoint inhibitors are detailed in Table 6
.

2.
Target detection of antibody anti-tumor drugs: the dominant population of ICIs treatment is a hot issue
of clinical concern.
Microsatellite instability high (MSI-H) or mismatch repair-deficient (dMMR) and PD-L1 on immune or tumor cells are currently highly unstable (MSI-H) or mismatch repair gene defects Status is considered a potential predictive biomarker of response to treatment with ICIs
.
Among the indications approved by NMPA, there are 4 drugs that can be used for MSI-H or dMMR advanced solid tumors, namely envolimab, tislelizumab, serplulimab and pembrolizumab; There are 4 drugs involved in PD-L1 status (tislelizumab, pembrolizumab, nivolumab, and atezolizumab), including 5 related tumors (urothelial carcinoma, non-small cell lung cancer, liver cancer, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma).
8 indications
.

According to whether target detection is required, refer to the drug insert approved by the NMPA and the "Guidelines for the Clinical Application of New Antitumor Drugs (2021 Edition)", and divide antibody antitumor drugs into two categories: targets that need to be detected and targets that do not need to be detected, as shown in Table 7 for details
。

3.
Indication management of biosimilars: Biosimilars are slightly different from the indications of the original drug, and it is recommended that the drug should be selected
according to the needs of the condition and the effectiveness, safety and economy of the drug.

Clinical Question 5

Usage and dosage of antibody antitumor drugs

Antibody antineoplastic drugs have different dosage calculation methods, including calculation based on body surface area, body weight, and fixed dose, as detailed in Table 8
.

Some antineoplastic drugs require a loading dose for initial use, as detailed in Table 9
.
If pertuzumab is delayed and the interval between two consecutive infusions is <</b14> weeks, the the weeks, the loading dose the interval

Most antibody antitumor drugs need to be used in combination with chemotherapy drugs, and the administration cycle of antibody antitumor drugs is also different to match the cycle of chemotherapy, as shown in Table 10
.

Clinical Question 6

Medication management for special patients

1.
Elderly patients: According to the results of relevant in vivo pharmacokinetic studies, the elderly generally do not need to adjust the dose
of antibody antitumor drugs.

2.
Pregnant and lactating patients: The pre-marketing study of antibody antitumor drugs is not included in the pregnant population, but according to the drug mechanism of action in the drug label, animal experimental studies and post-marketing clinical studies, it is recommended that the use of antibody antitumor drugs
should be avoided during pregnancy.
For patients with family planning, effective contraception is recommended during the period of use of these drugs and for a specific period of time after the last dose
.
For lactating patients, because human IgG will be secreted into breast milk, antibody antitumor drugs may be potentially risky to breastfed infants and young children, so it is recommended that lactating women should stop breastfeeding during and after receiving antibody antitumor drugs, different drug elution periods are different, the specific elution time is shown in Table 11
.

3.
Pediatric patients: The vast majority of antibody antitumor drugs have not been clinically studied in people under 18 years of age, and the safety and efficacy
of such drugs in children have not been determined.
Only four drugs (Table 12) are clearly defined for use in children, and other antineoplastic drugs are recommended to be evaluated and selected
based on relevant clinical studies and clinical benefits and risks.

4.
Drug management of other special patients: the use of antibody anti-tumor drugs will increase the risk of adverse reactions in some special patients, and it is recommended that patients with special physiological states such as liver and kidney insufficiency and a variety of underlying diseases should strengthen monitoring when using antibody anti-tumor drugs, and adjust drug treatment according to the corresponding recommendations
.
The recommendations for medication treatment for patients with special physiological conditions are detailed in Table 13
.

(3) Pharmacoeconomic evaluation

Clinical Question 7

Pharmacoeconomic evaluation of antibody antitumor drugs

The price of antibody antitumor drugs is greatly affected by the relevant policies of national drug negotiation and centralized procurement, and there is no sufficient pharmacoeconomic basis to make recommendations
for drug selection.

Based on expert consensus, it is recommended that cost-effective drugs
be preferred under the recommendation of the same clinical evidence, combined with the monthly treatment cost or course of treatment cost, patient willingness to pay and medical insurance policy.

(4) Storage and configuration management of antibody antitumor drugs

Clinical Question 8

Storage management of antibody antitumor drugs

Antibody antitumor drugs are easily affected by environmental factors such as temperature and light, and improper storage will lead to drug failure
.
Routine storage and transportation temperature of antibody antitumor drugs is generally 2~8 °C, protected from light
.
It is recommended that its storage and transportation should be carried out in strict accordance with the requirements of the manual (evidence level: A; Highly recommended)
.

Clinical Question 9

Configuration management of antibody antitumor drugs

The antibody antitumor drugs listed in China, except for the original trastuzumab (containing preservatives in the compound), other drugs do not contain preservatives
.
It is recommended that the configuration of antibody antitumor drugs should be in a sterile environment, using sterile equipment, ready to use
.
Before configuration, the properties of the drug should be observed, and the changes in the properties of the drug such as turbidity, precipitation, discoloration, crystallization and the slight rupture of the bottle body should not be used
.
At the same time, a traceability management system for relevant drug allocation is formulated, and the whole process of drug allocation can be traced
.

The configuration of antibody antitumor drugs has a great influence
on the stability of drugs and the accuracy of dosing doses.
The stability during and after configuration is affected by factors such as concentration, pH, mechanical force
, etc.
Studies have shown that dilution of antibody drugs will reduce the concentration of protective carbohydrates, surfactants or arginine and other excipients in pharmaceutical preparations, which in turn affects the pH value and ionic strength of the drug solution itself, which may affect the polymerization tendency of protein molecules themselves, resulting in reduced
chemical stability of antibody molecules.
In addition, changes in the gas-liquid boundary area generated by stirring, shaking and other operations can also affect the aggregation level of antibody antitumor drug molecules, which in turn affects
the stability of drugs.

It is recommended that the configuration of antibody antitumor drugs should strictly follow the operational requirements of the instructions, and the appropriate type and specification of solvents should be selected during the configuration process to avoid excessive shock, ensure that the drug is fully dissolved, and the final concentration of the drug after configuration should be within an appropriate range (evidence level: A; Highly recommended)
.

