Principles of cancer systemic therapy

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					   Principles of cancer
    systemic therapy
 chemotherapy
hormonal therapy
Therapy of cancer         (and not only...)
► local              ► systemic
   surgery             chemotherapy
   radiotherapy
                        hormonal therapy
   other
     ►kriotherapy
                        biological therapy
     ►hyperthermia
     ►laser
     ►etc...
Treatment of cancer – assessment of
                   response
 WHO                          RECIST
► complete    response (CR)

► partial   response (PR)

► stable    disease/no change (SD)

► progressive    disease (PD)
Chemotherapy
Kinetics of cancer treatment
Chemotherapy – classes of drugs

► alkylating  agents
► antimetabolites
► antibiotics
► plant alkaloids
   Vinca alkaloids
   taxanes
► topoisomerase       inhibitors
► miscellaneous
               Chemotherapy
        – mechanism of action
alkylating agents
   chemical interaction with DNA by forming
    covalent bonds with nucleic acid

     misreading  of DNA code
     cross-linking of DNA
     single-strand breaks
     double-strand breaks

   alkylation of RNA and proteins
                  Chemotherapy
         – mechanism of action
antimetabolites
   antifolates   – disruption of folate-dependent metabolic
   processes essential for cell replication by inhibition of
         dihydrofolate reductase
         glycinamide ribonucleotide formyltransferase
         thymidylate synthase

   purine analogues                       interference
   pirimidine analogues                   with synthesis
                                           of DNA precursors
   adenosine analogues
            Chemotherapy
      – mechanism of action
antibiotics
►anthracyclines
   intercalation between DNA base pairs
   inhibition of DNA topoisomerases I and II
   free radical formation
►bleomycin
  intercalation of DNA at G-C and G-T
   sequences, resulting in spontaneous
   oxidation and formation of free oxygen
   radicals that cause strand breakage
            Chemotherapy
      – mechanism of action
antibiotics(2)
►mitomycin C
   alkylation and cross-linking of DNA
   lipid peroxydation

►actinomycin   D
   DNA intercalation
   single strand breaks formation
   free radical formation
            Chemotherapy
      – mechanism of action
topoisomerase inhibitors
►topo I inhibitors
   inhibition of topo I
   interruption of the elongation phase of
    DNA replication
►topo II inhibitors
  stabilization of the DNA-topo complex,
   leading to inability to synthesize DNA
   and G1 block
            Chemotherapy
      – mechanism of action
plant alkaloids
►Vinca alkaloids
   tubulin binding
   blockage of microtubule polimerization
   impaired mitotic spindle formation
►taxanes
  promotion of microtubule assembly and
   stability
  M phase block
  induction of apoptosis
                  Cell cycle
                       M
                    (mitosis)
         G2
       (gap 2)
                                  G1
                                (gap 1)




                                    cells that
      S                           cease division
(DNA synthesis)
                   Chemotherapy
          – mechanism of action
► cycle/phase     non-specific
   alkylating agents
► phase   specific
   G1 phase                  G2 phase
     ► L-asparaginase            ► bleomycin

     ► steroids                  ► topo   I inhibitors
   S phase                   M phase
     ► antimetabolites           ► Vinca   alkaloids
     ► anthracyclins             ► taxanes
                                 ► topo   II inhibitors
     Chemosensitivity of tumors
►   high         medium                low
ALL              ovarian cancer         NSCLC

Hodgkin’s        breast cancer          cervical cancer
 disease          osteosarcoma           endometrial
NHL              head & neck             cancer
testicular        cancer                 adult soft

 cancer           multiple myeloma        tissue sarcoma
                                          malignant
SCLC             bladder cancer
                                           melanoma
Wilms’ tumor     colorectal cancer
                                          liver cancer
                                          pancreatic
                                           cancer
     Chemotherapy - indications
Neoplasms in Which Chemotherapy is the Primary
Therapeutic Modality for Localized Tumors
• Large cell lymphomas
• Burkitt's lymphoma
• Childhood and some adult stages of Hodgkin's disease
• Wilms' tumor
• Embryonal rhabdomyosarcoma
• Small cell lung cancer
• Central nervous system lymphomas
     Chemotherapy - indications
Neoplasms in Which Primary Chemotherapy Can
Allow for Less Mutilating Surgery

