2023 Japan Society of clinical oncology clinical practice guidelines update for antiemesis

Background The Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023 was extensively revised to reflect the latest advances in antineoplastic agents, antiemetics, and antineoplastic regimens. This update provides new evidence on the efficacy of antiemetic regimens. Methods Guided by the Minds Clinical Practice Guideline Development Manual of 2017, a rigorous approach was used to update the guidelines; a thorough literature search was conducted from January 1, 1990, to December 31, 2020. Results Comprehensive process resulted in the creation of 13 background questions (BQs), 12 clinical questions (CQs), and three future research questions (FQs). Moreover, the emetic risk classification was also updated. Conclusions The primary goal of the present guidelines is to provide comprehensive information and facilitate informed decision-making, regarding antiemetic therapy, for both patients and healthcare providers.


Introduction
The Japan Society of Clinical Oncology Guidelines for Antiemetic Therapy was developed to appropriately evaluate and manage chemotherapy-induced nausea and vomiting and improve treatment efficacy, thereby improving patient quality of life (QOL) and, ultimately, patient prognosis.The initial Japan Society of Clinical Oncology (JSCO) Clinical Practice Guidelines for Antiemesis were published in 2010, with updates in 2015 (revised edition, version 2) and 2018 (revised edition, version 2.2) [1,2].Revisions were made in the third edition to reflect new evidence on antineoplastic agents, antiemetics, antineoplastic regimens.In addition, by appropriately assessing the balance between the benefits and harms of different antiemetic therapies based on the evidence, these guidelines aim to facilitate informed decisionmaking regarding antiemetic therapy for both patients and healthcare providers.

Guiding principles for the development
The antiemetic guideline update committee consisted of 23 working group members and 18 systematic review team members who are multidisciplinary healthcare professionals with expertise in antiemetic research (physicians, nurses, pharmacists, and epidemiologists), two patient advocates, and two secretaries.
In developing and revising these guidelines, the basic approach is to follow the 'Minds Clinical Practice Guideline Development Manual 2017' [3].Questions are developed based on the key clinical issues Table 1.Systematic reviews of each question are conducted, and recommendations are determined based on the obtained results [4].The quality of evidence and definitions are presented in Table 2.The recommendations are generally presented based on a combination of the direction of the recommendation (two directions) and the strength of the recommendation (two levels), as listed in Table 3.The strengths of the recommendation, Extended author information available on the last page of the article quality of evidence, and agreement rate were then concurrently stated.The consensus-building method involves web voting using the GRADE grid.Consensus is achieved when the concentration of votes for a specific statement pertaining to each item exceeds 80%, thereby influencing the determination of recommendations [5].The working group members and patient advocates conducted the voting.If a consensus was not reached in the first round of voting, discussions were held, and a second round of voting was conducted.If consensus was not reached in the second round, the process and summary of the results were documented in the statement.

The classification and terminology of the questions in this guideline
The questions in this guideline comprise "background questions (BQ)," "clinical questions (CQ)," and "future research questions (FQ)."BQs represent fundamental knowledge that includes clinical characteristics, epidemiological features, and the overall flow of medical practice.The BQs encompass widely understood issues requiring documentation in the guidelines.CQs focus on the significant but less familiar issues based on the recent evidences wherein a systematic review has been performed, and evidence-based recommendations can be provided.FQs are unresolved issues wherein a systematic review could not be completed owing to insufficient evidence or other constraints, precluding the formulation of evidence-based recommendations.

Emetic risk classification of the antineoplastic agents
The classification of emetogenicity for antineoplastic agents is primarily based on the incidence of emesis occurring within 24 h following the administration of antineoplastic agents without prophylactic antiemetic administration.High emetic risk (> 90% patients experience acute emesis), moderate emetic risk (30 < -90% of patients experience acute emesis), low emetic risk (10-30% of patients experience acute emesis), and minimal emetic risk (< 10% of patients experience acute emesis) are determined through non-systematic reviews of randomized controlled trials, analysis of product labeling, the evaluation of emetic classification in other international guidelines, and informal consensus.

Literature search
For this update, we conducted a literature search covering the period from January 1, 1990, to December 31, 2020, using PubMed, Cochrane Library, andIgaku Chuo Zasshi (ICHUSHI) databases.For questions related to nonpharmacological therapy and patient support, an additional search was conducted using CINAHL.The formula used to search the literature is published on the JSCO website [4].
The priority for literature adoption was as follows: (1) randomized controlled trials, (2) non-randomized

Conflicts of interest for the guideline
In accordance with the JSCO guidelines for the management of conflicts of interest (COIs), the members of the guideline update working group and those of the systematic review team submitted self-disclosures of financial COIs.The COI Committee reviewed these submissions and confirmed that none of the members had any significant financial COI (http:// www.jsco-cpg.jp/).If a voting member had a COI, such as being a lead author or a corresponding author of a paper related to the evidence that forms the basis of the recommendation, or if they had a financial COI with the company or companies involved in the manufacture or sale of the related drugs or medical devices beyond the criteria outlined in the Japan Medical Association's "Guidance on Eligibility Criteria for Participation in Clinical Practice Guideline Development," they abstained from voting.

