Combination Therapies in the Treatment of Advanced Esophageal Cancer: Insights from Recent Clinical Trials

Advanced esophageal cancer presents substantial challenges due to its aggressive nature and limited treatment options, with current standard therapies often yielding poor outcomes. As incidence rates continue to rise and monotherapies remain ineffective, investigating combination therapy options has become critical. Recently, there has been increasing interest in combining chemotherapy, radiotherapy, targeted therapy, and immunotherapy to improve patient outcomes. This systematic review aims to evaluate the effectiveness and safety of these integrated treatment approaches using the latest clinical trial findings. Methods: A comprehensive search of PubMed, Cochrane Library, and ClinicalTrials.gov identified studies published between January ۲۰۱۸ and June ۲۰۲۴. Keywords utilized included "esophageal cancer," "combination therapy," "chemotherapy," "radiotherapy," "targeted therapy," and "immunotherapy." We included randomized controlled trials (RCTs) and phase II/III clinical studies that reported data on progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs). Studies that did not focus on advanced esophageal cancer, relevant combination therapies, or lacked sufficient data on OS, PFS, or AEs, as well as studies in non-English languages, were excluded. Data extraction and quality assessment used the Cochrane risk-of-bias tool for RCTs. Results: Fourteen trials passed the inclusion criteria, covering a wide range of combination therapies and enrolling ۷۳۹۴ patients with advanced esophageal cancer. These studies demonstrated that combination therapies offered better OS and PFS improvements than monotherapies, varying effectiveness based on disease stage and histological subtype. Specifically, chemotherapy combinations plus immune checkpoint inhibitors, such as Pembrolizumab and Nivolumab, consistently revealed significant benefits, especially in patients with high PD-L۱ expression. For instance, The KEYNOTE-۵۹۰ trial reported a ۲۷% reduction in the risk of death (HR = ۰.۷۳; ۹۵% CI: ۰.۶۲–۰.۸۶; p < ۰.۰۰۰۱), and the CheckMate-۶۴۸ trial showed a ۲۶% reduction (HR = ۰.۷۴; ۹۵% CI: ۰.۶۱–۰.۹۰; p = ۰.۰۰۲۱). Additionally, KEYNOTE-۵۹۰ found a ۳۵% reduction in disease progression (HR = ۰.۶۵; ۹۵% CI: ۰.۵۵–۰.۷۶; p < ۰.۰۰۰۱), and CheckMate-۶۴۸ reported a ۱۹% reduction (HR = ۰.۸۱; ۹۵% CI: ۰.۶۷–۰.۹۹; p = ۰.۰۳۵۵) with Nivolumab and chemotherapy. Furthermore, combining radiotherapy with chemotherapy and targeted treatments, like HER۲ inhibitors, has enhanced local tumor control and reduced the risk of metastasis. However, these combination treatments were also associated with a higher likelihood of severe AEs, such as neutropenia, fatigue, and gastrointestinal disturbances. Conclusion: Combination therapies represent notable advancements in treating advanced esophageal cancer, resulting in higher survival rates than traditional methods. The promising outcomes from combination therapies suggest they may soon become integral parts of standard treatment protocols for advanced esophageal cancer. Although minimizing toxicity and side effects remains difficult, ongoing research and clinical trials are gradually refining these treatments. Balancing improved survival with treatment-related toxicity management is crucial, underscoring the need for strategies focusing on efficacy and quality of life. Future trials Concentrating on optimizing combination regimens, identifying biomarkers for patient stratification, developing strategies to manage AEs, and investigating novel agents like bispecific antibodies and CAR-T cells have the potential to elevate treatment efficacy even further. The potential of individualized medicine and innovative therapeutic agents offers hope for better outcomes.

کلیدواژه ها:

Esophageal cancer ، Combination therapy ، Chemotherapy ، Radiotherapy ، Immunotherapy