•Anal carcinoma
•Bladder carcinoma
•Breast cancer
•Laryngeal cancer
•Osteogenic sarcoma
•Soft tissue sarcomas
      Chemotherapy - indications
Neoplasms in Which Clinical Trials Indicate an
Expanding Role for Primary Chemotherapy in the
Future
•Non–small cell lung cancer
•Breast cancer
•Esophageal cancer
•Nasopharyngeal cancer
•Other cancers of the head and neck region
•Pancreatic cancer
•Gastric cancer
•Prostate cancer (hormones)
•Cervical carcinoma
     Chemotherapy - indications
Neoplasms in Which Chemotherapy May Be
Used for Metastases and/or Widespread Disease

•Embryonal carcinoma

•Choriocarcinoma

•Non-Hodgkin's lymphoma

•Leukemias (acute lymphoblastic leukemia, acute myeloid
leukemia)
 Mechanisms of treatment failure

► inadequacy    of tumor vasculature, leading
 to poor exposure to chemotherapeutic
 agents

► selection   of chemoresistant cells by
 selective killing of chemosensitive
 subpopulation
Chemotherapy - mechanisms of drug
                                 resistance
Cellular
►   decreased drug accumulation
       influx
       efflux
      altered intracellular trafficking of drug
►   decreased drug activation
►   increased inactivation of drug or toxic metabolite
►   increased repair of drug-induced damage to DNA, proteins or membranes
►   increase in an alternative metabolic pathway bypassing the target
    mechanism
►   altered drug targets
►   altered co-factor or metabolite level
►   altered gene expression
      DNA mutation, amplification or deletion
      altered transcription, post- transcription processing or translation
      altered stability of macromolecules
    Chemotherapy - mechanisms of
                  drug resistance (2)
Host-related
► pharmacologic and anatomic drug barriers
► host-drug interactions
      or  drug inactivation by normal tissues
     relative increase in drug sensitivity of normal tissues
►   host-tumor interactions
Functional
►   „kinetic resistance” of cells in G0
►   „pharmacologic resistance” – inability to achieve
    sufficient drug concentrations
        Methods to increase
    the efficacy of chemotherapy
► standard   dosing


► high   dose


► dose-dense
 Chemotherapy – toxicity
► myelosuppression

► immunosuppression

► nausea/vomiting

► alopecia

► mucositis

► diarrhea

► flu-like   symptoms
Chemotherapy – toxicity                 (2)
 ► gonadal   damage
     sterility
     hormonal changes
 ► organ   damage
       cardiotoxicity
       pulmonary damage
       hepatotoxicity
       nephrotoxicity
 ► neuroxicity
 ► localcomplications (extravasation)
 ► second malignancies
         Chemotherapy – routes of
             administration
► oral               ► intrapericardial

► intravenous        ► intraarterial

► intramuscular      ► isolatedorgan
► intrathecal          perfusion
► intraperitoneal       portal vein
                        limb
► intrapleural
      Chemotherapy - strategy
       drug – used rarely
► single
► combination
   provides maximal cell kill within tolerable
    toxicity
   provides broader range of coverage of resistant
    cells in a heterogeneous tumor
   prevents/slows the development of resistant
    cells
          Development
   of combination chemotherapy
► drugs  effective in particular tumor
► different mechanisms of action
► non-overlapping toxicity
► different patterns of resistance
► drugs used in their optimal dose and
  schedule
► drugs given at consistent (as short as possible)
  intervals
        Setting of use of systemic
                 therapy
► as   a single modality
   radical/definitive
   palliative
► in   combined (multimodality) therapy
   before local treatment (induction, neoadjuvant)
   during local treatment (concomitant)
   alternating with local treatment
   after local treatment (adjuvant)
          Multimodality therapy
► induction
   possibility to assess effect of treatment in vivo
   early introduction of systemic therapy (prevention
    of development of chemoresistance)
   undisturbed blood supply
   prevention of tumor seeding during surgery
   enabling of decreasing the extent of surgery
   lack of interfering toxicities form other treatments