Clinical Question 10

Infusion monitoring of antineoplastic drugs

The infusion of antibody antitumor drugs should be carried out in an environment with complete resuscitation equipment, and the drug should be rewarmed according to the requirements of the instructions before infusion, an effective intravenous channel should be established, and professional nursing staff should regularly patrol the whole process during the infusion process, adjust the appropriate drip rate, and check the infusion pipeline and the patient's condition
.
If an infusion reaction occurs, it should be handled
according to the infusion reaction treatment procedure.
If it is necessary to continue the infusion, the drip rate should be slowed down, and the corresponding solvent flush should be applied after the infusion
.

It is recommended that antineoplastic drugs be infusion set by professional nursing staff, complete the infusion within the specified time at an appropriate infusion rate, and monitor the infusion reactions that may occur during the infusion process to ensure the safety of the use of such drugs (level of evidence: A; Highly recommended)
.

(5) Combination of antibody antitumor drugs

Clinical Question 11

Antineoplastic drugs are used in combination with chemotherapy drugs

Antibody antitumor drugs are mostly used in combination with other chemotherapy drugs, and most of them have no special requirements when used in combination; In view of the high incidence of infusion reactions of some drugs and the need to identify them in time, combined with the experimental design of clinical studies of antibody antineoplastic drugs, it is recommended that this class of drugs be used before other chemotherapy drugs, and allow observation time (level of evidence: B; Weak recommendation)
.

Clinical Question 12

The combined use of two antibody-like antitumor drugs

When combined with antibody antitumor drugs, attention should be paid to the order of administration, and most drugs have no special requirements; Where the order of administration is required, it is recommended to administer the drug according to the order of administration in the label or clinical trial (level of evidence: B; Highly recommended)
.

At present, the combination of two antibody antitumor drugs is not uncommon, but the recommended drugs for clarifying the specific order of administration are relatively limited
.
When sindilimab is administered in combination with bevacizumab, sindilimab should be given first at intervals of at least 5 minutes
.
When ipilimumab is combined with nivolumab, nivolumab should be infused first, followed by ipilimumab
infusion on the same day.
When pertuzumab and trastuzumab are combined, the two must be used sequentially, and can be administered in any order, and it is recommended to observe for 30~60 min after giving pertuzumab before continuing to give trastuzumab or chemotherapy
.
When atezolizumab is used in combination with bevacizumab, bevacizumab should be infused within the same day after atezolizumab.

Clinical Question 13

Combination of antibody antitumor drugs with other classes of drugs

The interaction study of antibody antitumor drugs in combination with other drugs is mainly the interaction
of ICIs with other drugs.
Drugs that have an impact on the intestinal flora and immune status, such as antibacterial drugs, proton pump inhibitors (PPIs), glucocorticoids, etc.
, will have a certain impact
on the efficacy of ICIs.

Studies have shown that the composition of the intestinal flora is an important factor
in regulating the host's response to immunotherapy.
Studies have shown that a certain proportion of tumor patients receiving immunotherapy use antibacterial drugs or PPIs, and antibacterial drugs and PPIs affect the intestinal flora through different mechanisms of action; In the process of immunotherapy, the main role of glucocorticoids is to prevent cerebral edema, improve the complications associated with tumors such as poor appetite, dyspnea, fatigue, and immune-related adverse events (irAEs) for the treatment of moderate and severe immunotherapy-related adverse events Pretreatment is given before immunotherapy to reduce gastrointestinal and allergic reactions, etc
.
This guideline uses literature searches to determine
whether the use of these drugs affects the effects of immunotherapy.

1.
Antibacterial drugs and ICIs: The use of antibacterial drugs will affect the overall survival rate and progression-free survival rate of immunotherapy in tumor patients, and for tumor patients receiving immunotherapy, unless clinically absolutely necessary, it is recommended to be 1~3 before treatment Antimicrobials should be avoided for months (level of evidence: A; Highly recommended)
.
When antimicrobials must be used, it is recommended that immunotherapy be delayed (level of evidence: C; Weak recommendation)
.

One meta-analysis showed that antimicrobial use was associated with shorter overall survival and progression-free survival, along with reduced disease response and increased disease progression, but there was considerable heterogeneity
in the results of the study.
Studies have reported that antimicrobial therapy 2 months or 1 month before PD-1/PD-L1 monoclonal antibody therapy shortens progression-free survival (PFS).
and overall survival (OS).

Patients with antimicrobials before treatment with ICIs combined with antimicrobials had worse overall survival than ICIs treatment, but studies have also shown that the combination of PD-1 monoclonal antibodies and antimicrobials induces T Cell activation shows synergistic anti-pancreatic cancer effects
.

The reason for poor immunotherapy results in patients treated with antimicrobials is related to
significant differences in antibodies in patients receiving antimicrobials.
In lung cancer patients, antimicrobials are associated with differences in interferon γ, interleukin-8, and macrophage inflammatory protein cytokines.

Although it is unclear whether antimicrobials cause these differences, combination antimicrobials should be avoided given the more common use of antimicrobials in patients with tumors and the potential adverse effects of antimicrobials
on immunotherapy outcomes.

2.
PPIs and ICIs: patients receiving immunotherapy should be cautiously combined with PPIs (level of evidence: B; Weak recommendation)
.
Histamine H2 receptor blockers are an option when acid-suppressing agents must be used (level of evidence: C; Weak recommendation)
.

Early meta-analysis showed no statistically significant difference in the association between the use of PPIs and ICIs in patients treated with OS or PFS
。 One meta-analysis showed that the use of PPIs in patients with solid tumors reduced OS and PFS; In subgroup analyses, non-small cell lung cancer, urothelial cancer, and multiple other malignant tumor types were consistent with the overall analysis, but PFS results in melanoma patients were the opposite of the overall analysis; The use of PPIs in patients older than 65 years of age also has adverse
prognostic effects.
Studies have shown that the use of PPIs is significantly associated with
poor prognosis in patients who receive PPIs within 30 days before and after the start of ICIs treatment.
The reason for the difference in the effect of PPIs on immunotherapy outcomes is that PPIs may interfere with the gut microbiota associated with the efficacy of ICIs, as well as PPIs It can adjust the pH value of the tumor microenvironment, promote the occurrence of immune response, and prevent tumor immune escape
.
Given the potential impact of PPIs on immunotherapy, it is recommended to avoid PPIs or switch to antihistamines and _H2 receptor antagonists
during immunotherapy.

