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Medical Students 2011 - N. Pavlidis - INTRODUCTION TO CANCER TREATMENT- Basics in Systemic Treatment
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Medical Students 2011 - N. Pavlidis - INTRODUCTION TO CANCER TREATMENT- Basics in Systemic Treatment

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  • The original hypothesis for Iressa was that in a number of tumours EGFR expression was associated with a poor prognosis and that inhibition of the enzyme would have a number of effects that would impact on tumour growth. This hypothesis was supported by preclinical data.
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    • 1. Principles of Systemic Therapy in Cancer N. PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF IOANNINA GREECE ESO COURSE IOANNINA, JULY 2011
    • 2. Principles of …
      • Chemotherapy
      • Endocrine therapy
      • Immunotherapy
      • Targeting therapy
    • 3. INTRODUCTION TO CHEMOTHERAPY
    • 4. ALKYLATING AGENTS Mechanism of action : Target DNA, produce alkylation through formation of intermediates. No phase-specific drugs Busulfan Chlorambucil Cisplatin, Carboplatin, Oxaliplatin Cyclophosphamide, Ifosfamide Dacarbazine Mechlorethamine (Nitrogen Mustard) Melphalan Nitrosoureas Procarbazine Streptozotocin Temozolomide Thiotepa
    • 5. ANTIMETABOLITES Mechanism of action : Interfere with DNA synthesis. They are structural analogs or they inhibit several enzymes. S-phase specific Aracytidine Cytarabin Fludarabine Fluorouracil Leucovorin Capecitabine Gemcitabine Hydroxyurea Mercaptopurine Methotrexate Pemetrexed Pentostatin Raltitrexed Thioguanine Trimetrexate Uracil / Tegafur (UFT)
    • 6. ANTITUMOR ANTIBIOTICS Mechanism of action : A variety of mechanisms. They are derived from microorganisms. Cell cycle specific drugs Actinomycin-D Bleomycin Daunorubicin Doxorubicin Doxorubicin Liposomal Epirubicin Idarubicin Mitomycin Mitoxantrone
    • 7. MITOTIC SPINDLE AGENTS Mechanism of action : Bind to microtubular proteins, thus inhibit microtubule assembly resulting in dissolution of the mitotic assembly structure. M- phase specific drugs. Docetaxel Paclitaxel Vinblastine Vincristine Vindesine Vinorelbine
    • 8. TOPOISOMERASE INHIBITORS Mechanism of action : DNA Topoisomerases I and II are essential enzymes for transcription, replication and mitosis. The following drugs are able to inhibit these enzymes. Topoisomerease I inhibitors Irinotecan Topotecan Topoisomerase II inhibitors Etoposide Teniposide
    • 9. MISCELLANEOUS AGENTS Asparaginase Estramustine Hexamethymelamine Octreotide Velcade
    • 10. MODES OF CHEMOTHERAPY ADMINISTRATION
      • Intravenously
      • Intramuscularly
      • Orally
      • Local Drug Application
      • Intra-arterially (i.e. hepatic infusion, limb perfusion)
      • Intra-thecally
      • Intra-peritoneally
      • Intra-pleuraly
    • 11. PRINCIPLES OF COMBINATION CHEMOTHERAPY
      • Use drugs active as a single agent
      • Use drugs with different mechanisms of action
      • Use drugs with different mechanisms of resistance
      • Use drugs with different side-effects
      • Be aware of drug-drug interactions
    • 12. SYSTEMIC CHEMOTHERAPY NEOADJUVANT CHEMOTHERAPY [PREOPERATIVELY] Rationale
      • To make non-operable tumors operable
      • To achieve organ preservation
      • To select sensitivity for specific treatment (biomarkers)
      ADJUVANT CHEMOTHERAPY [POSTOPERATIVELY] Rationale
      • To kill micrometastatic disease
      • To increase disease-free survival
      THERAPY FOR METASTATIC DISEASE Rationale
      • Palliative intent (symptoms control)
      • To prolong survival
    • 13. CHEMOTHERAPY CAN ALSO BE GIVEN AS :
      • Dose Intensification Treatment
      • Strategy to overcome drug resistance through:
      • (i) highest possible dose
      • (ii) shortest possible intervals
      • (iii) with supportive use of G-CSF
      • High Dose Chemotherapy
      • Marrow-ablative doses of chemotherapy to increase tumor cell-kill, while rescuing the host with:
      • (i) autologous bone marrow
      • (ii) donor bone marrow
      • (iii) peripheral stem-cells
      • Metronomic Chemotherapy
      • Oral chronic administration of chemotherapy (i.e. cyclophosphamide, etoposide, vinorelbine) has both antitumorigenic and antiangiogenic effect on tumor endothelial tumor cell. Endothelial cells are 10-100 times more susceptible to chemotherapy.
