Background: Digestive tract cancers, including esophageal, gastric, colorectal, liver, pancreatic, gastrointestinal stromal tumors (GISTs), and digestive blastomas, accounted for 26% of cancer cases and 38% of cancer-related deaths worldwide in 2020. Managing these malignancies is challenging due to frequent advanced-stage diagnosis, complicating treatment and resulting in poor prognoses. Radiotherapy has evolved from a palliative approach to a curative treatment for several digestive tract cancers, with advances in techniques like three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiotherapy (SBRT) improving precision and efficacy. Materials and Methods: PubMed was searched from inception to September 2024 using various keywords with Boolean modifiers and operators. The abstracts were screened, and any relevant articles were imported into a reference manager. Additionally, the references of the selected articles were further screened for any further relevant articles. Results: This literature review examines the integration of radiotherapy into multimodal treatments, such as neoadjuvant chemoradiation for esophageal and gastric cancers, as demonstrated by the CROSS study. Challenges include resistance to therapy, often mediated by molecular mechanisms involving non-coding RNAs, and significant side effects like gastrointestinal toxicity and fatigue. The emerging role of the gut microbiome in influencing radiotherapy efficacy and side effects is also highlighted. Conclusion: Despite successes, overcoming resistance and reducing side effects remain significant challenges. Advances in radiotherapy techniques, combined with a deeper understanding of molecular biology and the gut microbiome offer promising avenues for enhancing efficacy and tolerability.
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