International Consensus on Resistance, Rebound, and Recurrence in Pediatric Low-Grade Glioma with MAPK Inhibition Therapy: Established Using a Modified Delphi Method

Academic Background

Pediatric low-grade glioma (PLGG) is the most common type of tumor in the central nervous system of children. Although these tumors have a relatively high overall survival rate, many patients struggle with alternating periods of tumor stability and progression due to the inability to perform radical resection. In the modern era of molecular targeted therapies, as PLGGs are often associated with the activation of the RAS/MAPK pathway, these treatments have been widely applied in clinical trials. Recently, the U.S. Food and Drug Administration (FDA) approved the combined use of BRAF and MEK inhibitors for PLGGs with the BRAFV600E mutation. However, with the widespread use of targeted therapies, issues such as drug resistance, tumor recurrence after treatment, and rapid rebound growth after cessation of therapy have increased. Currently, there is no clear consensus on the definitions and management of these different growth patterns. Therefore, the International Pediatric Low-Grade Glioma Coalition (IPLGGC) established the “Resistance, Rebound, and Recurrence (R3)” working group aimed at developing consensus definitions and recommendations for these tumor growth patterns using a modified Delphi method.

Source of the Paper

The paper authored by Patricia O’Hare, Tabitha Cooney, Peter de Blank, and others, from multiple prestigious institutions worldwide such as the UCL Great Ormond Street Institute of Child Health and Harvard Medical School, is published in the 2024 issue of the journal Neuro-Oncology.

Research Workflow

Research Methods and Steps

The research process adopted a revised version of the Delphi method, including the following steps:

1. Initial Workshop: A preliminary virtual workshop was held to discuss the three growth patterns of pediatric low-grade glioma (PLGG): resistance, rebound, and recurrence. The terms were defined in detail, and the question framework was constructed.

2. First Round of Survey: An email invitation was sent to 43 experts to participate in the first round of the Delphi questionnaire survey. These experts included specialists in pediatric neuro-oncology, neuropathology, and neuroradiology.

3. Second Round of Survey: After the first questionnaire, a second anonymous questionnaire was conducted to evaluate the level of agreement on the options.

4. Third Stage Workshop: After the second round of the questionnaire, a face-to-face workshop was held to further discuss and attempt to resolve issues that did not reach consensus.

5. Data Analysis: Qualitative and quantitative analyses were performed on the results of each round of the questionnaire, with an in-depth analysis of issues that could not reach consensus.

Survey Participants and Data Collection

In the first round of the Delphi questionnaire survey, 33 experts participated, including 16 pediatric oncologists, 12 pediatric neuro-oncologists, three neuroradiologists, and two pediatric neurologists. In the second round, 26 experts participated.

Main Definitions and Consensus

Through these steps, the paper established consensus definitions for PLGG tumor growth patterns, as detailed in the table below:

Pattern	Definition
Resistance	Tumor growth (≥25%) occurring during systemic therapy (e.g., during MAPK inhibitor therapy), preferably confirmed by a second scan.
Rebound	Rapid growth (≥25%) of existing lesions within six months after stopping systemic therapy, preferably confirmed by a second scan.
Recurrence	Tumor regrowth (≥25%) or new lesions appearing six months after stopping treatment, preferably confirmed by a second scan.

Research Results

The significant findings of this study include:

1. Resistance: During treatment, PLGGs may show increased growth by 25% or more due to resistance.
2. Rebound Phenomenon: Particularly within three to six months after stopping MAPK inhibitor therapy, existing lesions may exhibit rapid growth, referred to as rebound.
3. Recurrent Growth: Tumor growth occurring six months after stopping treatment is defined as recurrent growth.

These definitions provide consistent terminology standards for future clinical trials and treatment, especially regarding the evaluation and management of tumor growth patterns in PLGG patients.

Conclusion and Value

Through this study, the authors not only discussed in detail the definitions of PLGG tumor growth patterns but also provided a valuable reference framework for academia and clinical practice. These consensus definitions and norms can help clinicians better understand and manage PLGG patients and promote collaboration and information exchange in the global academic community in this field.

The value of this study lies not only in its scientific and clinical applicability but also in its role in promoting future research. With clear definitions and consensus, future research and clinical trials will be more standardized and reproducible, thereby effectively improving treatment outcomes and the quality of life for PLGG patients.

Research Highlights and Future Prospects

A highlight of the research is the use of a revised Delphi method, enabling experts from multiple global fields to reach a consensus on this issue. Additionally, the study emphasizes the need for further data and broader participation to continuously deepen the understanding and management strategies of PLGG tumor growth patterns.

In the future, with the continuous advancement of molecular targeted therapy, the research team will continue exploring other possible tumor growth patterns and their management methods while focusing on the comprehensive impact of treatment on patients’ long-term quality of life and economic costs. These ongoing studies and discussions will bring more hope and benefits to PLGG patients and their families.