Objective:

To synthesize published incidence estimates of intratumoral and intracranial hemorrhage associated with MAPK-pathway targeted therapy across tumor types and propose a mechanistic and clinical framework for monitoring.

Approach:

• Search Strategy: A systematic search of PubMed/MEDLINE and Embase was conducted from inception through May 29, 2026, using specific hemorrhage descriptors combined with MAPK-pathway agents.
• Eligibility Criteria: Included human studies reporting intratumoral or intracranial hemorrhage temporally associated with MAPK-pathway agents, focusing on ITH and ICH.
• Data Extraction: Extracted variables included study design, patient demographics, tumor type, targeted agents, timing of hemorrhage, and clinical outcomes. Results were synthesized narratively due to heterogeneity.

Key Findings:

• Intratumoral hemorrhage is an established complication of certain brain tumors, particularly melanoma.
• Hemorrhage is a labeled warning for selumetinib and tovorafenib, with fatal CNS bleeding reported in dabrafenib-based regimens.
• There is a lack of unified incidence estimates and evidence-based monitoring guidance due to inconsistent reporting and phenotyping.

Interpretation:

The review highlights the need for better characterization of hemorrhagic events associated with MAPK-pathway inhibitors as their use expands in neuro-oncology.

Limitations:

• Heterogeneity in reporting and definitions of CNS-specific bleeding across studies.
• Rarity of events limits quantitative meta-analysis.
• Lack of standardized definitions for CNS hemorrhage.

Conclusion:

The findings highlight the need for better characterization of hemorrhagic events associated with MAPK-pathway inhibitors.