Mehmet Salih Iyikesici

Cancer cells exhibit metabolic reprogramming, including increased aerobic glycolysis, glutaminolysis, and altered lipid metabolism, which supports tumor growth and contributes to immune evasion. A growing but heterogeneous body of literature has investigated whether targeting these metabolic dependencies alongside standard oncologic treatment may provide therapeutic benefit. This review critically examines clinically investigated metabolically directed approaches, including metronomic chemotherapy, hyperthermia, high-dose intravenous vitamin C, hyperbaric oxygen therapy, fasting-related nutritional strategies, ketogenic diets, and insulin-based approaches, while distinguishing them from established targeted therapies, monoclonal antibodies, and immune checkpoint inhibitors. Emerging immunometabolic and microenvironmental targets are also discussed, including lactate transport, ferroptosis, autophagy and amino acid metabolism, cancer-associated fibroblasts, tumor-associated macrophages, abnormal vasculature, and immunosuppressive cytokine signaling. In addition, drug-delivery strategies are considered by distinguishing the established pharmaceutical role of dimethyl sulfoxide (DMSO) as a solvent or excipient from nanoparticle-, exosome-, and peptide-based targeting platforms. Available evidence is characterized according to clinical maturity, ranging from established phase III-supported therapies and randomized clinical evidence to early-phase, preclinical, or currently unproven approaches. Although several metabolically directed interventions have biological rationale and varying degrees of clinical support, no comprehensive multicomponent metabolic regimen has been validated in controlled clinical trials. Future development should prioritize stepwise, biomarker-informed prospective studies evaluating individual interventions and biologically justified combinations alongside standard-of-care therapy. Metabolically directed strategies should therefore be interpreted according to the evidence supporting each component rather than as a single established therapeutic regimen.

Cancer cells exhibit metabolic reprogramming, including increased aerobic glycolysis, glutaminolysis, and altered lipid metabolism, which supports tumor growth and contributes to immune evasion. A growing but heterogeneous body of literature has investigated whether targeting these metabolic dependencies alongside standard oncologic treatment may provide therapeutic benefit. This review critically examines clinically investigated metabolically directed approaches, including metronomic chemotherapy, hyperthermia, high-dose intravenous vitamin C, hyperbaric oxygen therapy, fasting-related nutritional strategies, ketogenic diets, and insulin-based approaches, while distinguishing them from established targeted therapies, monoclonal antibodies, and immune checkpoint inhibitors. Emerging immunometabolic and microenvironmental targets are also discussed, including lactate transport, ferroptosis, autophagy and amino acid metabolism, cancer-associated fibroblasts, tumor-associated macrophages, abnormal vasculature, and immunosuppressive cytokine signaling. In addition, drug-delivery strategies are considered by distinguishing the established pharmaceutical role of dimethyl sulfoxide (DMSO) as a solvent or excipient from nanoparticle-, exosome-, and peptide-based targeting platforms. Available evidence is characterized according to clinical maturity, ranging from established phase III-supported therapies and randomized clinical evidence to early-phase, preclinical, or currently unproven approaches. Although several metabolically directed interventions have biological rationale and varying degrees of clinical support, no comprehensive multicomponent metabolic regimen has been validated in controlled clinical trials. Future development should prioritize stepwise, biomarker-informed prospective studies evaluating individual interventions and biologically justified combinations alongside standard-of-care therapy. Metabolically directed strategies should therefore be interpreted according to the evidence supporting each component rather than as a single established therapeutic regimen.

