Principles  of  Systemic Therapy in  Cancer N. PAVLIDIS PROFESSOR  OF  MEDICAL  ONCOLOGY  UNIVERSITY  OF  IOANNINA  GREECE...
Principles  of   … <ul><li>Chemotherapy </li></ul><ul><li>Endocrine therapy </li></ul><ul><li>Immunotherapy  </li></ul><ul...
INTRODUCTION  TO   CHEMOTHERAPY
ALKYLATING  AGENTS Mechanism  of action : Target DNA, produce alkylation through formation of intermediates. No phase-spec...
ANTIMETABOLITES Mechanism  of action   : Interfere with DNA synthesis. They are structural analogs or they inhibit several...
ANTITUMOR  ANTIBIOTICS Mechanism of action  : A variety of mechanisms. They are derived from microorganisms. Cell cycle sp...
MITOTIC  SPINDLE  AGENTS Mechanism of action : Bind to microtubular proteins, thus inhibit microtubule assembly resulting ...
TOPOISOMERASE  INHIBITORS Mechanism of action : DNA Topoisomerases I and II are essential enzymes for transcription, repli...
MISCELLANEOUS  AGENTS Asparaginase  Estramustine Hexamethymelamine Octreotide Velcade
MODES  OF  CHEMOTHERAPY  ADMINISTRATION <ul><li>Intravenously </li></ul><ul><li>Intramuscularly </li></ul><ul><li>Orally <...
PRINCIPLES  OF  COMBINATION  CHEMOTHERAPY <ul><li>Use  drugs  active as a single agent </li></ul><ul><li>Use drugs with di...
SYSTEMIC  CHEMOTHERAPY  NEOADJUVANT  CHEMOTHERAPY  [PREOPERATIVELY] Rationale  <ul><li>To make non-operable tumors operabl...
CHEMOTHERAPY  CAN  ALSO  BE  GIVEN  AS :  <ul><li>Dose  Intensification  Treatment   </li></ul><ul><li>Strategy to overcom...
PARAMETERS  TO  BE  EVALUATED  IN  SYSTEMIC  TREATMENTS   <ul><li>COMPLETE  RESPONSE  (CR)   :  100%  disappearance of cli...
<ul><li>DISEASE-FREE  SURVIVAL  (DFS)   : From the time of treatment to    first  recurrence </li></ul><ul><li>OVERALL  SU...
 
CHEMOTHERAPY  TOXICITIES   ( I ) Bone  m arrow  s uppression   (anemia, leucopenia,  thrombocytopenia) Almost all Erythrop...
CHEMOTHERAPY  TOXICITIES   ( II ) Pulmonary  toxicity Bleom y c i n Alkylating s Gemcitabine Early   detection .  Corticos...
INTRODUCTION  TO  ENDOCRINE  THERAPY  (HORMONAL  AGENTS)
Endocrine  therapy <ul><li>Some cancers (eg. breast, prostate) require hormonal stimuli for their growth. </li></ul><ul><l...
ANTIESTROGENS <ul><li>Indication :  Breast  cancer </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Toremifene </li></ul><ul>...
<ul><li>Indications  : Breast  cancer, endometrial  cancer </li></ul><ul><li>Medroxyprogesterone acetate </li></ul><ul><li...
AROMATASE   INHIBITORS <ul><li>Indication  : Breast  cancer </li></ul><ul><li>Anastrazole </li></ul><ul><li>Exemestane </l...
LUTEINIZING  HORMONE –  RELEASING  HORMONE (LHRH  AGONISTS)   <ul><li>Indication : Prostate cancer and breast  cancer </li...
ANTIANDROGENS  <ul><li>Indication   : Prostate cancer </li></ul><ul><li>Bicalutamide </li></ul><ul><li>Flutamide </li></ul...
<ul><li>INTRODUCTION  TO  </li></ul><ul><li>IMMUNOTHERAPY  </li></ul>
CYTOKINES <ul><li>Indications   :  CML, hairy cell-leukemia, cutaneous T-cell    lymphomas, renal cancer, melanoma </li></...