3.
Glucocorticoids and ICIs: The use of glucocorticoids to treat immune-related adverse reactions or chemotherapy pretreatment does not reduce the OS of ICIs treatment and does not affect the prognosis ( Level of evidence: B; Weak recommendation)
.
ICIs are not recommended in patients on long-term glucocorticoid use at baseline (level of evidence: B; Weak recommendation)
.

Patients with tumors may have multiple indications
for glucocorticoid use.
Considering the potential inhibitory effect of glucocorticoids on T cell function, whether glucocorticoid use affects the efficacy and safety of ICIs is an important question of clinical concern
.
One network meta-analysis showed that in terms of OS and PFS, the hormone pretreatment group (ICIs plus platinum+ paclitaxel) was not significantly different from the untreated group (ICIs plus platinum + albumin-bound paclitaxel).
In terms of safety, the difference in adverse reaction rates at grade 3 and above was also not statistically significant
.
Retrospective analysis showed that the use of glucocorticoids for tumor-related complications (eg, cerebral edema, poor feeding, dyspnea, fatigue, etc.
) was an independent risk factor for PFS and OS in patients receiving immunotherapy, and subgroup analyses of non-small cell lung cancer showed similar results
.
The results of meta-analysis suggest that PFS and OS were worse in the group of patients treated with glucocorticoids combined with ICIs when using glucocorticoids for tumor-related complications.
Glucocorticoids had no effect
on PFS and OS when used for non-malignancy-related indications and irAEs.

4.
Intestinal flora and ICIs: there is currently no definitive clinical evidence that drugs that improve intestinal flora can enhance the effect of immunotherapy (level of evidence: C; No explicit recommendation).

Dietary interventions are the most cost-effective means of modulating the gut flora, and given the complexity of dietary management, an executable dietary regimen by a professional nutritionist is recommended (level of evidence: C; Weak recommendation)
.

The gut microbiota can influence the effectiveness of immunotherapy and play an important role
in the systemic immune response.
Numerous studies have shown that the composition of the gut flora is an important factor in regulating the host's response to anti-immunotherapy, and many drugs affect the effectiveness
of immunotherapy by affecting the intestinal flora.
Theoretically, probiotic formulations benefit patients receiving ICIs, however live bacteria have difficulty passing through the acidic environment of the upper gastrointestinal tract, and there is currently no high-quality clinical evidence that the use of probiotics or prebiotics is clearly associated with
improved immunotherapy outcomes.
Based on current clinical findings, routine use of probiotic supplements
is not recommended.

Antimicrobials can affect the intestinal flora, however studies have shown that the use of probiotics after receiving antimicrobial treatment may have the opposite effect and delay the recovery
of the intestinal flora.
A small study of melanoma patients showed that taking probiotic supplements reduced response rates by 70%.

Dietary interventions are the most cost-effective means
of regulating the intestinal flora.
There is evidence that dietary changes can significantly alter the gut microbiota
within 5 days.
Given the complexity of dietary management, an executable diet regimen
by a professional nutritionist is recommended.

Clinical Question 14

Special administration of antibody antitumor drugs

According to the drug instructions, envolimab and denosumab are administered by subcutaneous injection, and other anti-tumor drugs marketed in China are administered intravenously (evidence level: A; Highly recommended)
.

In patients with advanced lung cancer complicated by malignant pleural effusion, bevacizumab may be given with chest perfusion in combination with chemotherapy
.
Based on the low level of evidence from current studies, it is not possible to make a uniform recommendation for the treatment of malignant pleural effusion by pleural perfusion with bevacizumab (level of evidence: C; No explicit recommendation).

Malignant pleural effusion is a common complication of advanced lung cancer, which is prone to recurrent attacks and affects the treatment effect, seriously affecting the quality of life of patients, and is related to
poor prognosis.
Studies have shown that tumor secretion of vascular endothelial growth factor (VEGF) by binding to vascular endothelial growth factor receptors to promote neoangiogenesis and increase microvascular permeability is a new possible mechanism
.
There are also reviews to demonstrate the clinical efficacy and safety of bevacizumab combined with chemotherapy thoracic perfusion in the treatment of this complication, and there is currently a lack of unified dosage standards, dosing intervals and courses
of peritoneal perfusion bevacizumab at home and abroad.
In most studies, the dose of intraperitoneal perfusion bevacizumab is 100~300 mg/time, and there are also studies where the single dose is 5 mg/kg
.

In addition, studies comparing low-dose (3 mg/kg) and high-dose (5 mg/kg) bevacizumab in the treatment of peritoneal effusion showed no significant difference in efficacy at different doses, but more adverse events
occurred in the high-dose group.
In a prospective study of bevacizumab intraperitoneal perfusion in the treatment of refractory malignant peritoneal effusion, investigators evaluated the tolerability and safety of weekly bevacizumab 2.
5 mg/kg, 5 mg/kg, and 7.
5 mg/kg, and the results showed that 3 The incidence of grade 4 adverse reactions was 7.
7%.

(6) Monitoring of adverse reactions of antibody antitumor drugs and adjustment of therapeutic drugs

The adverse reactions of antibody antitumor drugs are obviously related
to the characteristics and targets of their preparations.
Antibody drugs can cause adverse reactions such as immune reactions and infusion reactions in the body; ADC drugs have the toxicity of antibody drugs and cytotoxic drugs at the same time, and the incidence of hematological adverse reactions is significantly higher than that of ordinary antibody drugs
.
ICIs drugs commonly irAEs, human epidermal growth factor receptor 2 (HER-2).
Target drugs should pay attention to adverse cardiac reactions, and antibody drugs for the treatment of hematological tumors should pay attention to adverse reactions
such as virus reactivation.
In addition, there were significant differences in the incidence of adverse reactions of different types of drugs of the same class, such as the incidence of immune hepatic adverse reactions of pembrolizumab injection of ICIs was 0.
9%, while the incidence of nivolumab injection was 6.
5%.
Therefore, understanding the type, incidence, disposal and pharmaceutical monitoring methods of adverse drug reactions can help to select drugs according to the individual characteristics of patients and improve the safety of
patient treatment.