    • 14. PARAMETERS TO BE EVALUATED IN SYSTEMIC TREATMENTS
      • COMPLETE RESPONSE (CR) : 100% disappearance of clinical and/or laboratory markers
      • PARTIAL RESPONSE (PR) :  50% disappearance of clinical and / or laboratory markers
      • STABLE DISEASE (SD) : Stability of markers (  3 months)
      • PROGRESSION OF DISEASE (PD) : Progression of markers during treatment, up to 25% or appearance of new lesions
      • DURATION OF RESPONSE : the time from response to
      • OR TIME TO PROGRESSION (TTP) progression
      R ESPONSE
    • 15.
      • DISEASE-FREE SURVIVAL (DFS) : From the time of treatment to first recurrence
      • OVERALL SURVIVAL (OS) : From the time of diagnosis to death
      PARAMETERS TO BE EVALUATED IN SYSTEMIC TREATMENTS S URVIVAL
    • 16.  
    • 17. CHEMOTHERAPY TOXICITIES ( I ) Bone m arrow s uppression (anemia, leucopenia, thrombocytopenia) Almost all Erythropoietin, G-CSF, blood transfusions TOXICITY DRUG INDUCED ANTIDOTE Nausea- v omiting Platinum Anthracyclines Alkylating s Centrones (serotonin block): granisetron , ondasetron Alopecia Anthracyclines Taxanes Scalp-cooling techniques (not universally accepted) Cardiotoxicity Anthracyclines Cyclophosphamide 5-FU Early detection . Dexrazoxane
    • 18. CHEMOTHERAPY TOXICITIES ( II ) Pulmonary toxicity Bleom y c i n Alkylating s Gemcitabine Early detection . Corticosteroids Nephrotoxicity Platinum Methotrexate (↑dose) Adequate hydration Neurotoxicity Alkaloids Platinum Taxanes Early detection Gonadal d amage Alkylatings Others Sperm preservation Second m alignancies Alkylating s Avoid if possible responsible drugs and/or RT in curable diseases
    • 19. INTRODUCTION TO ENDOCRINE THERAPY (HORMONAL AGENTS)
    • 20. Endocrine therapy
      • Some cancers (eg. breast, prostate) require hormonal stimuli for their growth.
      • Specific receptors present on cell surface and nuclei.
      • Blocking these receptors will, theoretically result in blocking of cell division and therefore, tumour growth arrest.
    • 21. ANTIESTROGENS
      • Indication : Breast cancer
      • Tamoxifen
      • Toremifene
      • Raloxifene
      • Fulvestrant
      Mechanism of action : Occupy estrogen receptors. ANTIESTROGENS
    • 22.
