Dear Editor, We read with great interest the article published in the International Journal of Surgery entitled “Development and validation of a novel modified cancer cachexia index in patients with locally advanced gastric cancer undergoing neoadjuvant chemotherapy: A multicenter cohort study”1. This study proposed and validated a novel modified cancer cachexia index (mCXI) for patients with locally advanced gastric cancer (LAGC) receiving neoadjuvant chemotherapy (NACT). The findings indicate that the mCXI serves not only as an independent prognostic factor but also as a practical tool to optimize postoperative treatment strategies in patients with LAGC. However, we observed certain limitations that deserve further discussion. This article was written following the TITAN guidelines2. First, several core indicators appear to be missing from the proposed index. Cancer cachexia is a multifactorial syndrome driven by systemic inflammation, metabolic dysregulation, and hormonal imbalance, for which no standardized or effective treatment currently exists3. In patients with gastric cancer, cachexia significantly increases the risk of postoperative complications, impairs chemotherapy tolerance, and adversely affects overall survival4. Skeletal muscle atrophy is a hallmark feature of cancer cachexia; however, the modified cancer cachexia index (mCXI) does not incorporate the skeletal muscle index (SMI), relying instead on albumin (ALB), platelet count (PLT), and subcutaneous adipose tissue (SAT). Although fat depletion is also a recognized manifestation of cachexia and SAT has been included accordingly, the authors suggest that SAT is superior to SMI as a prognostic marker5,6. Nevertheless, the mechanistic rationale supporting this assertion remains insufficiently explored, which may undermine the conceptual robustness of the mCXI formula. While the heterogeneity of cachexia poses challenges to the standardization of cancer treatment, it also presents opportunities to develop individualized therapeutic strategies tailored to specific cachexia phenotypes7. Second, the predictive power of the model appears limited. Although the area under the curve (AUC) for overall survival (OS) and TRG2/3 was highest for mCXI after NACT, the predictive performance of mCXI for OS was not substantially different from that of TRG2/3 alone. The authors acknowledge this limitation and attribute it to the influence of multiple factors on prognostic outcomes; however, they nonetheless propose mCXI as a basis for indirect clinical guidance regarding adjuvant chemotherapy cycles. We believe that this interpretation could potentially overestimate the actual prognostic utility of the index. Third, the distribution of sample sizes between groups was uneven. While mCXI served as a stratification tool rather than an independent diagnostic indicator, its performance exceeded that of the traditional CXI and was corroborated by findings from external cohorts. However, the sample sizes of the internal and external cohorts (348 and 49 cases, respectively), as well as those of the mCXI low and high groups (245 and 103 cases, respectively), were not balanced. This imbalance may reflect a degree of instability in the experimental results and could limit the robustness of the conclusions. Fourth, the variables used in the index are not uniform. Specifically, the authors applied lymphocyte to monocyte ratio (LMR)/fibrinogen (FIB) in the CXI formula before NACT, whereas the ALB/platelet count (PLT) was used after NACT. Although the study demonstrates that the numerators function as positive predictors and the denominators as negative predictors, the underlying mechanisms of these indicators differ, and their responses to clinical treatment are not the same. On this basis, the authors did not provide a sufficient explanation for the consistency of predictive power across these heterogeneous variables, which raises concerns regarding the internal coherence of the mCXI formula. Finally, there is a lack of discussion regarding certain indicators. Although the dynamic CXI formula is introduced in the early part of the article, it is not further explored or discussed in the later sections. Future research could be strengthened by prospective studies with larger sample sizes and by providing an in-depth evaluation of the potential value of dynamic formulas in guiding clinical decision-making. In addition, despite the authors’ explanations, we believe that data on chemotherapy toxicity and tolerability – both key determinants of adjuvant chemotherapy cycles – should be included in the discussion to provide a more comprehensive perspective. In conclusion, if future studies can expand external cohorts and incorporate prospective, large-scale, longitudinal follow-up, while also addressing key factors such as chemotherapy toxicity and tolerability, the mCXI may achieve greater robustness and hold substantial clinical value as a prognostic indicator for patients undergoing NACT.
Ma et al. (Mon,) studied this question.