Clinical Question 15

Establishment of baseline detection indicators before medication

In order to effectively identify and prevent related adverse reactions, it is recommended that baseline detection indicators
should be established according to the actual clinical situation before the start of treatment.

Clinical Question 16

Pharmacological monitoring of adverse skin reactions

1.
Clinical symptoms: Adverse skin reactions are common adverse reactions of antibody anti-tumor drugs, occurring at all stages of treatment, most of them are mild, often manifested as acne-like rash, itching, hair loss, hand and foot skin reactions, vitiligo and other symptoms, of which rash is the most common skin adverse reaction
in the single or combined use of this type of drugs.

2.
Disposal suggestions: select different dosage forms of glucocorticoid drugs for symptomatic treatment
according to the severity of adverse reactions.
Grade 1~2 rash can continue antibody drug treatment and local corticosteroid treatment at the same time; Rashes caused by epidermal growth factor receptor (EGFR) and HER-2 drugs may be considered for oral tetracycline antibiotics for at least 6 weeks; A short course of systemic corticosteroids is recommended for grade 3 rash and prompt medical attention (level of evidence: B; Weak recommendation)
.

When Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) develops ) and other rare and fatal symptoms should be permanently discontinued antibody-based antitumor therapy
.
The specific management of rashes caused by ICIs can be managed according to the guidelines for the management of immune checkpoint inhibitory adverse effects, especially some specific adverse reaction types, such as carrelizumab reactive capillary hyperplasia
.

When using drugs with a high incidence of adverse effects, patients should avoid frequent rinsing with hot water, including hand washing, showering, bathing; Avoid skin irritation, use alcohol-free moisturizers, preferably moisturizers containing urea (5% ~ 10%); Avoid excessive sun exposure; Use sunscreen with a sun protection index ≥ 15 and apply every 2 hours (level of evidence: B; Weak recommendation)
.

Clinical Question 17

Pharmaceutical monitoring of infusion reactions

1.
Clinical symptoms

Immediate infusion reactions caused by different antibody antineoplastic drugs have high heterogeneity in etiology and symptoms, and often present with mild to severe flushing, chills, fever, tachycardia, hypertension, dyspnea, nausea, vomiting, and syncope
.
The incidence of infusion reactions caused by different drugs varies widely, such as emmetrituzumab is 4.
0%, trastuzumab is 40%, and rituximab is as high as 77%.

Delayed reactions usually appear around 1~2 h or 14 days after administration, common rash, vasculitis, erythema multiforme, and more severe symptoms include SJS and TEN , infusion reaction is the focus of
pharmaceutical monitoring during medication.

Hypersensitivity reactions of antibody antitumor drugs are divided into two categories: allergic and non-allergic, and infusion reactions may be caused by a single mechanism or by a combination of multiple mechanisms, as shown in Table 14
.

2.
Disposal recommendations

(1) Assessment of high-risk factors: The treatment process of most antibody antitumor drugs may be accompanied by some type of infusion reaction, and its clinical symptoms may appear on the first day of infusion or a few days after the infusion, and the degree of performance is also different
.
Pharmacists should be aware of the patient's risk factors for infusion reactions before taking the drug, especially before the first use (level of evidence: C; Weak recommendation)
.
Possible risk factors include: (1) multiple doses (level of evidence: B; weak recommendation); (2) drug factors; (3) age; (4) Underlying diseases (such as chronic respiratory diseases, cardiovascular diseases, mastocytosis or clonal mast cell diseases); (5) whether there is a history of severe allergies; (6) Use of drugs that increase the risk (such as β receptor blockers, angiotensin-converting enzyme inhibitors, etc.
); (7) high tumor burden (pretreatment can be considered when there is a high risk of tumor lysis in the early stage of treatment) (level of evidence: A; Highly recommended)
.

(2) Pharmaceutical monitoring process: (1) High-risk screening before medication: screening high-risk patients
with infusion reactions through pharmacy consultation.
(2) Rapid identification of symptoms: According to the FDA's guidelines for the evaluation of immunogenicity of therapeutic protein products, it is recommended to base on the following three criteria as the basis for the diagnosis of hypersensitivity reactions: First, mainly involving skin and/or mucosal tissue-related symptoms (such as systemic urticaria, itching or flushing, lips- acute onset (from minutes to hours) of the uvula of the tongue); second, respiratory failure (such as dyspnea, wheezing, bronchospasm, stridor, decreased peak expiratory flow, hypoxemia), blood pressure reduction; Third, end-organ dysfunction-related symptoms (such as hypotension, syncope, incontinence) and gastrointestinal symptoms (such as abdominal cramps, vomiting) (evidence level: A; Highly recommended)
.
(3) According to the type of infusion reaction of the patient, symptomatic treatment should be given in accordance with relevant guidelines: patients with respiratory symptoms and/or hypotension have a high possibility of allergic reaction, and should be given epinephrine, fluid resuscitation, etc.
; Patients without respiratory symptoms and/or hypotension symptoms are more likely to have hypersensitivity reactions, and grade 1~2 reactions can try to improve the infusion reaction by lowering the titration rate, while administering antihistamines and/or glucocorticoids and other drugs; Grade 3~4 reactions should immediately stop the infusion and administer antihistamine and/or glucocorticoids, and it is not recommended that patients use antibody antitumor drugs again (evidence level: A; Highly recommended)
.

