Oral capecitabine or tegafur/gimeracil/oteracil as induction and adjuvant/maintenance chemotherapy in the management of stage III-IVb nasopharyngeal carcinoma: A systematic-review and meta-analysis.
Authors: Polintan Edgar Theodore , Guo Yuhe , Ramirez-Garcia Lucia , Lo Kevin Bryan , Nayak Sandeep Samethadka , Loong Herbert H. F. , Villalona-Calero Miguel Angel 
Published: June 2023

e18000 Background: According to practice guidelines, concurrent chemoradiotherapy or induction chemotherapy with subsequent chemoradiotherapy is the recommended regimen for Stage III-IV NPCA. Unfortunately, local and distant recurrence continue to be primary reasons for treatment failure. To improve existing treatment regimens, replacing infusional 5-fluorouracil with oral fluoropyrimidine equivalents was suggested due to lower hazard of death and progression. In this meta-analysis we will be investigating the use of oral fluoropyrimidines, namely capecitabine and tegafur/gimeracil/oteracil, to elucidate their efficacy and effectiveness in Nasopharyngeal Carcinoma (NPCA) compared to standard chemotherapy regimens. Methods: A literature search of PubMed, Cochrane CENTRAL, and ClinicalTrials.gov was done in compliance with the PRISMA-P guidelines. After screening 908 records and selecting 32 articles for full-text assessment, 29 articles were included in the systematic-review and 15 in the meta-analysis. Outcomes were assessed for quality of evidence using a modified GRADE criteria. Overall Survival (OS) was assessed as the primary endpoint. Secondary outcomes were Progression Free Survival (PFS), Disease Free Survival (DFS), Distant Metastasis Free Survival (DMFS) and Locoregional Recurrence Free Survival (LRFS). Risk Ratio (RR) was used as the measure of association for all outcomes. Significance was assessed using p-values and I2 for the presence of heterogeneity. All pooled outcomes were assessed with 95% confidence intervals (CI). Statistical analysis was done using Stata and Review Manager 5. Results: The PFS RR of the adjuvant/maintenance group and induction group, respectively, were 0.53 [95%CI 0.38, 0.72]; I2 = 41% (p < 0.001) and 0.59 [95%CI 0.37, 0.95]; I2 = 0% (p = 0.03). DFS, LRFS, and DMFS of the adjuvant/maintenance group were 0.61 [95%CI 0.44, 0.83]; I2 = 0% (p = 0.002), 0.48 [95%CI 0.28, 0.83]; I2 = 0% (p = 0.008) and 0.67 [95%CI 0.44, 1.01]; I2 = 0% (p = 0.06), respectively. The induction group's LRFS and DMFS, respectively, were 0.55 [95%CI 0.37, 0.82] (p = 0.004); I2 = 0% and 0.60 [95%CI 0.40, 0.91]; I2 = 25% (p = 0.02). The OS for the adjuvant and induction group were 0.51 [95%CI 0.38, 0.69]; I2 = 21% (p < 0.001) and 0.72 [95%CI 0.52, 1.00]; I2 = 14% (p = 0.05), respectively. Conclusions: Based on “Low to Moderate” levels of evidence, induction oral fluoropyrimidine-containing regimens are associated with significantly higher 2-3 year PFS and 3-5 year LRFS as well as DMFS with equivalent 2-5 year OS in previously-untreated Stage III-IVB NPCA. Meanwhile, adjuvant/maintenance oral fluoropyrimidine-containing regimens lead to significantly higher 2-5 year OS and 3-5 year PFS, DFS, DMFS and LRFS compared to induction CCRT alone in previously-untreated Stage III-IVB NPCA.