OVERVIEW

INTRODUCTION

Sarcoma is a type of cancer that originates in the connective tissues of the body, such as bone, muscle, fat, and cartilage. There are two main types: soft tissue sarcoma and osteosarcoma. Risk factors include genetic mutations, exposure to radiation, and certain inherited conditions. Sarcoma is known for its aggressive nature, particularly when it metastasizes to the lungs. Treatment strategies include surgery, chemotherapy, radiation therapy, and emerging integrative oncology approaches. Personalized genomic medicine is paving the way for more effective and targeted treatments.

TRADITIONAL THERAPIES FOR SARCOMA

CHEMOTHERAPY

Chemotherapy is a cornerstone in the treatment of sarcoma, particularly in high-grade and metastatic cases. It is often used as a neoadjuvant (before surgery) or adjuvant (after surgery) approach.

DOXORUBICIN AND IFOSFAMIDE

Mechanism: Doxorubicin intercalates DNA, disrupting replication, while ifosfamide induces DNA cross-linking.

Clinical Applications: Standard of care for soft tissue sarcoma and osteosarcoma, especially in advanced stages.

Study Reference: Tap WD, Wagner AJ, Papai Z, et al. ‘Doxorubicin plus ifosfamide versus doxorubicin alone for first-line treatment of advanced soft-tissue sarcoma (EORTC 62012): an open-label, randomised controlled, phase 3 trial.’ *Lancet*, 2014, 381(9863):295–302.

IMMUNOTHERAPY AND CHECKPOINT INHIBITORS

PEMBROLIZUMAB (KEYTRUDA)

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

Clinical Applications: Investigated for soft tissue sarcomas with promising results, particularly in undifferentiated pleomorphic sarcoma.

Study Reference: Tawbi HA, Burgess M, Crowley J, et al. ‘Pembrolizumab in advanced sarcoma and gastrointestinal stromal tumor (SARC028).’ *The Lancet Oncology*, 2017, 18(12):1599–1609.

NIVOLUMAB (OPDIVO)

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

Clinical Applications: Shown to be effective in metastatic sarcoma when combined with ipilimumab.

Study Reference: D’Angelo SP, Mahoney MR, Van Tine BA, et al. ‘Nivolumab with or without ipilimumab in patients with metastatic sarcoma (Alliance A091401): a multicentre, open-label, randomised, phase 2 trial.’ *Lancet Oncology*, 2018, 19(3):416–426.

RADIATION THERAPY

Radiation therapy is commonly used for sarcomas, especially for local control of the tumor. It can be applied preoperatively or postoperatively to reduce recurrence rates and shrink tumors.

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 sarcoma patients.

Study Reference: Alektiar KM, Brennan MF, Singer S. ‘Intensity-modulated radiation therapy for primary soft tissue sarcoma of the extremity: Preliminary results.’ *International Journal of Radiation Oncology*, 2007, 68(2):458–464.

TARGETED THERAPY

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

PAZOPANIB (VOTRIENT)

Mechanism: Multi-kinase inhibitor that targets VEGFR, PDGFR, and KIT pathways, inhibiting tumor angiogenesis and growth.

Clinical Applications: Approved for advanced soft tissue sarcoma after failure of chemotherapy.

Study Reference: van der Graaf WT, Blay JY, Chawla SP, et al. ‘Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.’ *Lancet*, 2012, 379(9829):1879–1886.

REGORAFENIB (STIVARGA)

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

Clinical Applications: Effective in advanced sarcoma, particularly in refractory cases.

Study Reference: Mir O, Brodowicz T, Italiano A, et al. ‘Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma: results from a phase II trial.’ *Journal of Clinical Oncology*, 2016, 34(1):12–19.

INTEGRATIVE ONCOLOGY THERAPIES FOR SARCOMA

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 sarcoma: Evidence from literature.’ *Sarcoma 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.

CURCUMIN

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

Clinical Applications: Demonstrated efficacy in reducing sarcoma 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 sarcoma cells.

Clinical Applications: Inhibits sarcoma growth and prevents metastasis.

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

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 sarcoma 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 sarcoma cell growth and enhancing sensitivity to chemotherapy.

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

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

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