Clinical Question 18

Pharmaceutical monitoring of pulmonary adverse effects

1.
Clinical symptoms: the incidence of adverse pulmonary reactions of antibody antitumor drugs is low, and the incidence of pulmonary adverse reactions of ICIs (about 5%) is higher than that of other antibody antitumor drugs
.
Pulmonary adverse reactions can be life-threatening and are one of the important causes of death caused by antibody antitumor drugs, which may occur from the beginning of administration to after discontinuation, and should be monitored
throughout the clinic.
The most common adverse pulmonary reaction of antibody antineoplastic drugs is non-infectious pneumonia, which belongs to drug-induced interstitial lung diseases, such as immune-related pneumonia and interstitial pneumonia
caused by antibody antitumor drugs targeting EGFR.
Respiratory failure caused by trastuzumab during infusion is dyspnea, decreased activity tolerance, and cough, and symptoms such as fever and chest pain may also occur
.
Emmetrituzumab and vebutuximab have reported fatal pulmonary adverse reactions, and the drug inserts of the two warn about the possible interstitial lung disease, and the incidence of emmetrituzumab non-infectious pneumonia and radiation pneumonia is 0.
8%~1.
1% and 1.
8%, respectively
。

2.
Disposal recommendations: Grade
pulmonary adverse reactions according to imaging and clinical manifestations.
Immune checkpoint suppression-associated pneumonia is graded and treated symptomatically as recommended by CSCO or National Comprehensive Cancer Network (NCCN) guidelines, including discontinuation of suspect drugs and glucocorticoid therapy, which does not respond well It can be treated with infliximab, mycophenolate mofetil and other drugs
.
Medication adjustment according to the drug label: when moderate (grade 2) and above pneumonia occurs, antibody antitumor drug treatment needs to be discontinued, and patients with grade 3 and above pneumonia need to consider permanently discontinuing this type of drug treatment (evidence level: A; Highly recommended)
.

Clinical Question 19

Pharmaceutical monitoring of renal adverse reactions

1.
Clinical symptoms: the renal adverse reactions of antibody antitumor drugs are mostly related to their mechanism of action, and common clinical symptoms include immune-related kidney injury, proteinuria and hematuria
.
Proteinuria and hematuria are mainly related
to antibody antitumor drugs affecting the microvessels and epithelium of the kidneys, causing permeability changes and bleeding.
The overall incidence of immune-related adverse renal reactions is low, often occurring weeks to months after medication, mostly manifested as acute tubulointerstitial nephritis, and combined medication can aggravate renal adverse reactions
.

2.
Disposal suggestions: it is recommended to test kidney function at the beginning of medication and during medication; When grade 2 renal adverse reactions occur, the use of antibody antitumor drugs should be suspended, creatinine and urine protein should be checked every 3~7 days, and glucocorticoids should be treated; Patients with grade 3 renal adverse reactions should permanently stop this type of drug treatment and use glucocorticoid therapy, if the disease is relatively severe or prolonged, moderate increase in hormones and prolonged treatment course, or addition to other immunosuppressive therapies such as infliximab, mycophenolate mofetil, etc.
(level of evidence: A; Highly recommended)
.

Clinical Question 20

Pharmacological monitoring of adverse hepatic reactions

1.
Classification of adverse liver reactions caused by antibody antitumor drugs: Adverse liver reactions mainly involve 3 categories: (1) Immune-related liver adverse reactions, the incidence is about 5%~10% , can occur as early as about 2 weeks after treatment, combined with other ICIs will increase the incidence of liver adverse reactions; Immune-related adverse liver reactions are usually insidious and may not be accompanied by obvious clinical manifestations, and regular monitoring of liver function after medication can help early detection
.
(2) Hematological tumor antibody drugs have the potential risk of causing viral hepatitis reactivation, and the proportion of adults infected with hepatitis virus in China is high, and such patients should routinely establish a baseline
for viral infection status assessment before receiving anti-tumor therapy.
(3) Liver function damage caused by conjugated cytotoxic drugs in ADC drugs, similar to hepatocyte damage and cholestatic damage caused by traditional cytotoxic drugs, such as serious liver adverse reactions
caused by oxaituzumab.

2.
Clinical manifestations: due to the lack of specific diagnostic markers, the diagnosis of drug-induced liver injury (DILI) is still based on an exclusive strategy based on detailed medical history, clinical symptoms and signs, serum biochemistry, etiological examination, imaging and histology.
For specific diagnostic and differential diagnosis procedures and strategies, please refer to the Guidelines for the Diagnosis and Treatment of Drug-induced Liver Injury
.
Grade of adverse hepatic reactions is based on the elevated level of liver function glutamate aminotransferase (ALT), aspartate alanine aminotransferase (AST) and the presence or absence of bilirubin, international standardized ratio, Albumin abnormalities are graded
.

3.
Disposal recommendations: standard liver biochemical examination should be performed in all patients before antibody antitumor drug treatment to assess whether there is liver damage at baseline, and biochemistry should also be regularly monitored to monitor the occurrence
of liver damage during treatment and after treatment.
For antibody-based antineoplastic drugs that are at risk of viral hepatitis reactivation, in addition to standard liver biochemical tests, patients must be screened for viral hepatitis before treatment, including at least hepatitis B surface antigen and hepatitis B core antibodies, and selective hepatitis B virus (HBV) DNA baseline establishment according to the results.
Patients were graded according to the results of the test and the risk of viral hepatitis reactivation was graded and managed at a level of evidence (level of evidence: A; Highly recommended)
.

Early detection of DILI signaling and taking appropriate measures can help prevent the occurrence of DILI to the greatest extent: (1) avoid the combination of drugs with liver adverse reactions as much as possible; (2) Detailed medical history, cautious selection of drugs with potential liver adverse reactions for people with underlying liver diseases or other potentially high-risk diseases; (3) Improve the patient's compliance with regular DILI monitoring, and avoid the patient taking any other drugs, herbs or health products
with potential liver adverse reactions without authorization.
The overall evidence for the use of DILI therapy for reducing DILI in patients with blood disorders is limited, and in principle prophylactic use of liver injury therapy is discouraged in all patients
.
Prophylactic hepatoprotective drugs may be considered in high-risk populations where moderate to severe DILI has occurred during the first (previous) antineoplastic therapy, and the patient needs to be re-exposed to the same antineoplastic regimen (rechallenge) or use of another regimen
with a higher risk of hepatic adverse effects.
Only a few of the hepatoprotective drugs have been studied
for the prevention of DILI.
Meta-analysis has shown that magnesium isoglycyrrhizinate can significantly reduce ALT levels in patients with DILI compared with other similar drugs, and has a better
safety profile.
Prophylactic studies of bicyclic alcohol have shown that prophylactic dicyclic alcohol can significantly reduce the incidence and severity of DILI in high-risk patients with underlying liver disease, advanced age (> 60 years), and previous chemotherapy with DILI, and have a good safety profile
。

