Principles of cancer systemic therapy

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Principles of cancer systemic therapy

• chemotherapy
• hormonal therapy

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Therapy of cancer (and not only...)

• systemic
• chemotherapy
• hormonal therapy
• biological therapy

• local
• surgery
• radiotherapy
• other
• kriotherapy
• hyperthermia
• laser
• etc...

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Treatment of cancer assessment of response

• WHO RECIST
• complete response (CR)
• partial response (PR)
• stable disease/no change (SD)
• progressive disease (PD)

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Chemotherapy
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Kinetics of cancer treatment
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Chemotherapy classes of drugs

• alkylating agents
• antimetabolites
• antibiotics
• plant alkaloids
• Vinca alkaloids
• taxanes
• topoisomerase inhibitors
• miscellaneous

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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

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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
• pirimidine analogues
• adenosine analogues

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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

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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

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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

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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

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Cell cycle
M (mitosis)
G2 (gap 2)
G2 (gap 2)
G1 (gap 1)

cells that cease division
S (DNA synthesis)
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Chemotherapy mechanism of action

• cycle/phase non-specific
• alkylating agents
• phase specific
• G1 phase
• L-asparaginase
• steroids
• S phase
• antimetabolites
• anthracyclins

• G2 phase
• bleomycin
• topo I inhibitors
• M phase
• Vinca alkaloids
• taxanes
• topo II inhibitors

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Chemosensitivity of tumors

• high
• ALL
• Hodgkinsdisease
• NHL
• testicular cancer
• SCLC
• Wilms tumor

• medium
• ovarian cancer
• breast cancer
• osteosarcoma
• head neck cancer
• multiple myeloma
• bladder cancer
• colorectal cancer

• low
• NSCLC
• cervical cancer
• endometrial cancer
• adult soft tissue sarcoma
• malignant melanoma
• liver cancer
• pancreatic cancer

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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
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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
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Chemotherapy - indications
Neoplasms in Which Clinical Trials Indicate an Expanding Role for Primary Chemotherapy in the Future 
Nonsmall 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
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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)
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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

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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

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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

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Methods to increase the efficacy of chemotherapy

• standard dosing
• high dose
• dose-dense

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Chemotherapy toxicity

• myelosuppression
• immunosuppression
• nausea/vomiting
• alopecia
• mucositis
• diarrhea
• flu-like symptoms

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Chemotherapy toxicity (2)

• gonadal damage
• sterility
• hormonal changes
• organ damage
• cardiotoxicity
• pulmonary damage
• hepatotoxicity
• nephrotoxicity
• neuroxicity
• local complications (extravasation)
• second malignancies

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Chemotherapy routes of administration

• oral
• intravenous
• intramuscular
• intrathecal
• intraperitoneal
• intrapleural

• intrapericardial
• intraarterial
• isolated organ perfusion
• portal vein
• limb

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Chemotherapy - strategy

• single drug used rarely
• 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

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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

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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)

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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

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Multimodality therapy

• concomitant
• no delay of any treatment modality
• synergistic effect of various modalities
• increased toxicity
• need to modify doses of individual treatment
  modalities

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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)

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Hormonal therapy
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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)

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Hormonotherapy indications

• breast cancer
• prostate cancer
• endometrial cancer
• renal cancer
• ovarin cancer
• cancer cachexia

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Hormones Affecting the Breast
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Effects of oestrogen on transcription
ofoestrogen responsive genes
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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

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Premenopausal estrogen production
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Methods of achieving ovarian ablation
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Effects of tamoxifen on transcriptionof
oestrogen responsive genes
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Response to hormonal therapy in relation to
estrogen and progesterone receptor expression
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(No Transcript)
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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

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Prostate cancer hormonal dependence
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Prostate cancer hormonal therapy

• estrogens
• orchidectomy
• androgen receptor antagonists
• LHRH agonists (medical castration)
• total androgen blockage

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Hormonotherapy - glucocorticosteroids

• mechanism of action
• antiinflamatory
• anabolic
• edema-reducing
• euphorising