<![CDATA[Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard for high-risk non-muscle-invasive bladder cancer (HR-NMIBC). However, toxicities and global shortages necessitate alternatives. Sequential gemcitabine and docetaxel (Gem/Doce) is a prominent candidate. To systematically analyze the efficacy, tolerability, and biomarker-driven selection of Gem/Doce versus BCG in BCG-naïve HR-NMIBC. Following PRISMA guidelines, databases (PubMed, Scilit, ScienceDirect, Google Scholar) were searched (2015–2026) for comparative studies in BCG-naïve HR-NMIBC patients. Out of 300 initial records retrieved, 58 duplicates were removed, leaving 242 unique articles for screening. Following title and abstract screening, 229 irrelevant papers were excluded, and 13 full-text manuscripts were assessed for eligibility. Ultimately, 6 high-quality studies met all selection criteria and were included in the qualitative synthesis. Evaluated outcomes included recurrence-free survival (RFS), progression-free survival (PFS), complete response (CR) rates, and adverse events. Risk of bias was assessed using MINORS. Six studies (1,126 patients) were synthesized. In unselected cohorts, Gem/Doce showed comparable or superior 24-month high-grade RFS (HG-RFS: 81% vs. 69%; HR 0.57, p=0.04) and fewer discontinuations due to toxicity (2.9% vs. 9.2%; p=0.02) than BCG. In pure Ta high-grade (TaHG) papillary disease, BCG was superior for RFS (62% vs. 37%, p=0.013) and PFS (97% vs. 83%, p<0.001; HR 13.54). Chronological age did not significantly affect response, though older patients showed stable RFS with Gem/Doce compared to a decline with BCG. AI-powered digital pathology (CHAI) and transcriptomic signatures (ESTIMATE) successfully predicted suboptimal BCG responses (RFS 56% and 63%) but exceptional Gem/Doce responses (RFS 90%). MINORS scores (17–22) indicated low bias. Sequential Gem/Doce is a highly effective, tolerable first-line alternative to BCG, particularly for older patients and those with adverse histologic or immune-score transcriptomic profiles. BCG remains superior for pure TaHG papillary disease. ]]>
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