This systematic review was designed to answer the PICOS question: (Population), adult patients with hematological malignancy receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) within conditioning protocols for HSCT; (Intervention), antiemetic prophylaxis regimens, including neurokinin-1 (NK1) receptor antagonist, 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, and/or corticosteroid and/or olanzapine;(Comparison) other antiemetic prophylaxis regimens; (Outcomes), complete control of vomiting and/or nausea during the overall phase, and adverse events; (Study design), Randomized clinical trials, systematic reviews, and meta-analysis.

This protocol is registered in the Prospective Register of Ongoing Systematic Reviews (PROSPERO) CRD42023406380 and was structured according to the Preferred Reporting Items for Systematic Review guidelines and Meta-Analysis Protocols (PRISMA-P 2015)15. The systematic review will be conducted according to PRISMA guidelines16.

The inclusion criteria are:

• -

  Men and women ≥18 years of age with hematological malignancy receiving HEC or MEC within conditioning protocols for HSCT.

• -

  Study design: Randomized clinical trials, systematic reviews, and meta-analysis

• -

  Studies written in English, French, Italian, or Spanish will be considered.

• -

  No time restrictions will be applied to this study.

The exclusion criteria are:

• -

  Another etiology for emesis and nausea (e.g. gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, and active peptic ulcer).

• -

  Pregnant or nursing women.

• -

  Other studies not indicated in the inclusion criteria (cohort studies, expert opinion, and narrative reviews).

The search for studies will be conducted in the following databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) via PubMed, EMBASE (via Embase.com), Cochrane database, and Clinical-Trials.gov to include relevant trials in progress.

For each article selected for inclusion, abstracts and full articles will be obtained.

We will use Medical Subject Heading (MeSH) or equivalent, keywords, and free-text search terms. We will adapt the search strategy to the remaining databases previously mentioned. Table 1 lists the search strategies of the PubMed and Embase databases in detail.

The reference list of each article will be manually reviewed, and a citation analysis will be performed to identify articles missed by the search strategy.

The research will be repeated immediately after the final analysis in order to enable new studies to be revised. If the inclusion criteria are met, they can be included in this review.

The selection of the articles will be carried out by 2 reviewers by duplicate and independently. After removing duplicates, a preliminary selection of papers will be made by analyzing titles and abstracts and the articles will be thoroughly examined by reading the entire text when required. The discrepancies in the selection will be resolved by consensus, and the decision will correspond to a third reviewer in the case of not reaching an agreement. The reasons for exclusion studies will be registered.

Full-text copies of included articles will be reviewed, and data will be extracted and entered into a structured Microsoft Excel, Microsoft Corporation (Redmond, WA, USA) database. The following variables will be collected:

• •

  Study characteristics: Study design, aims, setting and dates, and study duration.

• •

  Patient characteristics: Average age or age limits for inclusion in each study, sex, ethnicity, number of participants recruited/allocated/evaluated, participants with lost to follow-up, hematological malignancy and stage, type of conditioning regimen (myeloablative, reduced-intensity, and non-myeloablative), number of days of chemotherapy, and emetogenic risk of the conditioning regimen.

• •

  Outcomes measured: In this study, the primary outcome to be evaluated will be the complete control of nausea and vomiting in the acute, delayed, and overall phase.

  Clinical trials' design to approve drugs for preventing and treating CINV and PONV has undergone changes to better evaluate the effectiveness of candidate products17. Initially, trials measured the proportion of patients with emetic episodes as the primary endpoint. As time progressed, trial endpoints expanded to include other factors, such as the use of rescue medication to assess Complete Response and the presence and severity of nausea in evaluating Complete Control, Total Response, and Total Control17. Although many tools have been used to assess nausea and vomiting, there is currently no standard outcome for clinical trials investigating the effects of interventions to control chemotherapy-induced nausea and vomiting in cancer patients18. Therefore, we will consider this a variable measurement instrument until we assess how the majority of studies included in this review are measured. In addition to nausea and vomiting, other variables investigated in the selected studies will also be identified.

  The secondary outcomes of this study will include the incidence of adverse reactions, and the rate of improvement of quality of life.

Included studies will undergo a risk of bias and reporting quality assessment by 2 reviewers. If there is any disagreement, a third reviewer will be consulted. If there is still doubt regarding the methodology or the reporting of results, study authors will be contacted as appropriate. Included RCT will be assessed with the Cochrane Handbook's Risk of Bias (ROB) assessment tool19. The risk of bias assessment results will be summarized narratively, with complete assessments provided as an appendix.

A descriptive analysis of relevant study methodological and clinical characteristics will be provided. This summary will include the main study and patient features, interventions, reported outcomes, and risk of bias assessments.

To the best of our knowledge, this is the first systematic review comparing antiemetic combination therapies to prevent chemotherapy-induced nausea and vomiting caused by HEC or MEC in hematological patients undergoing HSCT.

Our study has several strengths. First, we will utilize a rigorous systematic review methodology that includes explicit and reproducible eligibility criteria, as well as sensitive search strategies for both study screening and data extraction. Study screening will be conducted independently and in duplicate by teams of two trained reviewers.

However, our study also has some limitations. It will rely on reported trial information, and our findings may be vulnerable to underreporting or selective reporting20,21. Nonetheless, we will perform an exploratory search on clinicaltrials.gov to locate potential studies without reported results and minimize publication bias. Another limitation is that the study only includes articles published in English, French, Italian, and Spanish, which may result in the loss of relevant information written in other languages. Nevertheless, most published studies are expected to be available within these languages. Additionally, no restrictions will be imposed on the publication years of the selected studies.

As previously stated, the decision-making process for preventing CINV is often challenging for both patients and physicians due to the lack of specific recommendations for antiemetic agents in international guidelines in this context9,11. The findings of this systematic review will reveal a comprehensive description of the benefits and risks of CINV antiemetic agents used in hematologic patients receiving HEC or MEC within conditioning protocols for HSCT, as well as the most appropriate combination of these drugs for different conditioning regimens.

As a result, this systematic review could be of great importance for patients dealing with the consequences of CINV in order to improve their quality of life, as well as for healthcare professionals responsible for providing care to hematological patients undergoing HSCT.