      • Indications : Breast cancer, endometrial cancer
      • Medroxyprogesterone acetate
      • Megestrol
      Mechanism of action : Occupy progesterone receptors . PROGESTINS
    • 23. AROMATASE INHIBITORS
      • Indication : Breast cancer
      • Anastrazole
      • Exemestane
      • Letrozole
      Mechanism of action : Reduce estrogen levels by interfering with aromatase which converts androstendione to estrone and then to estradiol
    • 24. LUTEINIZING HORMONE – RELEASING HORMONE (LHRH AGONISTS)
      • Indication : Prostate cancer and breast cancer
      • Goserelin
      • Leuprorelin
      • Triptorelin
      Mechanism of action : Reduce estrogen levels by inhibiting gonadotrophin release from the pituitary
    • 25. ANTIANDROGENS
      • Indication : Prostate cancer
      • Bicalutamide
      • Flutamide
      • Nilutamide
      Mechanism of action : Inhibit the uptake and binding of androgens in target tissues.
    • 26.
      • INTRODUCTION TO
      • IMMUNOTHERAPY
    • 27. CYTOKINES
      • Indications : CML, hairy cell-leukemia, cutaneous T-cell lymphomas, renal cancer, melanoma
      • Interferon –a
      • Interleukin – 2
      • Tumour necrosis factor
      Mechanisms of action : Activation of NK cells, of cytotoxic T-lymphocytes, induction of MHC class I, antiviral, antitumor and antiproliferative activities.
    • 28.
      • INTRODUCTION TO
      • TARGETING THERAPY
    • 29.  
    • 30. MONOCLONAL ANTIBODIES
        • Directed against CD 20 antigen of B lymphocytes
        • For B-cell lymphomas
      Mechanism of action : Attack certain cell targets RITUXIMAB (Mabthera)
    • 31.
      • Binds to the extracellular domain of HER 2 (or c-erb-B2) transmembrane receptor protein.
      HER-2 : 17%-30% TRASTUZUMAB (Herceptin)
      • For breast cancer that overexpresses HER 2 protein
    • 32.
      • Blocks the action of vascular endothelial growth factor (VEGF)
      • For colorectal cancer,
        • renal cancer
        • breast cancer
        • NSCLC
        • brain tumours
      BEVACIZUMAB (Avastin)
    • 33.
      • Against EGFR receptor
      • For colorectal cancer
      • head – neck cancer
      CETUXIMAB (Erbitux)
    • 34. SMALL MOLECULES AND INTRACELLULAR SIGNAL TRANSDUCTION TYROSINE KINASE INHIBITORS
    • 35.
      • Potent selective inhibitor of the P210 BCR-ABL tyrosine kinase (occupies the ATP binding site of the BCR-ABL protein resulting in induction of apoptosis). Inhibits also receptor kinases for PDGFR, stem cell factor and c-kit .
      • For CML
      • Gastrointestinal
      • Stromal Tumors (GIST)
      IMATINIB (Gleevec)
    • 36. ERLOTINIB (Tarceva) / GEFITINIB (Iressa) Invasion Metastasis Growth Factor Secretion B1 B1 Cell Membrane Nucleus TKI Antibody
        • Inhibits tyrosine kinases associated with transmembrane cell surface receptors, including the EGFR.
        • For NSCLC
      Anti-Apoptosis Proliferation
    • 37.
      • Multitaeget tyrosinase kinase inhibitor of c-Kit, PDGFR, VEGF and FLT3
      • For renal cancer
      • GIST
      SUNITINIB (Sutent)
    • 38.
      • Multikinase inhibitor affecting VEGF receptors 1,2 and 3, PDGF- β , FMS-like tyrosine kinase 3 (Flt-3), c-KIT protein and RET receptor tyrosine kinase.
      • For renal cancer
      SORAFENIB (Nexavar)
    • 39.
      • Binds to and inhibits mTOR.
      • mTOR is a serine / threonine kinase of the P13K/AKT pathway
      • For renal cancer
      TEMSIROLIMUS (Torisel)
    • 40.
      • It is a tyrosine kinase inhibitor
      • Inhibits both EGFR / ErbB1 and HER-2 / ErbB2 tyrosine kinases
      • For breast cancer
      LAPATINIB (Tykerb)
    • 41.
      • T HANK Y OU

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