   delay in local treatment (risk of progression)
   increased risk of local treatment complications
            Multimodality therapy
   concomitant
     no delay of any treatment modality
     synergistic effect of various modalities

     increased toxicity
     need to modify doses of individual treatment
      modalities
            Multimodality therapy
   adjuvant
     no delay in local treatment
     higher sensitivity of microscopic tumor foci

     lack of possibility to assess efficacy of treatment
     delayed start of systemic treatment (possibility of
      develppment of resistance)
     impaired blood supply (and drug penetration)
Hormonal therapy
            Hormonotherapy
        – mechanism of action
► hormone   deprivation
  removal of hormone producing tissue (ablation)
  inhibition of hormone production
  blocking of hormone receptors
► exogenous   hormone treatment (additive
 therapy)
  Hormonotherapy – indications

► breast   cancer
► prostate   cancer
► endometrial      cancer
► renal   cancer
► ovarin   cancer
► cancer   cachexia
Hormones Affecting the Breast
Effects of oestrogen on transcription of
      oestrogen responsive genes

                                   co-act
                                                transcription
                      AF1 AF1
                       E EAF2
 H                  loss of HSPs
 S
 P
     ER   +E     phosphorylation,
                    dimerisation
               conformational change
                                                transcription
                      AF1 AF1
                       E EAF2          co-act
Hormonotherapy of breast cancer
     = estrogen depletion
► estrogen     source ablation
     castration (surgery or RT)
     adrenalectomy
► removal   or inhibition of gonadotropin action
     hypophysectomy
     LHRH agonists
     danazol
     progestagens
► estrogen     receptor blocking
     tamoxifen and other SERM
     fulvestrant
► inhibition   of peripheral estrogen synthesis
     aromatase inhibitors
                    Premenopausal
                  estrogen production
                     Gonadotrophins
   a/LHRH              (FSH + LH)                             Oestrogens

                                           Ovary


                                                       Tamoxifen
                   Pituitary gland Adrenal
    LHRH                           glands
(hypothalamus)                            Androgens         Oestrogens

                           ACTH                                    aromatase
                                                                   inhibitors
                                                        Peripheral
    ACTH = adrenocorticotrophic hormone;               conversion
    FSH = follicle-stimulating hormone;
    LH = luteinising hormone;
                                                   (aromatase enzyme)
    LHRH = LH-releasing hormone
  Methods of achieving ovarian
           ablation



   Surgical
                      Irradiation,
(oophorectomy)
                    Chemotherapy,
                     or Goserelin
    Effects of tamoxifen on transcription
       of oestrogen responsive genes
                                              transcription
                                co-act
                    AF1 AF1                   AGONISM
                    T T
                      AF2



H                  loss of HSPs
                 phosphorylation,
S
P
    ER   +T        dimerisation
              conformational change
                                              no transcription
                    AF1 AF1
                                             ANTAGONISM
                    T T
                      AF2
                                    co-act
 Response to hormonal therapy in relation to
estrogen and progesterone receptor expression
         80

         70

         60

         50

         40

         30

         20

         10

          0

    ER        -   +     -      +
    PR
              -   -     +      +
                                    Clark, 1984
Hormonotherapy – past and present

► 1896– Beatson: oophorectomy causes
 remission of breast cancer in young women
► ER/PgR    – first predictive factors in oncology
► low   toxicity       long term use
   advanced disease
   adjuvant treatment of early disease
   chemoprevention
   Prostate cancer – hormonal
                      dependence
                   Testosterone              Testes




Hypothalamus      Pituitary
                                              Prostate


                              Prolactin
               LHRH


                                          Adrenal


               Cortisol                       Adrenal
                                             androgens
Prostate cancer – hormonal
                   therapy
► estrogens

► orchidectomy

► androgen    receptor antagonists

► LHRH     agonists (medical castration)

► „total   androgen blockage”
   Hormonotherapy
- glucocorticosteroids

mechanism of action
► antiinflamatory

► anabolic

► edema-reducing

► euphorising

				
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posted:6/30/2012
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