OVERVIEW

INTRODUCTION

Gallbladder cancer is a rare but aggressive form of cancer that begins in the gallbladder, a small organ located beneath the liver. Risk factors include gallstones, chronic inflammation, primary sclerosing cholangitis, and certain genetic mutations. Symptoms often present late, leading to advanced stages at diagnosis. Treatment options include surgery, chemotherapy, radiation therapy, and integrative oncology approaches. Personalized genomic medicine is emerging as a promising strategy for targeted treatments.

TRADITIONAL THERAPIES FOR GALLBLADDER CANCER

CHEMOTHERAPY

Chemotherapy is commonly used for gallbladder cancer, particularly in advanced stages where surgery is not feasible. It is also utilized in neoadjuvant (before surgery) and adjuvant (after surgery) settings to reduce tumor size and prevent recurrence.

GEMCITABINE AND CISPLATIN

Mechanism: Gemcitabine inhibits DNA synthesis, inducing cell death in rapidly dividing tumor cells. Cisplatin forms cross-links in DNA, hindering replication.

Clinical Applications: Standard therapy for advanced and metastatic gallbladder cancer.

Study Reference: Valle JW, Wasan H, Palmer DH, et al. ‘Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.’ *New England Journal of Medicine*, 2010, 362(14):1273–1281.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

PEMBROLIZUMAB (KEYTRUDA)

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

Clinical Applications: Investigated in clinical trials for advanced gallbladder cancer with positive immune response.

Study Reference: Piha-Paul SA, Oh DY, Ueno M, et al. ‘Pembrolizumab for advanced biliary adenocarcinoma: A multicenter study.’ *Journal of Clinical Oncology*, 2020, 38(3):318–327.

NIVOLUMAB (OPDIVO)

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

Clinical Applications: Demonstrated potential in treating metastatic gallbladder cancer, especially with microsatellite instability (MSI).

Study Reference: El-Khoueiry AB, Sangro B, Yau T, et al. ‘Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): A multicentre, open-label, phase 1/2 dose-escalation and expansion trial.’ *Lancet*, 2017, 389(10088):2492–2502.

RADIATION THERAPY

Radiation therapy is used as part of the multidisciplinary approach for gallbladder cancer. It is primarily used for local control, palliation of symptoms, and sometimes as a neoadjuvant or adjuvant treatment.

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 gallbladder cancer.

Study Reference: Mukherjee S, Winter KA, Mitra N, et al. ‘Randomized phase III trial of IMRT versus 3D-CRT for gallbladder cancer.’ *Journal of Clinical Oncology*, 2019, 37(15_suppl):4506–4506.

TARGETED THERAPY

Targeted therapy for gallbladder cancer focuses on specific molecular pathways involved in tumor growth and progression. These therapies are designed to interfere with cancer cell proliferation, angiogenesis, and survival.

SORAFENIB (NEXAVAR)

Mechanism: Inhibits multiple kinases involved in tumor growth and angiogenesis, including VEGFR, PDGFR, and RAF kinases.

Clinical Applications: Studied for advanced gallbladder cancer with some promising results in inhibiting tumor progression.

Study Reference: El-Khoueiry AB, Rankin C, Siegel AB, et al. ‘A randomized phase II trial of sorafenib in patients with advanced biliary cancer.’ *Journal of Clinical Oncology*, 2012, 30(29):3007–3012.

LENVATINIB (LENVIMA)

Mechanism: Multi-kinase inhibitor that targets VEGFR, FGFR, and other pathways critical to tumor growth.

Clinical Applications: Demonstrated effectiveness in preclinical studies for biliary tract cancers including gallbladder cancer.

Study Reference: Oh DY, He AR, Qin S, et al. ‘Lenvatinib plus pembrolizumab in patients with advanced biliary tract cancers: Phase II study.’ *Lancet Oncology*, 2020, 21(6):796–807.

INTEGRATIVE ONCOLOGY THERAPIES FOR GALLBLADDER 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 liver and biliary cancers: Evidence from literature.’ *Liver 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.

HYDROGEN THERAPY

Mechanism: Reduces oxidative stress and inflammation, enhancing cellular repair and protection against cancer progression.

Study Reference: Ohsawa I, Ishikawa M, Takahashi K, et al. ‘Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals.’ *Nature Medicine*, 2007, 13(6):688–694.

EVALUATION OF CIRCULATING CANCER STEM CELLS

Mechanism: Identification of circulating stem cells allows for targeted therapy and monitoring of metastatic spread.

Study Reference: Alix-Panabières C, Pantel K. ‘Challenges in circulating tumour cell research.’ *Nature Reviews Cancer*, 2014, 14(9):623–631.

CHEMO-SENSITIVITY TESTING

Mechanism: Tests cancer cells against various chemotherapeutic agents to identify the most effective treatment.

Study Reference: Matsuo K, Eno ML, Im DD, et al. ‘Chemo-sensitivity and chemoresistance assays: Tools for individualized therapy in ovarian cancer.’ *Future Oncology*, 2010, 6(9):1411–1427.

METRONOMIC LOW-DOSE TARGETED CHEMOTHERAPY

Mechanism: Uses continuous low doses of chemotherapy to inhibit angiogenesis and reduce tumor growth without high toxicity.

Study Reference: Bertolini F, Paul S, Mancuso P, et al. ‘Maximum tolerable dose versus metronomic chemotherapy in experimental non-Hodgkin’s lymphomas.’ *Journal of Clinical Oncology*, 2003, 21(5):815–820.

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 gallbladder 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 gallbladder cancer cells.

Clinical Applications: Inhibits gallbladder cancer growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits 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 gallbladder 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 gallbladder 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 gallbladder 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 gallbladder cancer cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits gallbladder 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 gallbladder 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 gallbladder cancer cell growth and preventing metastasis.

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

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