OVERVIEW

INTRODUCTION

Pancreatic cancer is one of the most aggressive forms of cancer, often diagnosed at an advanced stage. It primarily arises from exocrine cells, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Early detection remains challenging due to vague symptoms, leading to poor survival rates. Advanced treatments, including chemotherapy, immunotherapy, and integrative oncology approaches, are utilized to improve outcomes.

TRADITIONAL THERAPIES FOR PANCREATIC CANCER

CHEMOTHERAPY

Chemotherapy is the mainstay of treatment for advanced pancreatic cancer. It is often used in combination with other modalities to extend survival and manage symptoms.

FOLFIRINOX

Mechanism: A combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin that disrupts DNA replication and induces apoptosis.

Clinical Applications: First-line treatment for metastatic pancreatic cancer with good performance status.

Study Reference: Conroy T, Desseigne F, Ychou M, et al. ‘FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.’ *New England Journal of Medicine*, 2011, 364(19):1817–1825.

GEMCITABINE

Mechanism: Inhibits DNA synthesis by mimicking nucleosides, blocking cellular replication.

Clinical Applications: Standard treatment for advanced pancreatic cancer, often combined with nab-paclitaxel.

Study Reference: Von Hoff DD, Ervin T, Arena FP, et al. ‘Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.’ *New England Journal of Medicine*, 2013, 369(18):1691–1703.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

PEMBROLIZUMAB (KEYTRUDA)

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

Clinical Applications: Effective in treating metastatic pancreatic cancer with mismatch repair deficiency (dMMR).

Study Reference: Le DT, Durham JN, Smith KN, et al. ‘Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.’ *Science*, 2017, 357(6349):409–413.

NIVOLUMAB (OPDIVO)

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

Clinical Applications: Demonstrated promise in clinical trials for advanced pancreatic cancer when combined with other therapies.

Study Reference: Brahmer JR, Tykodi SS, Chow LQ, et al. ‘Safety and activity of anti–PD-L1 antibody in patients with advanced cancer.’ *New England Journal of Medicine*, 2012, 366(26):2455–2465.

RADIATION THERAPY

Radiation therapy is commonly used in pancreatic cancer to shrink tumors and manage symptoms. It is often combined with chemotherapy to enhance treatment effectiveness.

STEREOTACTIC BODY RADIATION THERAPY (SBRT)

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

Clinical Applications: Effective in local control of unresectable pancreatic tumors.

Study Reference: Herman JM, Chang DT, Goodman KA, et al. ‘Phase 2 multi-institutional trial evaluating stereotactic body radiation therapy for locally advanced pancreatic cancer.’ *Journal of Clinical Oncology*, 2015, 33(17):1927–1934.

TARGETED THERAPY

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

ERLOTINIB (TARCEVA)

Mechanism: Inhibits epidermal growth factor receptor (EGFR), preventing cell proliferation and survival.

Clinical Applications: Combined with gemcitabine for advanced pancreatic cancer.

Study Reference: Moore MJ, Goldstein D, Hamm J, et al. ‘Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.’ *Journal of Clinical Oncology*, 2007, 25(15):1960–1966.

OLAPARIB (LYNPARZA)

Mechanism: Inhibits PARP enzymes, enhancing DNA damage in cancer cells with BRCA1/2 mutations.

Clinical Applications: Maintenance therapy for metastatic pancreatic cancer with BRCA mutations after chemotherapy.

Study Reference: Golan T, Hammel P, Reni M, et al. ‘Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.’ *New England Journal of Medicine*, 2019, 381(4):317–327.

INTEGRATIVE ONCOLOGY THERAPIES FOR PANCREATIC 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 pancreatic cancer: Evidence from literature.’ *Pancreatic 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 pancreatic 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 pancreatic cancer cells.

Clinical Applications: Inhibits pancreatic cancer growth and prevents metastasis.

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

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

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

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