Overview of Antineoplastic Agents and Cell Cycle (SIOP Africa.pptx

Principles of chemotherapy & Drug resistance
Classification/Mechanism of action
Be familiar with the potential common side effects of chemotherapy

The role of pharmacogenomics in shaping chemotherapy portocols

Patient and family education
Explore your role during/post chemotherapy

1. DR. M U STAFA SELIM Education and Training committee program Module 1: Basics of Oncology OVERVIEW OF ANTINEOPLASTIC AGENTS AND CELL CYCLE Lecturer of Pediatric Hematology Oncology, National Cancer Institute, Egypt. 09:00 AM Pacific Time 26 Feb 2025

2. Objectives Antineoplastic agents & Cell cycle Principles of chemotherapy & Drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

3. What is the success?

4. What should Hema/Onc team learn before giving chemotherapy ? Antineoplastic agents & Cell cycle

5. Objectives Antineoplastic agents & Cell cycle Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

6. History of Chemotherapy Basic Principles of Chemotherapy 1

7. The First Chemotherapeutic Agent Found History of Chemotherapy Basic Principles of Chemotherapy 1

8. History of Chemotherapy Basic Principles of Chemotherapy 1

9. ① ② ③ Toxicity and determine MTD Response rate and toxicity Efficacy vs. standard Clinical Trials Phases Phase 4- Post marketing servellance in public Basic Principles of Chemotherapy

10. Basic Principles of Chemotherapy Cytotoxic chemotherapy A gents that can kill you before the cancer does . ( bad news ) The good news is the medical bills and health insurance can kill you before the chemo. Patient view Cytotoxic chemotherapy A gents cause cell death or prevent cell growth, through inhibiting microtubule function, protein function, or DNA synthesis. Medical view C ytotoxic chemotherapy

11. The effective use of chemotherapy needs a deep understanding of the principles of tumor biology , cellular kinetics , pharmacology and drugs resistance Basic Principles of Chemotherapy

12. Drug disposition in the body, Clearance (rate of drug elimination) , Half life (time required to reduce the drug concentration by 50%) , AUC (quantitates total drug exposure) , Volume of distribution (relates plasama conc to total amount of drug in the body) , Bioavailability (rate and extent of absorption of a drug), Biotransformation (enzymatic metabolism of a drug) Age, organ function, drug interactions Basic Principles of Chemotherapy Pharmaco kinetics Definitions Effects of drug on the body, relationship between drug concentration and effect Pharmaco dynamics Genetic variations on spectrum of drug action ( eg., the inherited deficiency of the thiopurine methyltransferase (TPMT) enzyme that results in severe intolerance to thiopurine therapy). Pharmaco genomics 1

13. G0 - resting phase, cell has left the cell cycle G1 - cells increase in size, ready for DNA synthesis S - DNA replication G2 - cells increase in size, ready for mitosis M - mitosis Basic Principles of Chemotherapy Cell cycle Definitions 1

14. G0 - resting phase, cell has left the cell cycle G1 - cells increase in size, ready for DNA synthesis S - DNA replication G2 - cells increase in size, ready for mitosis M - mitosis Basic Principles of Chemotherapy Cell cycle Definitions Alkylating agents eg., Cyclophosphamide, Ifosfamide A ntimetabolitie s ; eg. Mercaptopurine, MTX, Arac Plant alkaloids ; eg., Vincristine Non specific A ntitumor Antibiotics & Hormones Asparaginase Bleomycin, Irinotecan, Mitoxantrone 1

15. Cell kill is limited with bolus dosing Prolonged continuous infusion or frequent intermittent dosing represents a more rational intensification strategy than dose escalation “ Recruitment ” may increase cell kill. Basic Principles of Chemotherapy What are the implications for treatment with agents that are cell cycle dependent? 1

16. The rate of cell loss Doubling time (the length of the cell cycle) The Growth fraction (the % of actively dividing cells) The rate of growth of a tumor is a reflection of → Basic Principles of Chemotherapy Key points about Tumor Kinetics

17. Tumors characteristically exhibit a sigmoid-shaped Gompertzian growth curve, In which tumor doubling time varies with tumor size. Tumors grow most rapidly at small tumor volumes. As tumors become larger, growth slows based on a complex process dependent on: Cell loss and tumor blood and oxygen supply. Basic Principles of Chemotherapy Key points about Tumor Kinetics 1

