The Potential of Integrative Cancer Treatment Using Melatonin and the Challenge of Heterogeneity in Population-Based Studies: A Case Report of Colon Cancer and a Literature Review

Abstract

Melatonin is a multifunctional hormone regulator that maintains homeostasis through circadian rhythms, and desynchronization of these rhythms can lead to gastrointestinal disorders and increase the risk of cancer. Preliminary clinical studies have shown that exogenous melatonin alleviates the harmful effects of anticancer therapy and improves quality of life, but the results are still inconclusive due to the heterogeneity of the studies. A personalized approach to testing clinical parameters and response to integrative treatment with nontoxic and bioavailable melatonin in patient-centered N-of-1 studies deserves greater attention. This clinical case of colon cancer analyzes and discusses the tumor pathology, the adverse effects of chemotherapy, and the dynamics of markers of inflammation (NLR, LMR, and PLR ratios), tumors (CEA, CA 19-9, and PSA), and hemostasis (D-dimer and activated partial thromboplastin time). The patient took melatonin during and after chemotherapy, nutrients (zinc, selenium, vitamin D, green tea, and taxifolin), and aspirin after chemotherapy. The patient's PSA levels decreased during CT combined with melatonin (19 mg/day), and melatonin normalized inflammatory markers and alleviated symptoms of polyneuropathy but did not help with thrombocytopenia. The results are analyzed and discussed in the context of the literature on oncostatic and systemic effects, alleviating therapy-mediated adverse effects, association with survival, and N-of-1 studies.

Keywords: N-of-1; aspirin; cancer; green tea; hemostasis; inflammatory markers; integrative treatment; melatonin; selenium; taxifolin; vitamin D; zinc.

Figure 1

Dynamic study of the ratio of neutrophils/lymphocytes (NLR, green line) and lymphocytes/monocytes (LMR, black line). The blue line indicates the doses of Mel supplementation. Arrows indicate the time of surgery (S) and the chemotherapy (CT) interval as well as intake of aspirin (As) and prescribed antibiotics: amoxicillin and then azithromycin (Am-Az) or azithromycin alone (Az). Cut-off values for NLR (adverse at >2.72, dashed green line) and LMR (adverse at ≤2.83, dotted line) were taken from reference [69]. The yellow area indicates the withdrawal interval of Mel intake.

Figure 2

Dynamic study of the ratio of platelets/lymphocytes (PLR, black line) and platelets (PLT, triangles). Designations are the same as in Figure 1. The cut-off value for PLR (adverse at >219, dotted line) is taken from reference [69]. The dashed green line indicates the lower limit of the reference range for PLT. The blue line indicates the doses of Mel supplementation. The yellow area indicates the withdrawal interval of Mel intake.

Figure 3

Dynamic study of tumor markers: PSA (black line) and CEA (green line). The designations are the same as in Figure 1. The dashed line indicates the upper limit of the reference range for PSA. The blue line indicates the doses of Mel supplementation. The yellow area indicates the withdrawal interval of Mel intake.

Figure 4

Dynamic study of the level of D-dimer (black line) and the activated partial thromboplastin time (APTT, green line). The designations are the same as in Figure 1. The upper limits of the reference range for D-dimer (dotted line) and APTT (dashed green line) are shown. The blue line indicates the doses of Mel supplementation.

Figure 5

Conceptual scheme of integrative treatment with Mel in patients with gastrointestinal cancer for clinically relevant N-of-1 studies, which include monitoring stratified patients using imaging, blood tests, and questionnaires. Imaging studies: computed tomography, magnetic resonance imaging, positron emission tomography, ultrasonography, and angiography. Blood tests: monitoring of hematological and biochemical parameters, including markers of inflammation and tumors, markers of organ function and hemostasis, control of Mel production, and deficiency of essential micro/macroelements and vitamins. Stratification of patients: stratification by molecular pathology to select eligible participants and reduce heterogeneity; molecular–genetic and histological profiling of primary tumors and metastatic specimens and liquid biopsies for analysis of circulating tumor DNA and tumor cells; and the use of oncogenomics and next-generation sequencing technology. Conventional therapy: surgery, CT, RT, immunotherapy, and targeted therapy; stratification of patients by the response to therapy when comparing effectiveness vs. adverse effects based on pharmacogenomics [262]. Integrative treatment with Mel: the influence of Mel on effectiveness, adverse effects, quality of life, relapse, and survival when used in combination with conventional, maintenance, metronomic, and palliative therapies. Maintenance therapy is repeated treatment to prolong remission. Metronomic CT: a new type of CT in which anticancer drugs are administered repeatedly in lower doses over a long period to treat cancer with fewer adverse effects; metronomic CT is noteworthy as an N-of-1 study, designed either as a stand-alone treatment modality or in combination with Mel. Palliative treatment in combination with Mel to improve quality of life by normalizing sleep, correcting circadian rhythms and organ function, and relieving symptoms of chronic diseases and complications associated with cancer.