1. Drugs development: more accelerated process
    1. Conditional approval: Shorter development (only 1 RCTs phase II is required) and review time
    2. End-point of RCTs:
      1. MOSTLY Progression-free survival: time interval between relapse
        1. Chosen by companies as the end-point of the most recent RCTs.
      2. Overall survival: months gained from treatment to death.
        1. Focuses more on the patient, Longer follow-up
    3. They are subjected to PAES/PASS studies: post-marketing surveillance
  2. Treatment (notes)
    1. Therapeutic drug monitoring can be used to obtain info of anti-cancer drugs plasma concentration during therapy--> toxicity measurement
      1. high cost, performed on few drugs, not always necessary
    2. Genomic sequencing of the patient --> presence of certain mutations --> adequate treatment with controlled PD and PK
  3. Features of oncological agents
    1. Narrow(-est) therapeutic index
    2. They all share a certain degree of TOXICITY
      1. Cardiovascular toxicity: arrhythmias and QT prolongation by anti-emetic drugs, heart failure , thrombo-embolism (tamoxifen), general risk of ischemia and TdP
    3. DRUG INTERACTION (primary relevance)
      1. With NON anti-cancer drugs: antiemetic, analgesic, anticoagulants, anti-depressants, fatigue-treating drugs will be administered too.
        1. ANTI-DEPRESSANTS: Frequently prescribed (psychiatrist). E.g . St. John's wort widely used by cancer patients: lowers anti-cancer drugs effects.
        2. ANTI-EMETICS: they are added (one or more) to the chemotherapy therapy according to the patient's risk (CINV)
          1. MAIN CLASSES: They differ in half-life
          2. CLASSIFICATION of CINV: Acute (5-6h), delayed (days 2-5), breakthrough, anticipatory, refractory
          3. ACUTE: It's related to serotonin release (in the gut: peripheral pathway) --> it's managed by blocking serotonin receptors (Ondansetron)
          4. DELAYED: It's related to substance P release (medulla: central pathway) --> Nk1 receptor antagonist is prescribed (Aprepitant)
          5. Breakthrough: CINV occurs despite prophylaxis --> implement new anti-emetic
          6. Anticipatory: CINV occurs before treatment --> strongly influenced by anxiety --> benzodiazepines
          7. Refractory: CINV occurs in the subsequent cycles
          8. If the conditions are co-existent, different concomitant drugs will be prescribed or specific combinations containing both active principles (e.g.: NEPA)
          9. CLASSIFICATION of emetogenic potential of anti-cancer drugs
          10. HIGH (>90% of patients): Cisplatin, cyclophosphamide
          11. 3/4 drugs regimen: serotonin receptor antagonist + NK1 antagonist + dexamethasone + olanzapine
          12. MODERATE: MOST of drugs: cyclophosphamide (low doses), doxorubicin, irinotecan, oxaliplatin, ribociclib
          13. Dual therapy
          14. LOW: Fluorouracil, Liposomal doxorubicin, cetuximab, trastuzumab-entasine, osimertinib, entrectinib
          15. MINIMAL: Atezolizumab, trastuzumab, CPI class
          16. Anti-dopaminergic drugs are used
          17. METOCLOPRAMIDE (PLASIL): blocks type 2 dopamine receptor, type 3 and 4 serotonin receptors --> more effective but able to enter BBB (side effects in pyramidal pathways)
          18. DOMPERIDONE: blocks type 2 dopamine receptors only --> safer but also acts on the heart channels --> QT prolongation
          19. RISK FACTORS: age, female sex, PMH of nausea, chosen drug side effects
      2. With ANTI-CANCER drugs: to increase efficacy, decrease resistance development and side effects (toxicity)
  4. Classification
    1. CONVENTIONAL CHEMOTHERAPY: CYTOTOXIC DRUGS (hematological and solid tumours)
      1. Cytotoxic, genotoxic and mutagenic properties
        1. Mainly target cellular pathways, altering transcription and synthesis of cancer genes, hampering immune response
          1. Cell-cycle specific (CCS): target only PROLIFERATING CELLS inhibiting S phase, non-SELECTIVE
          2. Not very effective in slow proliferative cancer cells (colorectal cancer)
          3. Side effects targeting other proliferating sites (intestinal mucosa, hair)
          4. Cell-cycle non specific (CCNS): target both PROLIFERATING and NON-PROLIFERATING CELLS, in all cell cycle phases.
        2. Can be combined in treatment
      2. FEATURES
        1. LOG-KILL hypothesis
          1. Given dose of chemotherapy kills the same fraction of tumour cells regardless of the size of the tumour at the time of treatment.
        2. Administered in cycles --> To hamper resistance/toxicity developed through the therapy
          1. Also to allow healthy cells recovery
        3. DRUG RESISTANCE types: pre-target, on-target, post-target.
          1. P-GLYCOPROTEIN mechanism: mediates absorption, metabolism and elimination in SEVERAL tissues --> changes plasma concentration
