Letter to the Editor: Commentary on “Prognostic significance of the albumin-to-alkaline phosphatase ratio in gastrointestinal cancer patients: a systematic review and meta-analysis”

Dear Editor,

We read with great interest the recent meta-analysis by Zhu et al, which evaluated the prognostic significance of the albumin to alkaline phosphatase ratio (AAPR) in gastrointestinal malignancies[1]. Their study provides a timely synthesis of current evidence and highlights AAPR as a potentially valuable prognostic biomarker across several cancer types. We commend the authors for their rigorous methodology and their efforts in consolidating prognostic data from multiple clinical cohorts.

Several additional considerations, however, warrant further discussion to refine the interpretation and future clinical applicability of AAPR as a prognostic tool.

First, the prognostic performance of AAPR was not evaluated in relation to cancer-specific biological heterogeneity across gastrointestinal cancers. Malignancies of the stomach, colon, rectum, pancreas, and hepatobiliary system differ substantially in cancer biology, metastatic behavior, systemic inflammatory responses, and host–cancer interactions. These distinctions are clinically relevant because albumin and alkaline phosphatase are strongly influenced by cancer burden, liver involvement, biliary obstruction, and catabolic stress^[2,3]. Pooling these cancer types without stratification may therefore dilute or obscure cancer-specific prognostic signals. Future analyses stratified by cancer subtype would help determine whether AAPR represents a broadly applicable prognostic construct or one driven primarily by hepatobiliary cancer biology.

Second, the analysis did not account for nonmalignant determinants of alkaline phosphatase elevation, which may confound the observed associations. Alkaline phosphatase is affected by multiple physiological and pathological processes unrelated to cancer progression, including bone turnover, metabolic bone disease, hepatic steatosis, cholestatic disorders, endocrine conditions, and medication-related effects[4]. Failure to adjust for these factors may lead to systematic misclassification of patients into high-risk AAPR categories and may exaggerate the apparent prognostic value of the ratio. Prospective datasets incorporating detailed comorbidity profiling are necessary to clarify whether AAPR reflects cancer-specific biology or a combination of unmeasured systemic conditions.

Third, AAPR was analyzed solely as a baseline measurement, despite its inherently dynamic nature. Albumin levels vary in response to nutritional status, systemic inflammation, perioperative stress, and treatment-related improvement. Alkaline phosphatase may likewise fluctuate with cancer evolution, therapy-related biliary changes, or progression of hepatic involvement. Restricting analyses to a single time point risks overlooking clinically meaningful longitudinal changes. Incorporating time-dependent analyses, dynamic AAPR trajectories, or evaluation of peri-treatment changes could markedly enhance the prognostic value of this biomarker and improve its translational relevance.

In conclusion, the study by Zhu et al contributes important evidence regarding the prognostic role of AAPR in gastrointestinal cancers. Addressing cancer-specific heterogeneity, adjusting for nonmalignant determinants of alkaline phosphatase elevation, and incorporating time-varying biomarker analyses would further strengthen the evidence base and support the more reliable application of AAPR in clinical decision making.

This letter is reported in accordance with the TITAN Guidelines 2025[5].

Ethical approval

Not required for this type of article as it does not involve human participants, clinical interventions, or patient-identifiable data.

Consent

Not applicable. No patient data or identifiable information are included.

Sources of funding

This research did not receive any specific funding.

Author contributions

Y.W.: drafted the manuscript and performed the literature review; P.L.: participated in conceptual design and critical revision; Y.Z.: supervised the work, finalized the manuscript, and is the corresponding author. All authors reviewed and approved the final version of the manuscript.

Conflicts of interest disclosure

The authors declare no conflicts of interest related to this work.

Research registration unique identifying number (UIN)

Not applicable. This article is a commentary and does not require research registration.

Guarantor

Yikun Zhang.

Provenance and peer review

Not commissioned.

Data availability statement

Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.