Drug therapy for DILI should be rationally selected
for the different types and severity of liver damage caused by the drug, combined with current evidence-based medical evidence.
There is currently no evidence-based medical evidence for multi-drug combination applications with the same or similar mechanism of action, and combined use
should be avoided in clinical practice.
Drug selection: (1) drug-induced reactivation of viral hepatitis: strong, highly resistant barrier and well-safe nucleoside (acid) first-line antivirals such as entecavir, tenofovir cilexetil and tenofovir alafenamide are the main treatment (evidence level: A; strongly recommended); (2) DILI caused by ICIs: hormones and immunosuppressants are the main treatment methods, which can be referred to the European Medical Oncology Society, NCCN and CSCO and other guidelines for appropriate management (level of evidence: A; strongly recommended); (3) Hepatocyte injury DILI: mainly to reduce ALT and AST, in DILI Overall evidence in the field is inadequate, with only a few drugs being randomised controlled studies, such as magnesium isoglycyrrhizinate, which have been shown to be effective and safe in the treatment of acute DILI (level of evidence: A; Highly recommended)
.

Clinical Question 21

Pharmaceutical monitoring of hematologic adverse reactions

1.
Clinical symptoms

(1) Most of the hematological adverse reactions caused by ICIs were irAEs, and the common hematological adverse events were anemia (19.
62%) and thrombocytopenia (11.
58% ), febrile neutropenia (8.
68%), neutropenia (6.
64%), pancytopenia (3.
49%), immune thrombocytopenic purpura ( 3.
10%), disseminated intravascular coagulation (2.
94%), autoimmune hemolytic anemia (2.
90%), leukopenia (2.
27%), lymphadenopathy ( 2.
27%), etc
.
The median onset time of blood adverse reactions is generally 5.
7 weeks, but it may be between
1~84 weeks.
Haemolytic anaemia and immune thrombocytopenic purpura are the most common adverse effects of haematology, with a median time of onset of 40 days
.
Studies have shown that the incidence of all grades and grade 3~5 anemia is 9.
8% and 5%, respectively, if multiple cell lines are affected, to deal with simple red blood cell aplastic anemia, Evaluation
for autoantibodies, aplastic anaemia, and bone marrow suppression.
Thrombocytopenia is relatively rare, the incidence of all grades of thrombocytopenia is about 2.
8%, and the grade 3~5 is 1.
8%; The cause of thrombocytopenia should be evaluated for the cause of thrombocytopenia, and factor VIII-related acquired bleeding abnormalities associated with clotting factors should be considered
.

(2) ADC: Hematological adverse reactions are common adverse reactions of ADC drugs, different ADCs The antibodies and cytotoxic drugs of the class drugs are different, and the adverse reactions are also different, including pancytopenia, neutropenia, thrombocytopenia, etc.
, and severe hematological adverse reactions can further increase the risk of
bleeding and infection.

In the global population, the incidence of all grades of thrombocytopenia caused by emmetrastuzumab is 20%~38%, and the incidence of grade 3 and above is 2%~13%.
； The risk of thrombocytopenia was higher in Asian populations, reaching 52.
5%~69.
8%, and the incidence of grade 3 and above was 29.
8%~45.
0%
。 Neutropenia may be related to
the primary disease, the nature of the target cells, or the myelosuppressive effects of cytotoxic drugs.
Vedicitumab is an anti-HER-2 antibody conjugated to monoMethyl auristatin E (MMAE), The incidence of neutropenia was 41.
9%, and the incidence of grade 3 and above was 14%.

Olgaituzumab is an ADC targeting CD22, and common (≥20%) hematologic adverse reactions are thrombocytopenia, neutropenia, anemia, leukopenia, neutropenia with fever, The incidence of hematologic adverse reactions is higher
when combined with cytotoxic drugs.
When berintoumab is used for the treatment of relapsed or refractory precursor B-cell acute lymphoblastic leukemia in adults, the incidence of neutropenia is 31%, and the incidence of grade 3 and above is 28%; The incidence of anemia was 25%, and the incidence of grade 3 and above was 19%; Thrombocytopenia is 21%, and the incidence of grade 3 and above is 18%; Leukopenia is 8% and the incidence of grade 3 and above is 7%.

(3) Other antibody antitumor drugs: Adverse hematological reactions are not common adverse reactions when used as a single drug, and may lead to an increase
in the incidence of chemotherapy-related adverse hematological reactions when combined with chemotherapy.

2.
Disposal recommendations

For ICIs-related hematologic adverse reactions, grade and symptomatic treatment
according to CSCO or NCCN guidelines.
For grade 3 or above hematologic adverse reactions, it is usually taken to stop the drug, mainly high-dose hormone therapy, add other immunosuppressants if necessary, and do a good job in infection prevention and control and supportive treatment
.
When hematological adverse reactions occur for ADC drugs, the dose is adjusted
according to the drug insert.
When hematological adverse reactions occur with bispecific antibodies and other antibody antineoplastic drugs, it is not recommended to reduce the dose, and pretreatment or symptomatic treatment of neutropenia or thrombocytopenia can be carried out according to CSCO or NCCN guidelines (level of evidence: A ； Highly recommended)
.

Clinical Question 22

Pharmaceutical monitoring of adverse cardiovascular reactions

1.
Clinical symptoms: Adverse cardiac reactions of anti-HER-2 drugs are more common, which is related to its inhibition of HER-2 expression in cardiomyocytes, resulting in benign cardiomyocytes ultrastructural changes, and then producing reversible type II cardiac adverse reactions.

Clinical manifestations are usually left ventricular insufficiency such as left ventricular ejection fraction (LVEF) decrease, arrhythmia, myocardial lesions, hypertension, etc.
, and congestive heart failure and even cardiac death
can occur in severe cases.

The mechanism of cardiovascular adverse reactions of antiangiogenic drugs is not clear, and may be related to
their physiological effects such as regulating vasoconstriction and maintaining blood pressure.
In addition, VEGF regulates nitric oxide and prostacyclin production and inhibits platelet aggregation, which is related to
the causes of arterial or venous thromboembolism during treatment.
Common clinical adverse cardiovascular reactions are hypertension, congestive heart failure, and thromboembolism
.