Background: Metastatic pancreatic adenocarcinoma carries a dismal prognosis, and treatment options after progression on standard chemotherapy remain limited. We report a metabolic response in a patient with drug-resistant disease treated with a combined multimodal regimen that paired dose-reduced (“activated”) multi-agent chemotherapy with targeted agents and metabolic/microenvironmental support, set against an unusually long overall survival. Case Presentation: A 46-year-old man was diagnosed with inoperable, locally advanced/stage IV pancreatic adenocarcinoma in June 2023 and maintained disease control for approximately 2.5 years on a combined multimodal regimen, termed here metabolically controlled oncologic therapy (MCOT): dose-reduced chemotherapy given with regional hyperthermia, hyperbaric oxygen, and a carbohydrate-restricted diet. In February 2026 he developed local recurrence and diffuse liver metastases, and by May 2026 had deteriorated rapidly, with ¹⁸F-FDG PET/CT showing a peak SUVmax of 18.2 and CA 19-9 of 2788 U/mL. His regimen was intensified to a low-dose, multi-agent “activated” chemotherapy protocol combined with lenvatinib, everolimus, hyperthermia, and hyperbaric oxygen. Clinical Findings and Outcomes: One month later, his performance status had recovered from ECOG PS 2 to PS 0, CA 19-9 was 31 U/mL, and follow-up PET/CT showed a 63.7% decrease in SUVmax (from 18.2 to 6.6). Treatment-related adverse events included Grade 1 nausea, Grade 1 vomiting, and thrombocytopenia; no Grade 2 or higher non-hematological toxicity was observed. Conclusions: In selected patients who are considered to have exhausted standard options, a combined multimodal regimen pairing dose-reduced chemotherapy with metabolic and microenvironmental support may produce a well-tolerated metabolic response. As a single, uncontrolled observation, these findings cannot establish causality and require confirmation in prospective, controlled studies.

Hyperthermia is an adjunct therapeutic approach that induces stress responses in biological tissues via controlled heat and can enhance cancer therapy. However, many RF-based systems are fixed and limited in experimental flexibility. Therefore, the development of portable RF hyperthermia platforms is essential for in vitro optimization and preclinical investigations. This study developed a mobile 13.56 MHz RF hyperthermia system and evaluated its thermal performance and preliminary in vitro biological effects. A mobile prototype including an RF generator, matching unit, electrode chamber, sample holder, and touchscreen interface was built. Human cancer cell lines (A549 and MDA-MB-231) and non-cancerous HUVEC cells were exposed to RF power levels of 40 W and 50 W for 10 min to assess the biological effects of thermal exposure. Apoptotic responses were analyzed by Annexin V-FITC/PI flow cytometry. The system generated temperatures ranging from 40 to 50 °C depending on the applied RF power and experimental conditions. RF exposure increased apoptotic populations in a cell-dependent manner. MDA-MB-231 cells showed significantly increased apoptotic populations compared with their corresponding untreated controls, whereas A549 cells exhibited a temperature-dependent shift toward increased necrosis at higher power levels. HUVEC responses indicated limited selectivity under the tested conditions. Overall, the developed platform demonstrated both technical feasibility and biological activity, providing a practical tool for controlled in vitro RF hyperthermia studies. The findings support further mechanistic investigations and future preclinical studies aimed at optimizing RF-assisted therapeutic strategies.

Achieving optimal therapeutic efficacy in colorectal cancer (CRC) remains challenging, highlighting the need for novel treatment strategies. This study evaluated whether radiofrequency (RF) hyperthermia enhances the anticancer effects of sunitinib malate and a newly synthesized tyrosine kinase (TK) inhibitor (compound 4). HCT116 CRC cells and BEAS-2B normal epithelial cells were treated with increasing concentrations of both agents in the presence or absence of RF exposure using a mobile RF device. Cell viability and death were assessed by MTT assay and flow cytometry (Annexin V/PI). RF exposure was associated with reduced viability and increased cell death in HCT116 cells (p < 0.05). Flow cytometric analysis confirmed that RF exposure may contribute to the observed reduction in viability. Notably, the findings suggest a possible beneficial contribution of RF hyperthermia to the observed cytotoxic effects, particularly near the IC50 concentration. In contrast, BEAS-2B cells maintained high viability with no significant changes (p > 0.05). These findings suggest that RF exposure may contribute to the observed cytotoxic responses in CRC cells while exerting limited effects on non-malignant cells, suggesting a promising strategy for targeted therapy.