        4. DRUG TOXICITY (PD): dose-dependent, time-dependent, patient-dependent; also could be unpredictable.
          1. Grading system of toxicity: ranges from 1-5 (section 4.2, 4.4, 4.8 of SPC)
          2. Can lead to therapy suspension, hospitalization, medical intervention
          3. Temporal classification
          4. Immediate onset: within 2 days: mostly vomiting
          5. Early onset (1-2 weeks): myelosuppression
          6. Delayed onset (within months, years): usually irreversible
      3. TYPES:
        1. 1. Alkylating agents:
          1. Cyclophospamide (her2 positive breast cancer): IV and oral administration, induces myelosuppression --> granulocytes count for dose adjustment, immunosuppressive drug
          2. Metabolised by hepatic cytochromes --> one pathway can induce acrolein production --> urothelial toxicity (hemorrhagic cystitis: SPECIFIC SIDE EFFECT)
          3. Can be co-administered with MESNA: displaces acrolein
          4. Posology varies significantly depending on the patient
        2. 2. Platinum combination complexes:
          1. Oxaliplatin (metastatic colorectal cancer): controlled IV injection (3-4h), more tolerated
          2. More selective for low proliferating cells, lower toxicity but peripheral neurotoxicity , mild myelosuppressor, renal impairments
        3. 3. Antimetabolites: endogenous metabolites antagonists.
          1. 3 classes: folic acid analogues (Methotrexate), pyrimidine analogues, PARP inhibitors
          2. Pyrimidine analogues: FLUOROURACIL (5-FU) DNA synthesis inhibition in GI tract cancers (in folfiri ... regimens)
          3. Synergistic effects: with folinic acid, oxaliplatin
          4. 80% undergoes catabolic pathway: if DPD is missing --> accumulation --> toxicity
          5. Side effects: Hand-foot syndrome, no co-administration with brivudine
          6. Drug interaction: no co-administration with brivudine, DPD congenital deficiency.
        4. 4, Antimitotics
          1. 1. TAXANES : microtubules stabilization --> mitosis is blocked (CCS)
          2. PACLITAXEL: IV administration for different cancers, metabolised by liver
          3. Can induced hypersensitivity --> pre-medication with anti-histamine, corticoids is recommended
          4. Side effects: myelosuppressor, neurotoxicity (peripheral).
          5. 2.TOPOISOMERASE INHIBITORS: class I and II
          6. CLASS I: IRINOTECAN: (large intestine cancers) metabolised into SN-38
          7. It is transformed into SN-38G by UGT1A1: if deficient --> toxic for GI tract mucosa --> diarrhea (Loperamide)
          8. CLASS II: Anthracyclines associated with early or delayed cardiotoxicity
    2. TARGETED THERAPY: inhibition of specific ONCOGENES and receptors --> more selective and effective (cytostatic and cytotoxic)
      1. SYNTHETIC LETHALITY approach: targets are growth factors (overly-expressed), INC kinases, angiogenesis mediators, immune system
      2. 2 FAMILIES:
        1. TKI: TYROSINE KINASE inhibitors (nibs)
          1. TARGETS:: RAF kinase, MEK, CDK 4/6 (Ribociclib), PI3K pathway, multikinase inhibitors
          2. Relevant: toxicity of CDK 4/6 inhibitors: neutropenia, diarrhea, thrombosis, interstitial lung disease, QT prolongation, skin toxicity
          3. e.g. EGFR inhibitor: osimertinib
          4. Oral administration (home treatment)
          5. Hepatic and renal clearance (pharmacokinetic interactions); not necessarily selective (off-target effect)
          6. Pharmacokinetic drug interactions with PPI --> reduce TKI absorption Pharmacokinetic drug interactions with cytochrome CYP inhibitors or inducers
        2. MONOCLONAL Abs (MoAbs): several pharmacodynamic properties such as CDC and ADCC
          1. e.g. EGFR inhibitor: cetuximab
          2. Parenteral administration via IV/subcutaneous
          3. Target-selective and target- specific clearance -->low pharmacokinetic interactions
          4. Toxicity: hypersensitivity, increased (autoimmunity) or depressed (infections, cancer) immune response
        3. INNOVATIVE: Antibody-drug conjugates (ADCs)
          1. e.g Trastuzumab entasine
    3. IMMUNOTHERAPY: immune system stimulation potentiation --> cancer cells destruction
      1. CLASSES:
          1. FEATURES
          2. Dosage is the same for all the patients: FLAT DOSE administered via peripheral IV line (home treatment)
          3. Delayed response: initially the tumour progresses
          4. irRECIST criteria have been designed to monitor immune-related response (specifically for immunotherapy)
          5. Long-lasting survival rate is higher (in terms of PFS or OS?)
          6. TARGETS: CTL4 , PD1 (both on T cells) and PD-L1 on tumour cells
          7. Mechanism of action in cancer cells: PD-L1 over-expressed on tumour cells--> inhibits T cell response
          8. PHARMACODYNAMIC: activation of immune cells --> T-cells and APCs kill the tumour cells
          9. OPPOSITE APPROACH compared to conventional and target chemotherapy
          10. IMMUNE-RELATED ADVERSE EVENTS (iRAEs) (increased in combination regimens): due to immune system over-stimulation --> arise within 4-10 weeks --> efficacy markers
          11. It can affect ALL the organs and yield MULTISYSTEM iRAEs, varies according to the drug --> corticosteroids for management
          12. Rare cardiotoxicity --> myocarditis with high fatality rate
          13. Drugs in clinical use:
  5. General comparison between therapy types
  6. Trials
    1. Umbrella trials: different drugs are tested to target different mutations of the same cancer
      1. E.g. lung cancer high heterogeneity
    2. Basket trials: the same drug (tissue-agnostic class) is used to target the mutation shared by different cancers
      1. E.g. pembrolizumab used in all metastatic or unresectable (...) solid tumours