The incidence of cardiovascular adverse reactions of ICIs is low, but the lethality is high, and the clinical manifestations are common with myocardial lesions (mainly myocarditis), pericardial effusion, arrhythmias, acute coronary syndrome and valvular lesions, and the fatality rate of central myositis is as high as 39.
7%~50%.

PD-1/PD-L1 inhibitors are more prone to myocarditis or pericardial disease than CTLA-4 inhibitors and may be associated with higher starting doses (e.
g.
, nivolumab ≥ 3 mg/kg).

Studies have suggested that the combination of the two ICIs increases the incidence of myocarditis, and the mortality rate of cardiovascular adverse effects (66%) is significantly higher than that of monotherapy (44%)
.

The mechanism of action of cardiovascular adverse reactions of anti-CD series antibody drugs is not clear, but studies have shown that the probability of adverse cardiac reactions in patients with underlying heart diseases increases, and atrial fibrillation and tachycardia during the infusion reaction of anti-CD series antibody drugs can also lead to the occurrence
of adverse cardiac reactions.

The incidence of adverse reactions of ADC is different due to different antibodies and cytotoxic drugs, and its adverse cardiac reactions are caused by ADC drugs with HER-2 target characteristics, which are similar to the cardiovascular adverse reactions of anti-HER-2 monoclonal antibodies.
The main clinical manifestation is a decrease
in LVEF.

2.
Disposal suggestions: patients should be strengthened before medication, establish a baseline of monitoring indicators such as electrocardiogram, echocardiography and troponin levels, correct risk factors such as cardiovascular disease, and timely standardize the treatment of concomitant cardiovascular diseases; Patients who have previously received anthracycline therapy require intensive monitoring; For adverse cardiovascular reactions that occur in treatment, the types and grades of adverse cardiovascular reactions are clarified according to the clinical manifestations combined with the terminology evaluation criteria and relevant guidelines of common adverse reactions, standardized symptomatic treatment is given, and a decision is made whether to discontinue the drug (level of evidence: A; Highly recommended)
.

Clinical Question 23

Pharmacological monitoring of adverse reactions of the digestive system

1.
Clinical symptoms

The gastrointestinal adverse reactions of antibody antitumor drugs are mainly divided into three categories, one is the immune-related gastrointestinal adverse reactions caused by ICIs, including immune diarrhea and colitis, immune pancreatic adverse reactions, etc.
The second category is gastrointestinal perforation caused by anti-angiogenic antibody drugs; The third category is common nausea, vomiting, diarrhea, constipation and other symptoms, of which the incidence of ADC drugs is high
.

2.
Disposal recommendations

(1) Immune-related gastrointestinal adverse reactions: The incidence of gastrointestinal adverse reactions of CTLA-4 monoclonal antibody is higher than that of PD-1/PD-L1 monoclonal antibody, and the combined use of the two will significantly increase the incidence and severity
of gastrointestinal adverse reactions.
Immune-related gastrointestinal reactions can occur at any time after drug use, or even months after treatment ends
.
Early recognition, timely and adequate hormone therapy, and rapid escalation
are recommended.
Stratified therapy
is given according to severity level.
Mild (grade 1) diarrhoea with any grade of asymptomatic amylase and lipase elevation generally do not require discontinuation of ICIs and symptomatic management (level of evidence: A; Highly recommended)
.
Grade 2 diarrhea and any grade of pancreatitis require suspension or permanent discontinuation of this type of therapy and glucocorticoid therapy, if symptoms do not resolve within 2 days, consider the addition of infliximab, and grade 4 adverse effects require permanent discontinuation of these drugs ( Level of evidence: A; Highly recommended)
.
Specific grading and symptomatic treatment can be handled according to NCCN and CSCO guidelines
.

(2) Gastrointestinal perforation: Gastrointestinal perforation is a common adverse reaction
of anti-angiogenic drugs.
Among them, the incidence of gastrointestinal perforation in bevacizumab for first-line treatment of ovarian cancer was 2%, and the mechanism of action may be related to gastrointestinal ischemia caused by inhibition of microcirculation; The onset time is within 50 days after bevacizumab treatment, and the severity varies from person to person, mild cases without any symptoms, only reflected in imaging examination; Severe patients are accompanied by abdominal abscess, fistula formation, etc
.

For patients with symptoms such as abdominal inflammation, tumor necrosis, and gastrointestinal obstruction, it is recommended to use bevacizumab with caution; If the patient has abdominal pain and other phenomena during treatment, it is necessary to check whether there is a possibility of gastrointestinal perforation in time; If gastrointestinal perforation occurs, immediate symptomatic treatment should be given and bevacizumab
should be permanently discontinued.

(3) Nausea, vomiting and other common gastrointestinal adverse reactions: Almost all antibody antitumor drugs may have common digestive tract adverse reactions
such as nausea and vomiting.
In domestic and foreign guidelines, the antibody antitumor drugs marketed in China are all extremely low emetogenic risk (≤10%) except ADC drugs, and ADC drugs have a low emetogenic risk (30%≥ incidence ≥ 10%)), symptomatic treatment with conventional antiemetic regimens (level of evidence: A; Highly recommended)
.

(7) Medication education for patients with antibody antitumor drugs

Clinical Question 24

Key points of patient medication education

The administration of antineoplastic drugs is done in medical institutions, but many adverse reactions occur outside medical institutions, so it is necessary to educate patients about medication
.
The content of medication education includes the name of the drug, the storage method of the drug, the purpose of medication, the dosage of the drug, the frequency of medication, the types of adverse reactions that may occur, the main clinical manifestations of adverse reactions, the degree of adverse reactions judgment, basic treatment common sense, and relevant indicators that need regular monitoring
.

Regarding the purpose of medication, drug name, drug dose, frequency of administration, etc.
, it has been summarized and recommended
in detail above.
Regarding adverse reactions, it is recommended to focus on the very common (incidence ≥ 10%) adverse reactions and the adverse reactions of the black box warning (Table 15); For patients who can be managed at home when it is convenient to identify the severity and mild disease, detailed education should be carried out on adverse reactions, such as rash and diarrhea, as detailed in Table 16
.
For patients with serious adverse reactions, timely medical treatment
is recommended.