18. Must achieve a fractional cell kill in a logarithmic fashion Multi-drug therapy Utilizing alternating non–cross-resistant therapies Maximum tolerated dose rate with supportive care Neo-adjuvant vs. adjuvant vs. concomitant chemotherapy 4 3 5 1 2 Strategies to have the best chance for cure Basic Principles of Chemotherapy (1-log-kill is 90% of cells, 2-log-kill is 99% of cells) ( Overcome drug resistance ) ( induction, intensification, and adjuvant regimens) What

19. Combination Chemotherapy? Why It provides maximum cell kill within the range of toxicity tolerated by the host for each drug; Basic Principles of Chemotherapy It offers a broader range of coverage of resistant cell lines in a heterogeneous tumor population; and It prevents or slows the development of new drug- resistant cell lines.

20. The maximum tolerated dose rate? ( Dose intensity ) Why ↓ A dose 20% → a loss of up to 50% of the cure rate. Basic Principles of Chemotherapy ↑ A dose a 2-fold → a 10-fold (1-log) increase in tumor cell kill in animal models .

21. 01 03 02 04 05 06 Active as single agents & can induce complete remissions Differing dose-limiting toxicities Given at consistent intervals Different mechanisms of action Used in their optimal dose and schedule Different patterns of resistance should be combined How to select drugs for Combination Regimens ? Basic Principles of Chemotherapy

22. Basic Principles of Chemotherapy Common Combinationm Chemotherapy Regimens 1

23. Rational of Chemotherapy Basic Principles of Chemotherapy To control symptoms or prolong life in a patient in whom cure is unlikely. curative vs palliative To induce remission and cure

24. Rational of Chemotherapy ( curative vs palliative ) Basic Principles of Chemotherapy Induction : High-dose, usually combination, The intent of inducing CR. Consolidation : A patient who has achieved a CR after induction, The intent of ↑ cure rate or prolonging remission. Intensification : Higher doses, The intent of ↑ cure rate or prolonging remission. Maintenance : Long-term, low-dose, single or combination The intent of delaying the regrowth of residual tumor cells. Neoadjuvant : Given in the preoperative or perioperative period To make non-operable tumors operable ( ↓ tumor bulk), To achieve organ preservation, Early eradication of micrometastasis, To assess tumor responsiveness to initial therapy. Adjuvant : A short course of high-dose, usually combination, In a patient with no residual cancer after surgery or RTH, The intent of killing micrometastatic disease & ↑ DFS. Salvage : A potentially curative, high-dose, usually combination, Regimen given in a patient who has failed or recurred. Metronomic chemotherapy: : Oral chronic administration of chemotherapy Has both antitumorigenic and antiangiogenic effect on tumor endothelial tumor cell (ex, Fibromatosis)

25. Rational of Chemotherapy Basic Principles of Chemotherapy

26. Complete response : disappearance of all evidence of disease and no appearance of new disease for a specified interval (usually 4 weeks). Partial response : a reduction by at least 50% in the sum of the products of the two longest diameters of all lesions, maintained for at least one course of therapy, with no appearance of new disease. Minimal response ( stable disease ): any response less than a partial response. Progression : growth of existing disease ≥ 25% or appearance of new disease during chemotherapy Overall survival (OS) : From the time of diagnosis to death. Disease free survival (DFS) : From the time of CR to first recurrence. Event free survival (EFS) : From the time of treatment to first event (eg progression or relapse or disapearance). Basic Principles of Chemotherapy Definitions of response * Clinical Endpoints in Evaluating Response to Chemotherapy * According to WHO guidelines Survival 1

27. Surface area based dosing Age based intra-thecal dosing Basic Principles of Chemotherapy How is chemotherapy dose calculated 1

28. Injection (IV, IA, IM) Intraperitoneal (IP) Intrathecal (IT) Topical Oral Basic Principles of Chemotherapy How is chemotherapy given? IV chemotherapy is often given through Central venous access device (CVAD). Hickman line – inserted into the chest Peripherally inserted central catheter ( PICC ) line – inserted into the arm Port-a-cath ( port ) – a device inserted under the skin of the chest or arm 1