<ul><li>INTRODUCTION  TO  </li></ul><ul><li>TARGETING  THERAPY  </li></ul>
 
MONOCLONAL  ANTIBODIES <ul><ul><li>Directed  against  CD 20  antigen  of  B  lymphocytes </li></ul></ul><ul><ul><li>For  B...
<ul><li>Binds  to  the  extracellular  domain  of  HER 2  (or c-erb-B2)  transmembrane  receptor  protein. </li></ul>HER-2...
<ul><li>Blocks  the  action  of  vascular  endothelial  growth  factor  (VEGF) </li></ul><ul><li>For  colorectal  cancer, ...
<ul><li>Against  EGFR  receptor  </li></ul><ul><li>For  colorectal  cancer </li></ul><ul><li>head – neck  cancer </li></ul...
SMALL  MOLECULES  AND INTRACELLULAR  SIGNAL  TRANSDUCTION  TYROSINE  KINASE  INHIBITORS
<ul><li>Potent selective inhibitor of the  P210 BCR-ABL tyrosine kinase  (occupies the ATP  binding site of the BCR-ABL pr...
ERLOTINIB  (Tarceva)   / GEFITINIB  (Iressa) Invasion Metastasis Growth Factor Secretion B1 B1 Cell Membrane Nucleus TKI  ...
<ul><li>Multitaeget  tyrosinase  kinase  inhibitor  of  c-Kit, PDGFR, VEGF and  FLT3 </li></ul><ul><li>For  renal  cancer ...
<ul><li>Multikinase  inhibitor  affecting  VEGF  receptors  1,2 and 3, PDGF- β , FMS-like tyrosine  kinase  3  (Flt-3), c-...
<ul><li>Binds  to  and  inhibits  mTOR. </li></ul><ul><li>mTOR  is  a  serine / threonine  kinase of the P13K/AKT pathway ...
<ul><li>It is a tyrosine kinase inhibitor </li></ul><ul><li>Inhibits  both  EGFR / ErbB1  and  HER-2 / ErbB2  tyrosine  ki...
<ul><li>T HANK  Y OU  </li></ul>
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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

  1. 1. Principles of Systemic Therapy in Cancer N. PAVLIDIS PROFESSOR OF MEDICAL ONCOLOGY UNIVERSITY OF IOANNINA GREECE ESO COURSE IOANNINA, JULY 2011
  2. 2. Principles of … <ul><li>Chemotherapy </li></ul><ul><li>Endocrine therapy </li></ul><ul><li>Immunotherapy </li></ul><ul><li>Targeting therapy </li></ul>
  3. 3. INTRODUCTION TO CHEMOTHERAPY
  4. 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. 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. 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. 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. 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. 9. MISCELLANEOUS AGENTS Asparaginase Estramustine Hexamethymelamine Octreotide Velcade
  10. 10. MODES OF CHEMOTHERAPY ADMINISTRATION <ul><li>Intravenously </li></ul><ul><li>Intramuscularly </li></ul><ul><li>Orally </li></ul><ul><li>Local Drug Application </li></ul><ul><li>Intra-arterially (i.e. hepatic infusion, limb perfusion) </li></ul><ul><li>Intra-thecally </li></ul><ul><li>Intra-peritoneally </li></ul><ul><li>Intra-pleuraly </li></ul>
  11. 11. PRINCIPLES OF COMBINATION CHEMOTHERAPY <ul><li>Use drugs active as a single agent </li></ul><ul><li>Use drugs with different mechanisms of action </li></ul><ul><li>Use drugs with different mechanisms of resistance </li></ul><ul><li>Use drugs with different side-effects </li></ul><ul><li>Be aware of drug-drug interactions </li></ul>
  12. 12. SYSTEMIC CHEMOTHERAPY NEOADJUVANT CHEMOTHERAPY [PREOPERATIVELY] Rationale <ul><li>To make non-operable tumors operable </li></ul><ul><li>To achieve organ preservation </li></ul><ul><li>To select sensitivity for specific treatment (biomarkers) </li></ul>ADJUVANT CHEMOTHERAPY [POSTOPERATIVELY] Rationale <ul><li>To kill micrometastatic disease </li></ul><ul><li>To increase disease-free survival </li></ul>THERAPY FOR METASTATIC DISEASE Rationale <ul><li>Palliative intent (symptoms control) </li></ul><ul><li>To prolong survival </li></ul>