Background: Metastatic pancreatic adenocarcinoma carries a dismal prognosis, and treatment options after progression on standard chemotherapy remain limited. We report a rapid metabolic response in a patient with drug-resistant disease treated with a combined multimodal regimen that paired dose-reduced (“activated”) multi-agent chemotherapy with targeted agents and metabolic/microenvironmental support, set against an unusually long overall survival. Case Presentation: A 46-year-old man was diagnosed with inoperable, locally advanced/stage IV pancreatic adenocarcinoma in June 2023 and maintained disease control for approximately 2.5 years on a combined multimodal regimen, termed here metabolically controlled oncologic therapy (MCOT): dose-reduced chemotherapy given with regional hyperthermia, hyperbaric oxygen, and a carbohydrate-restricted diet. In February 2026 he developed local recurrence and diffuse liver metastases, and by May 2026 had deteriorated rapidly, with 18F-FDG PET/CT showing a peak SUVmax of 18.2 and CA 19-9 of 2,788 U/mL. His regimen was intensified to a low-dose, multi-agent “activated” chemotherapy protocol combined with lenvatinib, everolimus, hyperthermia, and hyperbaric oxygen. Clinical findings and outcomes: One month later, his performance status had recovered from ECOG PS 2 to PS 0, CA 19-9 had fallen to 726 U/mL, and follow-up PET/CT showed a 63.7% decrease in SUVmax (from 18.2 to 6.6). The only adverse events were CTCAE v5.0 Grade 1 nausea and vomiting, with no Grade ≥2 toxicity. Conclusion: In selected patients who are considered to have exhausted standard options, a combined multimodal regimen pairing dose-reduced chemotherapy with metabolic and microenvironmental support may produce a rapid, well-tolerated metabolic response. As a single, uncontrolled observation, these findings cannot establish causality and require confirmation in prospective, controlled studies.

Breast cancer accounts for significant morbidity and mortality worldwide. Currently, treatment options in metastatic breast cancer consist of chemotherapy, along with endocrine, radiation, and/or biological therapies. Although advances in management have improved overall survival times, the treatment options for women with end-stage disease are mostly limited to supportive care. Herein, we present a case report that highlights the response of a 47-year-old premenopausal woman with end-stage (T4N3M1) breast cancer treated with metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT). The patient first noticed a right breast mass in late 2016, which was initially evaluated and ruled out as a cyst. Skin ulceration was observed in the region of the suspected cyst in May 2017. Subsequent bilateral breast ultrasound identified masses in both breasts and an enlarged right axillary lymph node. The diagnosis following biopsy was grade 3, estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor 2 negative (HER2-), invasive ductal carcinoma of the breast. Initially, the patient refused to receive conventional chemotherapy because of its potential for side effects and toxicity, but she sought medical treatment in August 2018 following extensive disease progression and deterioration of general health. On reevaluation, the patient was considered ineligible for conventional treatment due to her advanced end-stage disease, poor performance status (Eastern Cooperative Oncology Group score: 3), and advanced respiratory symptoms. Exploring other options, the patient was admitted to the ChemoThermia Oncology Center, Istanbul, Turkey in November 2018. At that time, the patient weighed 38 kg (body mass index: 18.1 kg/m²) and had extensive metastatic disease with lesions in the brain, lungs, mediastinum, liver, abdomen, and bones that were detected by magnetic resonance imaging of the brain (with contrast) and whole-body (18F)-fluorodeoxyglucose-positron emission tomography-computed tomography. The patient received a six-month treatment protocol comprised of MSCT, KD, HT, and HBOT, which eliminated all detectable lesions. The therapeutic response was sustained for two years with maintenance treatment comprising KD, dietary supplements, and repurposed medications. This single case report presents evidence of a complete and durable response to a treatment protocol combining MSCT and a novel metabolic therapy in a patient with end-stage breast cancer.