29. Benefits Reduces the need for repeated peripheral cannulation/venepuncture. Reduces trauma and anxiety Provide long-term venous access. Provide a safer route of administration for vesicant therapy (eg., VCR or Anthracyclin) Basic Principles of Chemotherapy What are benefits and drawbacks of CVAD? * Disadvantages Increased risk of infection. They all require routine care and maintenance to facilitate their effectiveness. A potential risk to the patient for developing bleeding, venous obstruction, cardiac tamponade, emboli, SVC/IVC obstruction and sepsis. CVADs have an increased risk of developing thrombi and/or fibrin sheaths. 1 * Developed for Markham Stouffville Hospital use by:Professional Practice Revised June 2021

30. High-dose systemic chemotherapy (Methotrexate, cytarabine) Drugs that penetrate the BBB (nitrosoureas, thiotepa, camptothecins) Disrupting the BBB (mannitol) Administration of drug into the intrathecal space (methotrexate, cytarabine) Basic Principles of Chemotherapy Strategies to enhance CNS penetration 1

31. Primary Resistance : When the cancer does not respond to standard chemotherapy from the first exposure. Acquired Resistance : When the tumour initially responds to chemotherapy and then becomes resistant. Drug Resistance Types: 1

32. ↑ MDR1 Decreased drug accumulation (Overexpression of the MDR1 (multidrug resistance) gene is the most notable mediator of drug resistance and encodes transmembrane p-glycoprotein, ↑P-glycoprotein, is an energy-dependent pump that serves to remove toxins or endogenous metabolites from the cell) ( most common ) Outside Decreased drug uptake by cells Increased or altered affinity of target Increased production of competitive substrate Inside Decreased intracellular drug activation Increased intracellular drug catabolism Increased DNA repair ↑ Bcl-2 Decreased apoptosis How ( drug resistance )

33. Drug Resistance Sum up for the different mechanism of resistance according to the drug * 1 * ASPHO pediatric Heh/Onc review course 2017

34. It occurs when the clinical effect of a given drug is altered by the action of another drug . Chemotherapy drugs generally have a narrow therapeutic index , making any DDI highly significant. Narrow therapeutic index (NTI) means where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. Drug interaction has three main types: pharmaceutical , pharmacokinetic , and pharmacodynamic . Drug Resistance A drug-drug interaction (DDI) 1

35. 1. Pharmaceutical interactions It occurs because of a physical or chemical incompatibility. Ex., Taxanes, epipodophyllotoxins, and 5-fluorouracil (5-FU) have been shown to precipitate in infusion fluids. Drug Resistance Drug resistance, DDI 1

36. 2. Pharmacokinetic interactions The liver metabolizes drugs through the cytochrome P450 (CYP450) enzyme system, which consists of approximately 100 isoenzymes such as CYP3A4, 2D6, 2C19, and 2C9. Some medications can also induce or inhibit the effects of these isoenzymes. Administration of chemotherapy agents that are catabolized by CYP450 with drug inducers (eg., Phenytoin) of these isoenzymes can facilitate chemotherapy clearance, potentially resulting in decreased efficacy and in turn to an increased risk of relapse.  On the other hand, administration of chemotherapy agents with inhibitors (eg., Proton pump inhibitors) of CYP450 can result in slow clearance and increased toxicity. ( Omeprazole delay the elimination of HDMTX) - (Omeprazole decrease absorption of TKIs) Drug Resistance Drug resistance, DDI 1

37. 2. Pharmacokinetic interactions NSAIDs (indomethacin, ibuprofen, and naproxen ), inhibit the formation of prostaglandins, leading to decreased renal perfusion and decreased methotrexate clearance when both agents are combined. Acetaminophen should also be avoided because of its potential to aggravate the hepatotoxicity of certain drugs such as imatinib (opioids could be prescribed as alternative). Azole antifungals (ex: Fluconazole ,voriconazole, and itraconazole) increase neurotoxicity (paralytic ileus, paralysis of extremities, and even seizures), when were administered with vinca alkaloids (vincristine, vinblastine). Amphotericin B increase the nephrotoxicity (HDMTX or cisplatin) when combined with them. Penicillins interfere with the proximal tubular secretion of methotrexate thus delaying the excretion of MTX and resulting in severe renal, hepatic, and hematologic toxicities. TMP/SMX may slightly increase MTX toxicit y. Both TMP and methotrexate block the reduction of dihydrofolate to tetrahydrofolate by inhibiting dihydrofolate reductase, resulting in additive methotrexate toxicity. Milk and dairy products (contain xanthine oxidase) decrease the bioavailability of mercaptopurine (converted into inactive metabolites) Drug Resistance Drug resistance, DDI 1

