Association of alkalization therapy with long-term survival in stage IV or recurrent colorectal cancer: interaction with RAS mutation status.

BACKGROUND: Stage IV or recurrent colorectal cancer remains difficult to treat, especially in patients with RAS-mutant tumors, for whom anti-EGFR antibodies are not effective. Increasing evidence indicates that acidification of the tumor microenvironment promotes invasion, metastasis, therapeutic resistance, and immune suppression. Alkalization therapy has therefore attracted interest as a supportive strategy to improve systemic acid-base and metabolic conditions. METHODS: We retrospectively analyzed patients with stage IV or recurrent colorectal cancer who first visited Karasuma Wada Clinic between 2014 and 2019 and underwent alkalization therapy with at least three urinary pH measurements. Two patients with BRAF-mutant tumors were excluded, leaving 129 patients for the primary analysis. Urinary pH was summarized using the 25% chronologically trimmed mean urinary pH. Overall survival (OS) was the primary endpoint. Among 80 patients with known RAS mutation status, a Cox proportional hazards model including interaction terms for urinary pH × RAS mutation status and urinary pH × liver metastasis was used as the primary analysis, followed by Kaplan-Meier analyses guided by the interaction structure. RESULTS: In the overall cohort, the 5-year OS rate was 0.212 (95% CI, 0.113-0.362). Among the 80 patients with known RAS status, the interaction between urinary pH and RAS mutation status was significant (HR, 0.22; 95% CI, 0.06-0.78; likelihood ratio test, p = 0.0199), indicating that the prognostic impact of urinary pH differed according to molecular background. The 5-year OS rates were 0.250 in the RAS wild-type group and 0.130 in the RAS mutation-positive group. Within the RAS mutation-positive subgroup, patients with urinary pH ≥7.0 had significantly better OS than those with urinary pH <7.0 (Gehan-Breslow-Wilcoxon test, p = 0.013). Among patients with both RAS mutation-positive disease and liver metastases, urinary pH ≥7.0 was likewise associated with significantly longer OS (log-rank p = 0.0141). CONCLUSIONS: Maintenance of urinary pH ≥7.0 under alkalization therapy was associated with longer survival in stage IV or recurrent colorectal cancer, particularly in clinically unfavorable subgroups defined by RAS mutation and liver metastasis. These findings support prospective evaluation of alkalization-oriented intervention as a complementary therapeutic strategy.