Key result
Alkalization therapy maintaining higher urinary pH is linked to ~78% lower mortality in RAS-mutated patients.
Why the study?
Stage IV or recurrent colorectal cancer remains difficult to treat, particularly in RAS-mutant tumors, and alkalization therapy has emerged as a strategy to counter tumor microenvironment acidification.
Does maintaining urinary pH ≥7.0 under alkalization therapy improve overall survival in patients with stage IV or recurrent colorectal cancer?
Cohort (n=129)
No
Does maintaining urinary pH ≥7.0 under alkalization therapy improve overall survival in patients with stage IV or recurrent colorectal cancer?
Maintaining a urinary pH ≥7.0 during alkalization therapy is associated with improved overall survival in stage IV or recurrent colorectal cancer, particularly in patients with RAS mutations and liver metastases.
Indicates poor long-term survival in this cohort; leaves open whether urinary pH modifies prognosis by RAS 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.
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Suzuki et al. (2026) conducted a cohort in Stage IV or recurrent colorectal cancer (n=129). Alkalization therapy (higher urinary pH) vs. Lower urinary pH was evaluated on Overall survival (interaction between urinary pH and RAS mutation status) (HR 0.22, 95% CI 0.06-0.78, p=0.0199). Maintenance of higher urinary pH under alkalization therapy was associated with significantly longer overall survival, particularly in the clinically unfavorable RAS mutation-positive subgroup (interaction HR 0.22).
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