Emetic risk classification of antineoplastic agents
The emetic risks of intravenous and oral antineoplastic agents are shown in Tables 4 and 5, respectively.In addition, the emetogenic properties of certain combination chemotherapies are depicted.

Background questions and future research questions with statements
BQs and FQs are shown in Table 6.

Clinical questions and recommendations CQ1: Is the addition or concurrent use of olanzapine recommended for the prevention of nausea and vomiting associated with highly emetogenic risk antineoplastic agents using a triplet antiemetic regimen (a 5-HT3 receptor antagonist + an NK1 receptor antagonist + dexamethasone)?
Recommendation: We recommend the addition or concurrent use of olanzapine to a triplet antiemetic regimen to prevent nausea and vomiting associated with antineoplastic agents with high emetogenic risk.

CQ2: Is it recommended to shorten the administration duration of dexamethasone to one day for the prevention of nausea and vomiting associated with highly emetogenic risk antineoplastic agents?
Recommendation: We suggest shortening the duration of dexamethasone administration to one day to prevent the nausea and vomiting associated with antineoplastic agents with a high emetogenic risk, especially in the case of AC regimens.

CQ3: Is the administration of an NK1 receptor antagonist recommended for the prevention of nausea and vomiting associated with moderately emetogenic risk antineoplastic agents?
Recommendation: We recommend the administration of NK1 receptor antagonists to prevent the nausea and vomiting associated with carboplatin regimens in moderate-emetogenic-risk antineoplastic agents.

CQ4: Is the addition or concurrent use of olanzapine to the triplet antiemetic regimen (a 5-HT3 receptor antagonist + an NK1 receptor antagonist + dexamethasone) recommended for the prevention of nausea and vomiting associated with moderately emetogenic risk antineoplastic agents?
Recommendation: We suggest the addition or concurrent use of olanzapine to the triplet antiemetic regimen to prevent the nausea and vomiting associated with moderate-risk emetogenic antineoplastic agents.

CQ5: Is the addition or concurrent use of olanzapine to the doublet antiemetic regimen (a 5-HT3 receptor antagonist + dexamethasone) recommended for the prevention of nausea and vomiting associated with moderately emetogenic risk antineoplastic agents?
Recommendation: No consensus was reached.CQ6: Is it recommended to shorten the administration duration of dexamethasone to one day for the prevention of nausea and vomiting associated with moderate emetogenic risk antineoplastic agents?

Summary
Adult antiemetic dosing information is listed in Table 7, and the standard model for antiemetic treatment regimens is detailed in the four diagrams shown in Fig. 1.

