Capsule Cancer 24 Sept 2024 PDF

Examples of anti-cancer drugs Alkylants cyclophosphamide, cisplatine, bléomycine Antifoliques méthotrexate Antipurine/pyrimidine fluorouracil, capecitabine Inhibiteurs de topoisomérases/agent in...

Examples of anti-cancer drugs Alkylants cyclophosphamide, cisplatine, bléomycine Antifoliques méthotrexate Antipurine/pyrimidine fluorouracil, capecitabine Inhibiteurs de topoisomérases/agent intercalant irinotécan, doxorubicine Poison du fuseau vincristine, paclitaxel Anticancéreux ciblés imatinib, bortézomib, tamoxifène Immunothérapie nivolumab, imiquimod, CAR T cells Anticancéreux ciblés, anticorps trastuzumab, cetuximab, bevacizumab See also the courses of Prof. C. Samer and Prof. F. Gervasio 1  BEVACIZUMAB Pharmaceutical form Class: monoclonal anti-VEGF antibody Humanized monoclonal IgG1 (immunoglobin) antibody produced in a Chinese Hamster Ovary mammalian cell expression system Molecular weight of approximately 149 kDa Stable 8 h upon refrigeration (if reconstituted) anticorps monoclonal qui cile l’efr —> grosse molecule qui est sous forme de solution pour perfusion —> sensible a la lumiere et conserver au frigo Solution for i.v. infusions, light sensitive 2  BEVACIZUMAB Vascular endothelial growth factor Vascular endothelial growth factor (VEGF): a signal protein produced by many cells (here endothelial cells) that stimulates the formation of blood vessels Vascular endothelial growth factor —> A l’interieur du vaisseau, les cellules de contact sont les cellules endotheliailes —> Recepteurs pour ce VEGF sur ces cellules endotheliales —> SOn action c’est de se fixer sur ce recepteur et le stimule pour favoriser la proliferation 3  BEVACIZUMAB Vascular endothelial growth factor While expressed in normal tissues, tumors release the VEGF protein in physiologically relevant levels, causing nearby blood vessels to sprout new vessels - a process called angiogenesis. Son role principal est de promouvoir la croissance de la tumeur, sa survie et sa permeabilité VEGF also: - Promotes tumor vessel survival and permeability - Stimulates tumor vessel growth 4  BEVACIZUMAB Bevacizumab: mechanism of action Selectively binds circulating VEGF, thereby inhibiting the binding of VEGF to its cell surface receptors (VEGFRs) on the surface of endothelial cells and tumors that would trigger angiogenesis se lie au VEGF pour l’empecher de se lier a son récepteur sur les cellules endotheliales —> Plsrs calsses de VEGF qui sont présent en des proporitons différentes selon les tissus. —> Diminuer la permeabilité vascu et la proliferation cellulaire 5  BEVACIZUMAB Mechanism of action regression des vaisseaux deja existants Normalisation des nouveaux vaisseaux : dans les tumeurs il y a bcp de vaisseaux entrecroisants, le but c’est de ramener les vaisseaux co normaleemnt https://www.youtube.com/watch?v=IqdVnCiy-sw 6  BEVACIZUMAB Indications (in adults) Metastatic colon or rectal cancer (1st line) In combination with the following chemotherapies: - 5-fluorouracil+folinic acid - 5-fluorouracil+folinic acid+irinotecan utilisé dans cancer colorectal : souvent en association avec chimiothéra (5-FU et FA) - capecitabine+oxaliplatin —> Differentes associations selon l’avanceement de la maladie voir les guidelines Metastatic colon or rectal cancer (2nd line) In combination with irinotecan or oxaliplatin-based chemotherapy in patients previously treated with irinotecan or oxaliplatin 7  BEVACIZUMAB Indications (in adults) Metastatic breast cancer, HER2-negative (1st line) In combination with paclitaxel pour le cancer du sein avec le paclitaxel —> Pour les patients négatifs au HER-2 : ? Metastatic or recurrent non-small cell lung cancer (1st line) In combination with cisplatin and gemcitabine-based chemotherapy Advanced and/or metastatic renal cell carcinoma (1st line) In combination with interferon alpha-2a (IFN-α2a) 8  BEVACIZUMAB Indications (in adults) Glioblastoma (grade IV) tumeuer cerebrale Relapsed glioblastoma after prior treatment with temozolomide Ovarian cancer (1st line) In combination with carboplatin and paclitaxel in patients, where the tumor could not be completely resected 9  BEVACIZUMAB Administration Metastatic colon or rectal cancer First-line treatment: 5 mg/kg body weight once every two weeks or 7.5 mg/kg body weight once every three weeks. Second-line treatment: 5 mg/kg or 10 mg/kg body weight once every two weeks or 7.5 mg/kg or 15 mg/kg body weight once every three weeks. Metastatic breast cancer 10 mg per kg body weight once every 2 weeks or 15 mg/kg body weight once every 3 weeks. 