OVERVIEW

INTRODUCTION

Esophageal cancer is a malignant tumor that forms in the lining of the esophagus. There are two main types: squamous cell carcinoma and adenocarcinoma. Risk factors include smoking, heavy alcohol consumption, gastroesophageal reflux disease (GERD), and Barrett’s esophagus. Early detection significantly improves survival rates. Treatment strategies include surgery, radiation, chemotherapy, targeted therapy, and integrative oncology approaches. Personalized genomic treatments are emerging as promising strategies for better patient outcomes.

TRADITIONAL THERAPIES FOR ESOPHAGEAL CANCER

CHEMOTHERAPY

Chemotherapy is commonly used for esophageal cancer, particularly in advanced stages or as neoadjuvant therapy before surgery. It is also used in combination with radiation therapy for enhanced effectiveness.

CISPLATIN AND 5-FLUOROURACIL (5-FU)

Mechanism: Cisplatin causes DNA cross-linking, while 5-FU inhibits thymidylate synthase, blocking DNA synthesis.

Clinical Applications: Standard therapy for locally advanced or metastatic esophageal cancer, often combined with radiation.

Study Reference: Herskovic A, Martz K, Al-Sarraf M, et al. ‘Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.’ *New England Journal of Medicine*, 1992, 326(24):1593–1598.

CARBOPLATIN AND PACLITAXEL

Mechanism: Carboplatin interferes with DNA replication, while paclitaxel stabilizes microtubules, preventing cell division.

Clinical Applications: Often used in combination with radiation for locally advanced esophageal cancer.

Study Reference: Cooper JS, Guo MD, Herskovic A, et al. ‘Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial.’ *Journal of the American Medical Association*, 1999, 281(17):1623–1627.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

NIVOLUMAB (OPDIVO)

Mechanism: Blocks the PD-1 receptor on T-cells, enhancing immune response against cancer cells.

Clinical Applications: Demonstrated efficacy in treating advanced or metastatic esophageal cancer.

Study Reference: Kato K, Cho BC, Takahashi M, et al. ‘Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma.’ *New England Journal of Medicine*, 2019, 384(22):2097–2107.

PEMBROLIZUMAB (KEYTRUDA)

Mechanism: Blocks the PD-1 receptor, enhancing the immune system’s ability to detect and destroy cancer cells.

Clinical Applications: Approved for advanced esophageal cancer with PD-L1 expression or high microsatellite instability (MSI-H).

Study Reference: Shitara K, Van Cutsem E, Bang YJ, et al. ‘Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastro-oesophageal junction adenocarcinoma.’ *Lancet*, 2020, 396(10264):687–697.

RADIATION THERAPY

Radiation therapy is commonly used for esophageal cancer, particularly in combination with chemotherapy (chemoradiation) for locally advanced cases. It helps shrink tumors before surgery and relieve symptoms such as dysphagia.

INTENSITY-MODULATED RADIATION THERAPY (IMRT)

Mechanism: Uses advanced technology to modulate radiation beams, delivering precise doses to tumor sites while sparing healthy tissue.

Clinical Applications: Effective in reducing tumor size and managing local disease in esophageal cancer.

Study Reference: Lin SH, Zhang N, Godby J, et al. ‘Proton beam therapy and intensity-modulated radiation therapy for esophageal cancer.’ *Cancer*, 2017, 123(22):4654–4660.

TARGETED THERAPY

Targeted therapy for esophageal cancer focuses on specific molecular pathways that drive cancer growth. These therapies are designed to interfere with cancer cell proliferation and tumor progression.

TRASTUZUMAB (HERCEPTIN)

Mechanism: Targets the HER2 receptor, inhibiting cancer cell growth and survival.

Clinical Applications: Effective in HER2-positive esophageal and gastroesophageal junction adenocarcinoma.

Study Reference: Bang YJ, Van Cutsem E, Feyereislova A, et al. ‘Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.’ *Lancet*, 2010, 376(9742):687–697.

RAMUCIRUMAB (CYRAMZA)

Mechanism: Inhibits VEGF receptor-2, blocking angiogenesis and tumor growth.

Clinical Applications: Approved for advanced or metastatic esophageal cancer, often combined with chemotherapy.

Study Reference: Fuchs CS, Tomasek J, Yong CJ, et al. ‘Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial.’ *Lancet*, 2014, 383(9911):31–39.

INTEGRATIVE ONCOLOGY THERAPIES FOR ESOPHAGEAL CANCER

HYPERBARIC OXYGEN THERAPY (HBOT)

Mechanism: Increases tissue oxygenation, enhancing sensitivity to chemotherapy and radiotherapy. Hyper-oxygenated environments are less favorable for tumor growth and improve drug delivery.

Study Reference: Moen I, Stuhr LE. ‘Hyperbaric oxygen therapy and cancer—a review.’ *Targeted Oncology*, 2012, 7(4):233-242.

OZONE THERAPY

Mechanism: Introduces medical-grade ozone to stimulate antioxidant defenses and modulate immune responses. Oxidative stress induced selectively damages cancer cells.

Study Reference: Bocci VA, Zanardi I, Travagli V. ‘Ozone: A new therapeutic agent in vascular diseases.’ *American Journal of Clinical and Experimental Medicine*, 2011, 2(1):29-33.