Discussion
This manuscript presents an English summary of the Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023.
In the present guidelines, the emetic risk classification has been revised to incorporate new antineoplastic agents and chemotherapy regimens.Currently, classification is based on the emetic risk during the acute phase without antiemetic therapy.However, obtaining such data during clinical trials for the development of antineoplastic agents is challenging.
It is important to note that sacituzumab govitecan and trastuzumab deruxtecan are at the high end of the moderate category for emetogenicity, and with the accumulation of future clinical trial results on antiemetic therapy, there is a possibility that they may be considered as candidates for the application of triple combination therapy including NK1 receptor antagonists.Currently, these agents are classified as having moderate emetic risk due to insufficient evidence regarding their emetogenic potential.However, contingent on the results of future clinical trials, they may be reclassified into the high emetic risk category.Therefore, when For highly emetogenic risk antineoplastic agents, a four-drug combination therapy using olanzapine, a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone is administered.In cases where the use of olanzapine is challenging, a three-drug combination therapy with a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone is administered 100 24/24 BQ2 What factors should be considered when choosing 5-HT3 receptor antagonists for highly emetogenic risk antineoplastic agents?
For highly emetogenic risk antineoplastic agents, in the context of three-drug combination therapy, the acute antiemetic effect is nearly equivalent between first-generation (e.g., granisetron) and second-generation (e.g., palonosetron) agents.However, there is a tendency for palonosetron to exhibit a better delayed antiemetic effect.In cases of four-drug combination therapy, either first-generation or second-generation agents can be chosen.Yet, in situations where it is necessary to shorten the administration period of dexamethasone or when the use of olanzapine is challenging, palonosetron is prioritized 100 24/24 BQ3 What antiemetic therapies are recommended for moderately emetogenic risk antineoplastic agents?For acute nausea and vomiting associated with moderate emetogenic risk antineoplastic agents, a combination of a 5-HT3 receptor antagonist and dexamethasone is administered.Carboplatin (AUC ≥ 4), which is at the high end of the moderate emetogenicity category, is administered as a triplet, with an NK1 receptor antagonist added to the regimen 100 24/24 BQ4 What factors should be considered when choosing 5-HT3 receptor antagonists for moderately emetogenic risk antineoplastic agents?
For moderately emetogenic risk antineoplastic agents, a two-drug combination therapy using the second-generation 5-HT3 receptor antagonist, palonosetron, and dexamethasone is administered.However, when adding an NK1 receptor antagonist, the first-generation 5-HT3 receptor antagonist can also be chosen 100 24/24 BQ5 What antiemetic therapies are recommended for low to minimal emetogenic risk antineoplastic agents?There is no clear evidence for prophylactic antiemetic therapy for low emetogenic risk antineoplastic agents, but in actual clinical practice, antiemetics such as dexamethasone and 5-HT3 receptor antagonists are widely administered.For minimal emetogenic risk antineoplastic agents, prophylactic antiemetic therapy is not administered 100 25/25 BQ6 What antiemetic therapies are recommended for anticipatory nausea and vomiting?
Optimal management involves achieving complete control of acute and delayed nausea and vomiting caused by cancer chemotherapy, with the goal of preventing patients from experiencing these symptoms.In cases of anticipatory nausea and vomiting, benzodiazepine anxiolytics are administered 100 24/24 BQ7 What antiemetic therapies are recommended for nausea and vomiting induced by radiation therapy?
Perform an emetogenic risk classification based on the site of radiation exposure and implement antiemetic therapy tailored to the risk.For high risk (total body irradiation), it is recommended to proactively administer 5-HT3 receptor antagonists and dexamethasone for prevention.For moderate risk (e.g., upper abdomen, craniospinal irradiation), it is advisable to administer 5-HT3 receptor antagonists prophylactically, and concurrent use of dexamethasone may also be considered 100 24/24 There is no evidence to recommend the addition of olanzapine after initial treatment with olanzapine for breakthrough nausea and vomiting.Consider administration of antiemetics other than olanzapine for management 100 22/22 using these agents, it is crucial to carefully monitor the patient's condition and flexibly adjust the antiemetic therapy as needed, such as considering the concomitant use of NK1 receptor antagonists.As new evidence on antiemetic therapy accumulates, the content of the guidelines will need to be updated accordingly.Readers are advised to stay informed about the latest findings regarding emetogenicity.
The emetogenic properties of certain combination chemotherapy are classified based on the incidence and severity of emesis observed with antiemetic therapy commonly used in clinical trials and in real-world clinical practice.
We had initially proposed 15 CQs for this update.However, because insufficient evidence prevented the completion of a systematic review for three of them, the three were categorized as FQs.Urgent attention is warranted for conducting clinical trials to address all three questions.
Prevention of nausea and vomiting in patients undergoing cancer chemotherapy is critical not only for treatment efficacy, but also for maintaining the overall quality of life.These guidelines are intended to promote and facilitate appropriate antiemetic therapy in clinical practice and serve as a supportive resource for clinicians and medical staff to make compassionate decisions tailored to individual patients undergoing cancer chemotherapy.By promoting the implementation of effective strategies, we hope to contribute to the overall success of cancer treatment and enhance

Table 1
Key clinical issues 1.Provide appropriate antiemetic therapy recommendations based on emetogenic risk and options presented 2. Provide appropriate recommendations for emetogenic risk and antiemetic therapy for novel anticancer therapies (new anticancer drugs and regimens) 3. Provide recommendations for proper evaluation of antiemetic therapy efficacy, prediction of efficacy, and highlight potential side effects 4. Review the health economic evaluation of antiemetic therapy 5. Evaluate the effectiveness of non-pharmacological interventions in antiemetic therapy 6.Consider support systems for proper implementation of antiemetic therapy

Table 4
Emetic risk category for intravenous antineoplastic agents

Table 4 (
Agents in italics are not approved for clinical practice in Japan FOLFIRINOX, FOLFOXIRI: 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin; S-1: tegafur, gimeracil, and oteracil * Carboplatin (AUC ≥ 4) is in the high end of the moderate category for emetogenicity ** Sacituzumab govitecan and trastuzumab deruxtecan are in the high end of the moderate category for emetogenicity, and with the accumulation of future clinical trial results on antiemetic therapy, there is a possibility that they may be considered as candidates for the application of triple combination therapy including NK1RA

Table 7
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