Swipe to see a list of all experts

Guide guidance experts

Hejie (Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College Cancer Hospital)

Xu Binghe (National Cancer Center, National Cancer Clinical Research Center, Drug Clinical Trial Research Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Yu Zhang (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology)

Jun Zhu (Peking University Cancer Hospital)

Miao Liyan (Affiliated Hospital of Soochow University)

LIU Lihong (Department of Pharmacy, China-Japan Friendship Hospital)

Tong Rongsheng (Department of Pharmacy, Sichuan Provincial People's Hospital)

ZHANG Lingli (West China Second Hospital, Sichuan University)

Jiang Ling (The First Affiliated Hospital of University of Science and Technology of China)

Jun Xia (GRADE Centre, University of Nottingham Ningbo China)

Zhai Suodi (Department of Pharmacy, Peking University Third Hospital)

Writing experts (alphabetical by surname, Hanyu Pinyin)

Fang Cao (Department of Clinical Pharmacy, Shaanxi Cancer Hospital, Xi'an Jiaotong University School of Medicine)

Chen Cheng (National Cancer Center, National Cancer Clinical Research Center, Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Chen Xiao (Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University)

Chen Wei (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College Cancer Hospital)

Dai Yuanyuan (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Dong Mei (Department of Pharmacy, Harbin Medical University Cancer Hospital)

Fang Luo (Department of Pharmacy, Cancer Hospital, University of Chinese Academy of Sciences)

Weiyi Feng (Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University)

FENG Yufei (Clinical Trial Institute, Peking University People's Hospital)

Huang Liangjiu (Department of Pharmacy, Hainan Cancer Hospital)

Ping Huang (Department of Pharmacy, Zhejiang Provincial People's Hospital)

Kan Lingyan (Department of Pharmacy, Shengjing Hospital, China Medical University)

Jin Pengfei (Department of Pharmacy, Beijing Hospital)

Leng Jiahua (Medical Insurance Service, Peking University Cancer Hospital)

Guohui Li (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College Cancer Hospital)

Liu Anchang (Department of Pharmacy, Qilu Hospital, Shandong University)

Liu Dong (Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology)

Liu Jiyong (Department of Pharmacy, Fudan University Cancer Hospital)

Tao Liu (Department of Pharmacy, Cancer Center, Sun Yat-sen University)

Liu Yuguo (Shandong Cancer Hospital)

Fei Ma (Department of Internal Medicine, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Qiu Feng (Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University)

Shi Chen (Department of Pharmacy, Union Hospital, Huazhong University of Science and Technology)

Yanqing Song (Department of Pharmacy, First Hospital of Jilin University)

Sun Yancai (Department of Pharmacy, Anhui Cancer Hospital)

Xie Ruixiang (Department of Pharmacy, Fujian Cancer Hospital)

Xiuqin Wang (Department of Pharmacy, Huanxing Hospital, Chaoyang District, Beijing)

Wei Jifu (Department of Pharmacy, Jiangsu Cancer Hospital)

Wei Yuhui (Department of Pharmacy, First Hospital of Lanzhou University)

Yang Jianhua (Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University)

Jun Yang (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Severe Winter (Department of Internal Medicine, Beijing Luhe Hospital, Capital Medical University)

Yan Suying (Department of Pharmacy, Xuanwu Hospital, Capital Medical University)

Qing Zhai (Department of Pharmacy, Fudan University Cancer Hospital)

Bo Zhang (Department of Pharmacy, Peking Union Medical College Hospital)

Zhang Jie (Department of Pharmacy, Tianjin Cancer Hospital)

ZHANG Jun (Department of Clinical Pharmacy, The First Affiliated Hospital of Kunming Medical University)

Zhang Wenzhou (Department of Pharmacy, Henan Cancer Hospital)

Zhao Guanren (Department of Pharmacy, PLA General Hospital)

Rongsheng Zhao (Department of Pharmacy, Peking University Third Hospital)

External Review Panel (in alphabetical order by surname, Hanyu Pinyin)

Andy Ling (Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University)

Sun Lulu (Pharmaceutical Affairs Management Research Department, Hospital Management Institute, National Health Commission)

Cai Shuang (Department of Pharmacy, The First Affiliated Hospital of China Medical University)

Cao Junling (Luoyang Hospital, Dongzhimen Hospital, Beijing University of Chinese Medicine)

Chen Wanyi (Department of Pharmacy, Chongqing Cancer Hospital)

Daihong Guo (Department of Pharmacy, PLA General Hospital)

Hao Zhiying (Department of Pharmacy, Shanxi Cancer Hospital)

Hu Xin (Department of Pharmacy, Beijing Hospital)

HUANG Hongbing (Department of Pharmacy, Sun Yat-sen University Cancer Center for Prevention and Treatment)

Lin Nengming (First Affiliated Hospital of Zhejiang University)

Lin Yang (Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University)

Liu Jiyong (Department of Pharmacy, Fudan University Cancer Hospital)

Yan Liu (National Cancer Center, National Cancer Clinical Research Center, Department of Nursing, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Meng Jun (Department of Pharmacy, Cancer Hospital of Chinese Academy of Medical Sciences Shenzhen Branch)

Qiu Tinglin (National Cancer Center, National Cancer Clinical Research Center, Medical Department, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Chen Wang (Department of Pharmacy, Tianjin Cancer Hospital)

Wang Jiawei (Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University)

WEI Wenqiang (National Cancer Center, National Cancer Clinical Research Center, Cancer Registry Office, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Xiao Hongtao (Department of Pharmacy, Sichuan Cancer Hospital)

Zhang Xianglin (Department of Pharmacy, China-Japan Friendship Hospital)

Zhu Zhu (Department of Pharmacy, Peking Union Medical College Hospital)

Secretarial group (alphabetical by last name, Hanyu Pinyin)

CHEN Zhe (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

FAN Linlin (National Cancer Center, National Cancer Clinical Research Center, Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Jia Bei (National Cancer Center, National Cancer Clinical Research Center, Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Qiao Yongqi (National Cancer Center, National Cancer Clinical Research Center, Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Qi Shuya (National Cancer Center, National Clinical Research Center for Oncology, Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College)

Yanting Wang (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Jun Yang (Department of Pharmacy, National Cancer Center, National Clinical Research Center for Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Author