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Cancer, Hypoxia, and Metabolism / Chemotherapy-induced Cardiotoxicity and Mitigation · Journal article
Frontiers in Oncology · August 7, 2026
Early or partial results. Treat as a signal, not a conclusion.
This retrospective cohort study reports an association between maintaining urinary pH ≥7.0 during alkalization therapy and longer overall survival in patients with stage IV or recurrent colorectal cancer, particularly in RAS-mutant and liver-metastatic subgroups. The observed interaction (HR 0.22, p = 0.0199) suggests differential survival benefit by RAS status, but the study lacks a control arm, randomization, and adjustment for concurrent oncologic treatments, precluding causal inference.
Retrospective cohort study. Stage IV or recurrent colorectal cancer patients attending Karasuma Wada Clinic 2014–2019, undergoing alkalization therapy; BRAF-mutant cases excluded.. Intervention: Alkalization therapy with monitoring of urinary pH; stratified by achievement of urinary pH ≥7.0 vs <7.0. n = 129. Karasuma Wada Clinic (single center, location not specified).
5-year OS rate in overall cohort 0.212 (95% CI, 0.113–0.362) Significant interaction between urinary pH and RAS mutation status (HR 0.22; 95% CI 0.06–0.78; p = 0.0199) In RAS mutation-positive subgroup, urinary pH ≥7.0 associated with significantly better OS vs <7.0 (Gehan-Breslow-Wilcoxon p = 0.013)
Urinary pH is a biomarker, not the alkalization intervention itself; mechanism and safety of alkalization therapy not characterized.
These findings suggest urinary pH maintenance may be associated with improved survival in RAS-mutant metastatic colorectal cancer, a molecularly unfavorable subgroup. However, the retrospective design and lack of control arm mean this cannot yet guide clinical practice; prospective randomized trials are needed before alkalization can be recommended as a complementary strategy.
Retrospective single-center cohort without randomization or control group; shows association between urinary pH and survival in RAS-mutant colorectal cancer but cannot establish causation or compare to standard care.
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These findings suggest urinary pH maintenance may be associated with improved survival in RAS-mutant metastatic colorectal cancer, a molecularly unfavorable subgroup. However, the retrospective design and lack of control arm mean this cannot yet guide clinical practice; prospective randomized trials are needed before alkalization can be recommended as a complementary strategy.
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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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