  13. 13. CHEMOTHERAPY CAN ALSO BE GIVEN AS : <ul><li>Dose Intensification Treatment </li></ul><ul><li>Strategy to overcome drug resistance through: </li></ul><ul><li>(i) highest possible dose </li></ul><ul><li>(ii) shortest possible intervals </li></ul><ul><li>(iii) with supportive use of G-CSF </li></ul><ul><li>High Dose Chemotherapy </li></ul><ul><li>Marrow-ablative doses of chemotherapy to increase tumor cell-kill, while rescuing the host with: </li></ul><ul><li>(i) autologous bone marrow </li></ul><ul><li>(ii) donor bone marrow </li></ul><ul><li>(iii) peripheral stem-cells </li></ul><ul><li>Metronomic Chemotherapy </li></ul><ul><li>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. </li></ul>
  14. 14. PARAMETERS TO BE EVALUATED IN SYSTEMIC TREATMENTS <ul><li>COMPLETE RESPONSE (CR) : 100% disappearance of clinical and/or laboratory markers </li></ul><ul><li>PARTIAL RESPONSE (PR) :  50% disappearance of clinical and / or laboratory markers </li></ul><ul><li>STABLE DISEASE (SD) : Stability of markers (  3 months) </li></ul><ul><li>PROGRESSION OF DISEASE (PD) : Progression of markers during treatment, up to 25% or appearance of new lesions </li></ul><ul><li>DURATION OF RESPONSE : the time from response to </li></ul><ul><li>OR TIME TO PROGRESSION (TTP) progression </li></ul>R ESPONSE
  15. 15. <ul><li>DISEASE-FREE SURVIVAL (DFS) : From the time of treatment to first recurrence </li></ul><ul><li>OVERALL SURVIVAL (OS) : From the time of diagnosis to death </li></ul>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
  17. 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
  18. 19. INTRODUCTION TO ENDOCRINE THERAPY (HORMONAL AGENTS)
  19. 20. Endocrine therapy <ul><li>Some cancers (eg. breast, prostate) require hormonal stimuli for their growth. </li></ul><ul><li>Specific receptors present on cell surface and nuclei. </li></ul><ul><li>Blocking these receptors will, theoretically result in blocking of cell division and therefore, tumour growth arrest. </li></ul>
  20. 21. ANTIESTROGENS <ul><li>Indication : Breast cancer </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Toremifene </li></ul><ul><li>Raloxifene </li></ul><ul><li>Fulvestrant </li></ul>Mechanism of action : Occupy estrogen receptors. ANTIESTROGENS
  21. 22. <ul><li>Indications : Breast cancer, endometrial cancer </li></ul><ul><li>Medroxyprogesterone acetate </li></ul><ul><li>Megestrol </li></ul>Mechanism of action : Occupy progesterone receptors . PROGESTINS
  22. 23. AROMATASE INHIBITORS <ul><li>Indication : Breast cancer </li></ul><ul><li>Anastrazole </li></ul><ul><li>Exemestane </li></ul><ul><li>Letrozole </li></ul>Mechanism of action : Reduce estrogen levels by interfering with aromatase which converts androstendione to estrone and then to estradiol
  23. 24. LUTEINIZING HORMONE – RELEASING HORMONE (LHRH AGONISTS) <ul><li>Indication : Prostate cancer and breast cancer </li></ul><ul><li>Goserelin </li></ul><ul><li>Leuprorelin </li></ul><ul><li>Triptorelin </li></ul>Mechanism of action : Reduce estrogen levels by inhibiting gonadotrophin release from the pituitary
  24. 25. ANTIANDROGENS <ul><li>Indication : Prostate cancer </li></ul><ul><li>Bicalutamide </li></ul><ul><li>Flutamide </li></ul><ul><li>Nilutamide </li></ul>Mechanism of action : Inhibit the uptake and binding of androgens in target tissues.