Aim: Systemic chemotherapy is a part of multi-modality treatment in patients with stage II-IV rectal cancer. In particular, patients not eligible for curative resection at the time of diagnosis require more efficient approaches to improve outcomes. Metabolically supported chemotherapy (MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor cell. This study aimed to examine the efficacy of MSCT combined with ketogenic diet, hyperthermia and hyperbaric oxygen therapy (HBOT) in patients with stage II-IV rectal cancer not eligible for surgery at baseline. Methods: Twenty-one patients diagnosed with stage II-IV rectal carcinoma who received metabolically supported chemotherapy (MSCT) combined with ketogenic diet, hyperthermia and HBOT were included. First-line chemotherapy regimen was oxaliplatin-based, whereas second line regimen was irinotecan-based. Overall survival and progression-free survival were estimated. Results: Mean duration of follow-up was 33.3±22.0 months. Mean overall survival was 58.6 months (95% CI, 43.3 - 73.9) and corresponding figure for progression-free survival was 45.1 months (95% CI, 28.9-61.2). Mean overall survival for patients with metastatic disease was 35.7 months. Multivariate analysis identified male gender and stage IV disease as independent predictors of worse progression free survival. No other parameter effected survival outcomes. Conclusion: Findings of this study are promising for potential use of this novel combinatorial protocol targeting multiple vulnerabilities of tumor cells in patients with advanced rectal cancer, particularly for patients with metastatic disease, without additional safety concerns. However, long term results are warranted to draw firm conclusion.

Ional treatment modalities targeting multiple tumor cell vulnerabilities. Materials and Methods: A total of 24 patients diagnosed with stage III–IV locally advanced or metastatic gastric adenocarcinoma that received metabolically supported chemotherapy (MSCT) combined with ketogenic diet, local hyperthermia, and hyperbaric oxygen therapy (HBOT) between April 2014 and October 2017 were included in this retrospective study. Survival outcomes were evaluated. Results: In 22 patients (88.0%), complete response was achieved. Mean duration of follow-up was 23.9 ± 12.7 months. Mean overall survival was 39.5 months (95% confidence interval [CI]: 28.1–51.0) and mean progression free survival was 36.5 months (95% CI: 25.7–47.2). No problems were encountered due to fasting, hypoglycemia, ketogenic diet, hyperthermia or HBOT. Conclusions: The combination treatment used in this study (MSCT together with a ketogenic diet, hyperthermia and HBOT) appears to be promising in the treatment of advanced gastric cancer. Further research and comparative clinical trials are warranted to support and standardize this novel treatment protocol....

Background: Despite introduction of new chemotherapeutic agents, outcomes of patients with metastatic pancreatic cancer are still poor. Metabolically supported chemotherapy (MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor cell. Objectives: This study aimed to examine the efficacy of metabolically supported administration of chemotherapy combined with ketogenic diet, hyperthermia, and hyperbaric oxygen therapy (HBOT) in patients with metastatic pancreatic cancer. Method: This retrospective observational study included 25 patients with metastatic pancreatic ductal carcinoma (stage IV) who received MSCT (either gemcitabine-based or FOLFIRINOX regimen administered concomitantly with induced hypoglycemia) plus ketogenic diet, hyperthermia, and HBOT combination. Survival outcomes were evaluated. Results: During the mean follow-up duration of 25.4 ± 19.3 months, median overall survival and median progression-free survival were 15.8 months (95% CI, 10.5–21.1) and 12.9 months (95% CI, 11.2–14.6), respectively. Age and gender did not have any effect on overall survival (p > 0.05 for all). Conclusions: MSCT administered together with ketogenic diet, hyperthermia, and HBOT appears to be a viable option with the potential to improve survival outcomes in patients diagnosed with metastatic pancreatic cancer. Further research, particularly with larger comparative clinical trials, is warranted.