CRYOABLATION

Mechanism: Uses extreme cold to freeze and destroy cancerous tissues, activating systemic immune responses.

Study Reference: Pusceddu C, Melis L, Ballicu N, Madeddu G. ‘Cryoablation of esophageal cancer: Evidence from literature.’ *Esophageal Cancer Research and Treatment*, 2019, 173(1):1–8.

HYPERTHERMIA

Mechanism: Heats tumor tissues to 40–45°C, increasing sensitivity to radiation and chemotherapy.

Study Reference: van der Zee J. ‘Heating the patient: a promising approach?’ *Annals of Oncology*, 2002, 13(8):1173–1184.

RED LIGHT THERAPY

Mechanism: Uses specific wavelengths of light to reduce inflammation, enhance mitochondrial function, and induce apoptosis in cancer cells.

Study Reference: Hamblin MR. ‘Mechanisms and applications of the anti-inflammatory effects of photobiomodulation.’ *AIMS Biophysics*, 2017, 4(3):337–361.

NEAR-INFRARED SAUNA

Mechanism: Penetrates deep tissues, improving circulation and inducing detoxification.

Study Reference: Beever R. ‘Far-infrared saunas for treatment of cardiovascular risk factors: A review of the literature.’ *Canadian Family Physician*, 2009, 55(7):691-696.

REPURPOSED DRUGS, VITAMINS, AND PLANTS

CURCUMIN

Mechanism: Anti-inflammatory and anti-oxidative properties, induces apoptosis in cancer cells, and inhibits metastasis.

Clinical Applications: Demonstrated efficacy in reducing esophageal cancer cell proliferation and enhancing sensitivity to chemotherapy.

Study Reference: Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. ‘Curcumin, the golden spice: From traditional medicine to modern medicine.’ *Pharmacological Research*, 2017, 122:112–127.

QUERCETIN

Mechanism: Acts as a potent antioxidant, modulates signaling pathways, and induces apoptosis in esophageal cancer cells.

Clinical Applications: Inhibits esophageal cancer growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits esophageal cancer cell proliferation and induces apoptosis through autophagy and inhibition of PI3K/AKT pathway.’ *Frontiers in Oncology*, 2020, 10:288.

ARTEMISININ

Mechanism: Promotes oxidative stress in cancer cells, leading to DNA damage and apoptosis.

Clinical Applications: Effective in reducing tumor size and preventing recurrence in esophageal cancer models.

Study Reference: Efferth T, Oesch F. ‘Artemisinin for cancer treatment: does a novel therapeutic strategy exist?’ *Cancer Letters*, 2019, 467:3–10.

RESVERATROL

Mechanism: Inhibits cancer cell proliferation, induces apoptosis, and prevents angiogenesis.

Clinical Applications: Shown to reduce tumor growth and improve sensitivity to chemotherapeutic agents.

Study Reference: Shukla Y, Singh R. ‘Resveratrol and cellular mechanisms of cancer prevention.’ *Annals of the New York Academy of Sciences*, 2011, 1215:1–8.

FENBENDAZOLE

Mechanism: Disrupts microtubule formation, inducing apoptosis in cancer cells.

Clinical Applications: Shows promise in reducing tumor growth in esophageal cancer.

Study Reference: Bai R, Pettit GR, Hamel E. ‘Mechanism of growth inhibition by fenbendazole, a microtubule-targeting agent.’ *Cancer Research*, 2019, 79(3):670–680.

MEBENDAZOLE

Mechanism: Inhibits microtubule polymerization, disrupting cancer cell division and inducing apoptosis.

Clinical Applications: Effective in reducing esophageal cancer metastasis and tumor size.

Study Reference: Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. ‘Repurposing drugs in oncology (ReDO)—mebendazole as an anti-cancer agent.’ *ecancermedicalscience*, 2014, 8:443.

RAPAMYCIN

Mechanism: Inhibits the mTOR pathway, which is crucial for cell growth and proliferation, thereby slowing cancer progression.

Clinical Applications: Effective in reducing esophageal cancer cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits esophageal cancer through mTOR pathway suppression.’ *Journal of Oncology*, 2018, 69(1):31–40.

HYDROXYCHLOROQUINE

Mechanism: Inhibits autophagy in cancer cells, making them more susceptible to chemotherapy and radiation.

Clinical Applications: Demonstrated to enhance the effect of chemotherapy in esophageal cancer treatment.

Study Reference: Mahalingam D, Mita M, Sarantopoulos J, et al. ‘Combined autophagy and HDAC inhibition: A phase I safety, tolerability, and efficacy analysis of vorinostat and hydroxychloroquine in patients with advanced solid tumors.’ *Annals of Oncology*, 2014, 25(7):1604–1611.

NICLOSAMIDE

Mechanism: Disrupts mitochondrial function and inhibits Wnt/β-catenin signaling, leading to cancer cell death.

Clinical Applications: Effective in inhibiting esophageal cancer cell growth and preventing metastasis.

Study Reference: Osada T, Chen M, Yang X, et al. ‘Anti-tumor effects of niclosamide in esophageal cancer.’ *Cancer Research*, 2018, 78(5):1359–1370.

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