10  BEVACIZUMAB Pharmacokinetics Absorption Monoclonal antibodies are large in size, do not readily cross cell membranes, and are unable to withstand proteolysis in the gastrointestinal tract. They are poorly absorbed via the oral route and are instead administered intravenously, intramuscularly or subcutaneously. peu d’absorption oral, donc donné en perf —> Long temps de demi vie (20 jours) Distribution T1/2: 20 days (range 11-50 days) >97% of serum VEGF is bound to bevacizumab Clearance 2.75-5 mL/kg/day 11  BEVACIZUMAB Pharmacokinetics (cont) Metabolism peut aller dans 2 voies Non-specific clearance : target-independent pinocytosis (a process by which the cell takes in the fluids along with dissolved small molecules) Target-mediated clearance: once bound, the antibody-antigen complex may be cleared via lysosomal degradation Elimination Catabolism (breakdown of complex molecules to simpler ones) or excretion (due to their size, monoclonal antibodies are not renally eliminated under normal physiological conditions) 12  BEVACIZUMAB Drug-drug Interactions peu d’interactions significatives No clinically significant pharmacokinetic interactions when administered concurrently with chemotherapy. Co-administration with sunitinib (Tyrosine Kinase Inhibitor (TKI), 50 mg daily): risk of microangiopathic hemolytic anemia (loss of red blood cells through destruction caused by factors in the small blood vessels) Co-administration with contraceptives: risk of thrombosis 13  BEVACIZUMAB Contraindications Hypersensitivity to the active substance according to the composition Recent surgery - must wait 28 days post-op as bevacizumab hinders wound healing Proteinuria (increased levels of protein in the urine) Hemorrhage Hypertension Pregnancy and lactation 14  BEVACIZUMAB Side effects EI : nombreux. Gastrointestinal (GI) perforation Haemorrhage and other thromboembolic events Fistulae (an abnormal connection between two hollow spaces) Nosebleed (epistaxis), wounds that do not heal Headache Hypertension The incidence of wound healing and surgical complications Renal injury and proteinuria https://www.avastin.com/hcp/mcrc/proposed-moa.html, www.compendium.ch 15 Flash card BEVACIZUMAB Class: monoclonal anti-VEGF Ab, anti-angiogenic, anti-neoplastic MoA: selectively binds circulating VEGF Indications: solid tumors (metastatic tumours of colon and rectum), in combination with other agents Side effects: GI perforation, haemorrhage, fistulae Interactions: sunitinib, contraceptive Dosage: 5-15 mg/kg body weight every 2-3 weeks 16  TRASTUZUMAB Pharmaceutical form A monoclonal antibody (humanized from mice) used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. Ac monoclonal humanisée depuis la souris. Utilisé pour le cancer sein HER2 positif et cancer estomac Other names: Herceptin, Kanjinti sous forme de poudre pour dilution pour perf White powder for dilution for infusion Single injection vials containing 150 mg of trastuzumab Vials for multiple injections containing 440 mg of trastuzumab Incompatible with dextrose 5% solution 17  TRASTUZUMAB Epidermal growth factor (EGF) Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its epidermal growth factor receptor, EGFR. —> trastuzumab se lie au recepteur her2 egfr ErbB/HER protein kinases includes EGFR, along with other closely related ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4) proteins https://www.nature.com/articles/onc2016393 19 18  TRASTUZUMAB Indications (in adults) Breast cancer (BC) Prior to initiation of trastuzumab, HER2 overexpression must be demonstrated in the patient's tumor tissue rechercher l’expression de HER2 —> Si il n’est pas exprimer, faut donner un autre ttt Monotherapy: Patients previously treated with chemotherapies In combination: with paclitaxel or docetaxel (untreated patients with metastatic BC) with an aromatase inhibitor for the treatment of postmenopausal patients with hormone receptor positive (untreated patients with metastatic BC) 19  TRASTUZUMAB Indications (in adults) Early Breast Cancer after surgery, chemotherapy (neoadjuvant or adjuvant) and radiation therapy after adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin 20  TRASTUZUMAB Indications (in adults) Les ttt sont adapté et personnalisé --> Adapté au stade et a l’invasion de la tumeur Treatment of Metastatic Gastric or Esophageal Cancer HER2-positive metastatic adenocarcinoma in combination with capecitabine or 5-fluorouracil and cisplatin (untreated patients) 21  TRASTUZUMAB Administration Metastatic breast cancer - weekly regimen Monotherapy Initial Dose: 4 mg/kg body weight, over 90-minute i.v. infusion Subsequent Doses: 2 mg/kg body weight, 30-minute i.v. infusion Combination with paclitaxel or docetaxel The dosage the same as for monotherapy. Paclitaxel or docetaxel