Abstract
We sincerely thank Dr. Jin for the thoughtful reading of our article and the constructive comments.1,2 We appreciate the opportunity to respond to the points raised, which we believe will help clarify certain methodological aspects and highlight avenues for future research.
Confounding Factors
We acknowledge that psychosocial support, diet, and exercise habits can influence fatigue, anxiety, and depression. While these variables were not explicitly controlled for in our analysis, the randomized, triple-blind design of the study was intended to minimize the risk of systematic bias by ensuring that both known and unknown confounders were evenly distributed between the intervention and placebo groups. Regarding concomitant medications, such as endocrine therapy, these were administered according to standardized institutional protocols based on our previous experience.2 -5 Although not explicitly detailed in the manuscript, treatments were comparable across both groups, as confirmed during baseline characteristic assessments. Future studies may benefit from more detailed tracking and reporting of concomitant therapies to further strengthen internal validity.
Subgroup Analyses
We agree that more granular subgroup analyses—such as stratifying by type or duration of adjuvant endocrine therapy—could yield valuable insights into whether melatonin’s efficacy varies across different treatment contexts. However, our sample size (n = 100) was not sufficient to support such detailed stratification without compromising statistical power. Conducting underpowered subgroup analyses increases the risk of Type II errors and spurious findings. We strongly recommend that future trials with larger cohorts consider these analyses to explore potential effect modifiers and identify patient subgroups that may benefit most from melatonin supplementation.
Exclusion Criteria and Generalizability
The exclusion of patients with comorbidities such as diabetes and hypertension was a deliberate choice to enhance internal validity by creating a more homogeneous study population. This allowed us to isolate the effects of melatonin on radiotherapy-induced symptoms with greater clarity. We recognize that this approach may limit the immediate generalizability of our findings to the broader breast cancer population, which often includes individuals with multiple comorbidities. However, we believe this trade-off was necessary for a phase II trial focused on establishing efficacy under controlled conditions. Subsequent studies involving more diverse patient populations—including those with common comorbidities—are essential to validate and extend our results to real-world clinical settings.
Objective Biomarkers
The inclusion of objective biomarkers, such as cortisol or thyrotropin-releasing hormone (TRH) levels, would indeed provide a more comprehensive, pathophysiologically grounded assessment of melatonin’s effects. However, practical constraints, including the high cost and limited availability of these assays in our setting, precluded their use. Moreover, in the context of symptom management, patient-reported outcomes (eg, fatigue, anxiety, and depression) are often more directly relevant to clinical practice and quality of life. That said, we fully endorse the integration of biomarker data in future research when logistical and financial resources permit, as this could offer valuable mechanistic insights and complement subjective measures.
Additional Considerations
Beyond the points raised by Dr. Jin, we also recognize other limitations noted in our discussion, such as the lack of serum melatonin level measurements to confirm adherence, and the absence of sleep quality or chronotype assessments. These factors could influence individual responses to melatonin and represent important directions for future investigation. Despite these limitations, we believe that the robust design, consistent findings, and clinical relevance of our study contribute meaningfully to the growing body of evidence on melatonin’s role in supportive cancer care.
In summary, we are grateful for the insightful feedback from Dr. Jin. The suggestions not only reinforce the strengths of our study but also help identify key areas for methodological refinement in future research. We hope that our work will inspire further rigorously designed trials to explore the full potential of melatonin in improving the well-being of cancer patients.
