OVERVIEW

INTRODUCTION

Liver cancer, primarily hepatocellular carcinoma (HCC), is one of the leading causes of cancer-related deaths worldwide. It is commonly associated with chronic liver diseases, including hepatitis B, hepatitis C, and cirrhosis. Early detection is critical for curative options such as resection or liver transplantation. For advanced stages, a combination of chemotherapy, targeted therapy, immunotherapy, and integrative oncology approaches are employed.

TRADITIONAL THERAPIES FOR LIVER CANCER

CHEMOTHERAPY

Chemotherapy is used primarily in advanced liver cancer cases where surgical options are not viable. Due to the liver’s unique structure and detoxification role, systemic chemotherapy is less commonly used.

DOXORUBICIN

Mechanism: Interferes with DNA replication and induces apoptosis by inhibiting topoisomerase II.

Clinical Applications: Primarily used in transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).

Study Reference: Llovet JM, Real MI, Montaña X, et al. ‘Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.’ *Lancet*, 2002, 359(9319):1734–1739.

CISPLATIN

Mechanism: Forms DNA cross-links, disrupting DNA replication and inducing apoptosis in cancer cells.

Clinical Applications: Used in combination therapy for advanced HCC, particularly in TACE protocols.

Study Reference: Takayasu K, Arii S, Ikai I, et al. ‘Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients.’ *Gastroenterology*, 2006, 131(2):461–469.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

NIVOLUMAB (OPDIVO)

Mechanism: Inhibits the PD-1 checkpoint pathway, enhancing T-cell function and anti-tumor activity.

Clinical Applications: Effective in advanced hepatocellular carcinoma (HCC) following sorafenib treatment.

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

PEMBROLIZUMAB (KEYTRUDA)

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

Clinical Applications: Used for unresectable or metastatic hepatocellular carcinoma following progression on sorafenib.

Study Reference: Zhu AX, Finn RS, Edeline J, et al. ‘Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.’ *Lancet Oncology*, 2018, 19(7):940–952.

RADIATION THERAPY

Radiation therapy is less commonly used for liver cancer due to the sensitivity of healthy liver tissue. However, advanced techniques like stereotactic body radiation therapy (SBRT) allow for precise targeting of tumors.

STEREOTACTIC BODY RADIATION THERAPY (SBRT)

Mechanism: Delivers high doses of radiation to liver tumors while sparing surrounding tissue.

Clinical Applications: Effective in local control of small hepatocellular carcinoma (HCC) lesions.

Study Reference: Bujold A, Massey CA, Kim JJ, et al. ‘Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma.’ *Journal of Clinical Oncology*, 2013, 31(13):1631–1639.

TARGETED THERAPY

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

SORAFENIB (NEXAVAR)

Mechanism: Inhibits multiple kinases involved in tumor cell proliferation and angiogenesis.

Clinical Applications: First-line therapy for advanced hepatocellular carcinoma (HCC).

Study Reference: Llovet JM, Ricci S, Mazzaferro V, et al. ‘Sorafenib in advanced hepatocellular carcinoma.’ *New England Journal of Medicine*, 2008, 359(4):378–390.

LENVATINIB (LENVIMA)

Mechanism: Blocks VEGF receptors and tyrosine kinases, inhibiting tumor angiogenesis and growth.

Clinical Applications: Alternative first-line therapy to sorafenib for unresectable hepatocellular carcinoma.

Study Reference: Kudo M, Finn RS, Qin S, et al. ‘Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.’ *Lancet*, 2018, 391(10126):1163–1173.

INTEGRATIVE ONCOLOGY THERAPIES FOR LIVER 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 cancer: 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.

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 liver 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 liver cancer cells.

Clinical Applications: Inhibits liver cancer growth and prevents metastasis.

Study Reference: Shan X, Zhou J, Ma T, et al. ‘Quercetin inhibits liver 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 liver 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 hepatocellular carcinoma.

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 liver 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 liver cancer cell growth and enhancing sensitivity to chemotherapy.

Study Reference: Jiang H, Shen Z, Luo H, et al. ‘Rapamycin inhibits hepatocellular carcinoma through mTOR pathway suppression.’ *Journal of Hepatology*, 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 liver 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 liver cancer cell growth and preventing metastasis.

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

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