given the day after the first dose of trastuzumab Combination with an aromatase inhibitor (e.g. anastrozole, decreasing the amount of estrogen) The dosage the same as for monotherapy No restrictions regarding the relative dosing times anastrozole and trastuzumab when administered concomitantly 22  TRASTUZUMAB Administration Metastatic breast cancer - every 3 weeks (alternative to weekly dosing) Advanced cancer of the stomach or esophageal junction Monotherapy and combination therapy with paclitaxel, docetaxel or an aromatase inhibitor Initial dose: 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later Subsequent doses: 6 mg/kg body weight are then repeated at 3-week intervals 23  TRASTUZUMAB Pharmacokinetics Absorption Peak and plasma concentrations (between weeks 16 and 32) were approx. 123 and 79 mg/mL T1/2: 1.7 and 12 days (for 10 mg and 500 mg, respectively) Metabolism metabolized intracellularly into smaller peptides and amino acids Clearance 0.173 - 0.337 L/day, dependent on the dosing regimen 24  TRASTUZUMAB Drug-drug Interactions Monotherapy and in combination with taxanes after anthracycline (doxorubicin, epirubicin): risk of heart failure In the presence of paclitaxel and doxorubicin, no changes in trastuzumab concentrations were observed In combination with capecitabine, higher concentrations and a longer half-life of capecitabine were observed 25  TRASTUZUMAB Contradictions Hypersensitivity to trastuzumab, hamster cell protein, or to any of the excipients of the drug or solvent Infusion-related reactions: dyspnea (shortness of breath), hypotension, nausea, fever, bronchospasm, tachycardia Heart failure or asymptomatic cardiac dysfunction Pulmonary infiltrates, pneumonia Les facteurs de croissances sont distribués partout dans le corps donc il faut etre prudent a cause Pregnancy and lactation des actions que ca pourrait avoir sur des recepteurs qu’on veut pas 26  Side effects Heart problems/ failure / toxicity - Hold treatment for at least 4 weeks Pulmonary toxicity Headache Diarrhea Nausea Embryo-fetal toxicity 27 Flash card TRASTUZUMAB Class: monoclonal anti-HER2 Ab, anti-angiogenic, anti-neoplastic MoA: Mediates antibody-dependent cellular inhibition of proliferation of cells that overproduce HER-2 protein Indications: Brest cancer Side effects: Heart and pulmonary toxicity Interactions: anthracycline, capecitabine Dosage: 4 mg/kg body weight, over 90-minute i.v. infusion 2 mg/kg body weight, 30-minute i.v. infusion 28  CETUXIMAB Pharmaceutical form Cetuximab (chimeric IgG1 monoclonal human/mouse antibody produced by a recombinant cell line in mouse myeloma cells) Solution for infusion: vials of 100 mg/20 ml and 500 mg/100 ml cetuximab (5 mg/ml). Other name: ERBITUX Protein structure https://go.drugbank.com/drugs/DB00002 29  CETUXIMAB Mechanism of action Cetuximab binds to EGFR, stops from dimerizing of EGFR leading to inhibition of EGFR signaling This will help ENHANCE response to chemotherapy and/or radiation Se lie au recepeteur egf —> inhibe toute la cascade de réaction qui découle de ce recepteur https://www.nature.com/articles/onc2016393 30  CETUXIMAB Indications (in adults) Metastatic colorectal carcinoma with the wild-type RAS gene and expressing qui ne sont pas mutés EGFR RAS wild-type status and EGFR expression should be established prior to initiating treatment with cetuximab In combination: FOLFIRI (folinic acid+fluorouracil+irinotecan) or FOLFOX (folinic acid+fluorouracil+oxaliplatin) Monotherapy: after failure of oxaliplatin and irinotecan therapy or in case of intolerance to irinotecan Advanced squamous cell carcinoma of the head and neck In combination: radiotherapy permet de potentialiser l’effet de ce ttt Metastatic squamous cell carcinoma of the head and neck In combination: cisplatin + 5-fluorouracil 31  CETUXIMAB Administration Prior to the first infusion, the patient should be pre-medicated with an antihistamine and a corticosteroid (to avoid infusion-related adverse events) Si c’est la premeire fois qu’on traite ce patient avec ce medoc, on doit le prémédiquer avec antihistaminique et GC pour limiter les EI possibles Cetuximab is administered once weekly. The initial dose is 400 mg/m2 of body surface area. Thereafter, treatment is continued with 250 mg/m2 of body surface area once weekly Cetuximab (5 mg/mL) is administered intravenously (slowly) by infusion pump Cetuximab does not have any drug interactions, but it does boost the effect of platinum drugs and radiation therapy 32  CETUXIMAB Pharmacokinetics Absorption After administration of a 400 mg/m2 initial dose followed by a 250 mg/m2 weekly dose, the steady-state levels of cetuximab was reached by the third weekly infusion T1/2: approx. 