38. 3. Pharmacodynamic interactions Pharmacodynamic interactions are those in which one drug has an antagonistic , or synergistic effect on another. In a synergistic reaction , leucovorin enhances the cytotoxicity of 5-FU (increasing the binding of the drug to thymidine synthase), this combination frequently is used in the management of colon cancer. Drug Resistance Drug resistance, DDI 1

39. Clinicians should know all of their patients’ current drugs, including drugs prescribed by other clinicians (herbal products, and nutritional supplements). Asking patients relevant questions about diet is recommended. The fewest drugs in the lowest doses for the shortest possible time should be prescribed. If possible, drugs with a wide safety margin should be used. Patients should be observed and monitored for adverse effects, particularly after a change in treatment. Some interactions may take ≥ 1 week to appear. Drug interactions should be considered as a possible cause of any unexpected problems. When unexpected clinical responses occur, prescribers should determine serum concentrations of selected drugs being taken, consult an expert in drug interactions, and adjust the dosage until the desired effect is produced. If dosage adjustment is ineffective, the drug should be replaced by one that does not interact with other drugs being taken. Drug Resistance Strategies to m inimize drug interactions 1 Pharmacodynamic & Pharmacokinetic interactions

40. Liposomal drugs , Liposomes are well defined lipid and lipoprotein vesicles that offer immense potential for targeting drugs to tumors (eg, doxorubicin (Doxil), daunorubicin (DaunoXome), cytarabine (DepoCyt), and amphotericin B (Abelcet). Advantages Provides selective passive targeting to tumor sites Increases efficacy and therapeutic index Improves delivery of hydrophobic molecules Reduces the toxicities of the encapsulated agent Avoids accumulation in vital organs and tissues Improves pharmacokinetics (reduced elimination, increased drug exposure time) Increases stability via encapsulation Enhances intracellular drug delivery to overcome drug resistance Drug Resistance Strategies to overcome chemotherapy resistance 1 Pharmacodynamic & Pharmacokinetic interactions

41. Objectives Antineoplastic agents & Cell cycle Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

42. Objectives Antineoplastic agents & Cell cycle Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

43. Alkylating Agents (Ifosfamide, Cyclo, ...) Platinum analogues (Cisplatin, Carboplatin,...) Antimetabolites (6mp, MTX, ARAc) Topoisomerase I inhibitors Topoisomerase II inhibitors (Doxo, vp16,...) Antibiotics (Bleomycin) Plant Products ( Anti-microtubule drugs ) Miscellaneous ( Asparaginase, Cortecosteroids, ATRA ) Kinase Inhibitors ( TKIs, Imatinib ) Other small molecule targeted agents ( Bortezomib ) Monoclonal antibodies ( Rituximab, Brentuximab ) Classification of Chemotherapeutic drugs ( Classification based on → Group name ) 2

44. Classification of Chemotherapeutic drugs ( Sum up mechanism of Action ) 2

45. Classification of Chemotherapeutic drugs What is the difference between traditional chemotherapy and targeted therapy? 2 Traditional chemotherapy cannot discriminate between cancer and normal dividing cells because they cause DNA damage or interfere with global mechanisms involved in cell replication, cell division, and protein synthesis. Targeted therapies are more able to differentiate cancer cells from normal cells either by recognizing a specific cell surface marker (monoclonal antibody or antibody drug conjugate) or by blocking a growth pathway upon which the cancer cell is uniquely dependent, often by virtue of a molecular change or mutation specific to the cancer cell. Growth pathway inhibitors are often “ cytostatic ” (prevent new growth), trigger apoptosis (programmed cell death), or induce terminal differentiation.