  25. 26. <ul><li>INTRODUCTION TO </li></ul><ul><li>IMMUNOTHERAPY </li></ul>
  26. 27. CYTOKINES <ul><li>Indications : CML, hairy cell-leukemia, cutaneous T-cell lymphomas, renal cancer, melanoma </li></ul><ul><li>Interferon –a </li></ul><ul><li>Interleukin – 2 </li></ul><ul><li>Tumour necrosis factor </li></ul>Mechanisms of action : Activation of NK cells, of cytotoxic T-lymphocytes, induction of MHC class I, antiviral, antitumor and antiproliferative activities.
  27. 28. <ul><li>INTRODUCTION TO </li></ul><ul><li>TARGETING THERAPY </li></ul>
  28. 30. MONOCLONAL ANTIBODIES <ul><ul><li>Directed against CD 20 antigen of B lymphocytes </li></ul></ul><ul><ul><li>For B-cell lymphomas </li></ul></ul>Mechanism of action : Attack certain cell targets RITUXIMAB (Mabthera)
  29. 31. <ul><li>Binds to the extracellular domain of HER 2 (or c-erb-B2) transmembrane receptor protein. </li></ul>HER-2 : 17%-30% TRASTUZUMAB (Herceptin) <ul><li>For breast cancer that overexpresses HER 2 protein </li></ul>
  30. 32. <ul><li>Blocks the action of vascular endothelial growth factor (VEGF) </li></ul><ul><li>For colorectal cancer, </li></ul><ul><ul><li> renal cancer </li></ul></ul><ul><ul><li>breast cancer </li></ul></ul><ul><ul><li>NSCLC </li></ul></ul><ul><ul><li> brain tumours </li></ul></ul>BEVACIZUMAB (Avastin)
  31. 33. <ul><li>Against EGFR receptor </li></ul><ul><li>For colorectal cancer </li></ul><ul><li>head – neck cancer </li></ul>CETUXIMAB (Erbitux)
  32. 34. SMALL MOLECULES AND INTRACELLULAR SIGNAL TRANSDUCTION TYROSINE KINASE INHIBITORS
  33. 35. <ul><li>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 . </li></ul><ul><li>For CML </li></ul><ul><li> Gastrointestinal </li></ul><ul><li>Stromal Tumors (GIST) </li></ul>IMATINIB (Gleevec)
  34. 36. ERLOTINIB (Tarceva) / GEFITINIB (Iressa) Invasion Metastasis Growth Factor Secretion B1 B1 Cell Membrane Nucleus TKI Antibody <ul><ul><li>Inhibits tyrosine kinases associated with transmembrane cell surface receptors, including the EGFR. </li></ul></ul><ul><ul><li>For NSCLC </li></ul></ul>Anti-Apoptosis Proliferation
  35. 37. <ul><li>Multitaeget tyrosinase kinase inhibitor of c-Kit, PDGFR, VEGF and FLT3 </li></ul><ul><li>For renal cancer </li></ul><ul><li>GIST </li></ul>SUNITINIB (Sutent)
  36. 38. <ul><li>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. </li></ul><ul><li>For renal cancer </li></ul>SORAFENIB (Nexavar)
  37. 39. <ul><li>Binds to and inhibits mTOR. </li></ul><ul><li>mTOR is a serine / threonine kinase of the P13K/AKT pathway </li></ul><ul><li>For renal cancer </li></ul>TEMSIROLIMUS (Torisel)
  38. 40. <ul><li>It is a tyrosine kinase inhibitor </li></ul><ul><li>Inhibits both EGFR / ErbB1 and HER-2 / ErbB2 tyrosine kinases </li></ul><ul><li>For breast cancer </li></ul>LAPATINIB (Tykerb)
  39. 41. <ul><li>T HANK Y OU </li></ul>

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