112 hours 5 jours Distribution The volume of the distribution is about 2-3 L/m2 and is independent of dose Clearance Clearance rate was 0.103 L/h. The elimination via catabolism https://go.drugbank.com/drugs/DB00002 33  Contradictions Hypersensitivity to cetuximab or any of the excipients Pregnancy and breastfeeding In patients with mCRC with RAS mutations or unknown RAS mutation status, the combination and oxaliplatin-based chemotherapy is contraindicated Pulmonary diseases 34  Side effects Metabolism and nutrition disorders (low magnesium, potassium, calcium) Gastrointestinal disorders (Mucositis) Infusion reactions Dermatologic toxicities/ skin reactions (skin peeling, redness, inflammation, and itchy/dry skin) Weakness, fatigue, weight loss Pulmonary toxicities Severe leukopenia or neutropenia (in combination with platinum-based chemotherapy) 35 Flash card CETUXIMAB Class: monoclonal anti-EGFR Ab, anti-angiogenic, anti-neoplastic MoA: Binds to EGFR stops from dimerizing of EGFR leads to inhibition of EGFR signaling Indications: Colorectal cancer, head & neck cancer, squamous cell carcinoma Side effects: Infusion-related, skin reactions, GI toxicity, electrolytes depletion Interactions: boosts the effect of platinum drugs and radiation therapy Dosage: 400 mg/m2 of body surface area. Thereafter, treatment is continued with 250 mg/m2 of body surface area, once weekly 36  QUIZ 26 September 2023  Question 1 – type A Which of these monoclonal antibody – mechanism target pairs is incorrect? A. Trastuzumab - HER2 receptor B. Cetuximab - VEGF inhibitor C. Rituximab - CD20 inhibitor D. Bevacizumab - angiogenesis inhibitor 38  Question 2 – type A Which of these monoclonal antibodies targets EGFR ? A. Bevacizumab B. Cetuximab C. Rituximab D. Trastuzumab  Question 3 – type A A 62-year-old woman with advanced Hodgkin's disease is to begin chemotherapy with doxorubicin + bleomycin + vinblastine + dacarbazine. Which of the following statements best explains the mechanism of anticancer action of doxorubicin? A. It intercalates between DNA strands and inhibit topoisomerase II B. It prevent microtubule disassembly into tubulin monomers C. It prevents assembly of tubulin dimers into microtubules D. It alkylates nucleophilic groups on DNA bases E. It blocks the synthesis of both ribonucleotides and deoxynucleotides 40  Question 4 – type A How does Cetuximab work? A. It targets and binds to the EGFR, which is found on the surface of many normal cells and cancer cells B. By binding to EGFR on the cancer cell, cetuximab blocks EGF from binding to this receptor (activation) C. Cetuximab stops the cell from continuing the pathway that promotes cell division and growth D. All are correct 41  Question 5 – type K’ ? Which facts on Cetuximab are correct: A. Should be administered before platinum based therapy with 5-FU and FOLFORI (leucovorin+5-FU+irinotecan) B. Should be premedicated with antihistamine C. Inhibits mitogenic and anti-apoptotic signals D. Does not induce metabolism- and nutrition-related disorders  Question 6 – type A 52-year old woman returns to oncology clinic for a follow-up visit. She is currently on multidrug regiment for metastatic breast cancer. She responds well to treatment targeting the HER2 receptors in cancer cells. She is recently diagnosed with cardiac disfunction. Which drug can be responsible for this side effect? A. Bevacizumab B. Cisplatin C. Cetuximab D. Trastuzumab E. Imatinib  Question 7 – type K’ Which statements concerning doxorubicin are correct? A. Interacts with CYP inhibitors and inducers B. Is used to treat multiple solid tumor types C. Does not affect cardiac cells D. May induce myelosuppression 44  Question 8 – type A Major toxicity of alkylating drugs can be: A. Alopecia (spot baldness) B. Myelosuppression ? C. Renal damage D. Hepatic failure 45  Question 9 – type K’ Bevacizumab is used for treatment of breast cancer: A. In HER2 positive patients B. In HER2 negative patients C. In combination with paclitaxel D. In combination with interferon alpha-2a  Question 10 – type A Combination chemotherapy: A. Should involve drugs with comparable mechanisms B. May be used in combination with surgical and radiation intervention C. Should involve drugs with differing toxicity profiles D. B and C E. A, B and C  Question 11 – type A Chemotherapeutic (anticancer) dosing principles: A. Drug should be administered at law or the maximum doses but with increased frequency B. Drug should be administered infrequently to minimize side effects C. Drugs more beneficial if major toxicities are nonoverlapping D. Drugs rarely effective in combination E. All answers are wrong