46. Alkylating Agents ( Cyclophosphamide ) 01 Classification of Chemotherapeutic drugs Therapeutic indications : L ymphomas, multiple myeloma, ovarian cancer, breast cancer Other: leukemias, solid tumors, immunosuppression, severe autoimmune diseases Contraindications : Severely impaired liver or renal function, acute infections, C ystitis, urinary tract obstruction Side effects : Bone marrow: myelosuppression dose-limiting, leukopenia (nadir 8–14 days after administration) and thrombocytopenia, anemia Gastrointestinal: nausea, vomiting (especially with doses > 600 mg/m2/day), mucositis, stomatitis, loss of appetite Liver : transient elevation of transaminases, cholestasis (rare) Kidney / genitourinary tract : hemorrhagic cystitis (dose-limiting), especially with high-dose therapy, bladder fibrosis, impaired renal function Cardiovascular : in 5–10% of cases with high-dose therapy, acute myocarditis / pericarditis, heart failure, hemorrhagic myocardial necrosis Pulmonary: with high-dose therapy, pulmonary fibrosis (rare), pneumonitis Skin : alopecia, erythema, hyperpigmentation, nail changes, dermatitis Nervous system: with high-dose therapy: acute encephalopathy Other: infertility, immunosuppression, fever, allergic reactions Chemo : Alkylating agent MOA : Cell-cycle-specific : non specific DNA and RNA alkylation, DNA strand breaks, cross-linking , DNA synthesis ↓ Dose & Administration Standard dose : oral or intravenous administration, various protocols: − 50–200 mg/m 2 /day p.o. on days 1–14 in the morning, / 28 days − 500–1,000 mg/m 2 /day i.v. on day 1 in the morning, every 21 days • High-dose therapy: up to 16,000 mg/m 2 /day i.v. Dose limiting toxicity Myelosuppression, hemorrhagic cystitis Kinetic : Oral bioavailability 90–100% - Terminal t½ 4-8 h Elimination: Initial hepatic hydroxylation, release of active metabolite, Hepatic degradation into inactive metabolites. Renal excretion of active and inactive metabolites, dialyzable.

47. Classification of Chemotherapeutic drugs Describe the mechanism of hemorrhagic cystitis with ifosfamide and cyclophosphamide and what can be done to prevent it. 2 Ifos and cyclo undergo hepatic transformation to both active and inactive metabolites. One ofthese metabolites, acrolein , is believed to bind to and irritate the urogenic epithelium and can cause profuse bleeding of the bladder that may be dose-limiting. Mesna (sodium-2-mercaptoethane sulfonate) is rapidly oxidized in plasma to an inert disulfide compound that is resorbed by the kidney and only converted back to its active form in the renal tubules. Therefore it combines and deactivates acrolein and acrolein-precursors by forming nontoxic thioethers only after these metabolites have been excreted in the urine. Prevention : giving ifosfamide and cyclophosphamide in conjunction with mesna, vigorous hydration, and frequent voiding, the incidence of hemorrhagic cystitis has been markedly reduced, even in the context of profound dose escalation.

48. 02 Platinum analogues ( Cisplatin ) Classification of Chemotherapeutic drugs Side effects : Bone marrow: myelosuppression, leukopenia, thrombocytopenia, anemia Gastrointestinal: severe N/V (prolonged, duration >24 h), loss of appetite, mucositis, diarrhea Liver: transient elevation of transaminases Kidney: electrolyte changes (Ca2+ ↓, Mg2+ ↓, K+ ↓, Na+ ↓), cumulative nephrotoxicity with renal tubular damage (dose-limiting), probably from inadequate hydration Skin: alopecia, dermatitis Local toxicity (extravasation): phlebitis, necrosis Nervous system: ototoxicity and peripheral neurotoxicity (dose-limiting, cumulative, with total doses > 100–200 mg/m2), dysgeusia, focal encephalopathy (rare), visual disturbances, optic neuritis, vertigo Cardiovascular: arrhythmias (rare), heart failure Other: infertility, allergic reactions (rare) Chemo : Platinum derivative MOA : Cell-cycle-specific : G1/ S phase Covalent binding of platinum complexes to DNA, RNA, and proteins, cross-linking . Dose & Administration Low dose: 15–20 mg/m 2 /day i.v. on days 1–5, every 3–4 weeks Medium dose: 50–75 mg/m 2 /day i.v. on days 1 + 8, every 3–4 weeks High dose: 80–120 mg/m 2 /day i.v. on day 1, every 3–4 weeks Therapeutic indications : Testicular tumors, ovarian cancer, bladder cancer S olid tumors ( H&N region, lungs, esophagus, cervix, endometrium, prostate, osteosarcoma, melanoma), NHL Contraindications : Impaired renal function, dehydration, acute infections Hearing disorders Kinetic : I nitial t½ 25–50 min, terminal t½ 60–90 h Elimination: renal excretion (90%) of unchanged drug and metabolites, biliary excretion (10%) Dose limiting toxicity Renal tubular damage, ototoxicity and peripheral neurotoxicity

49. 3A Antimetabolites 6-Mercaptopurine ( 6-MP ) Classification of Chemotherapeutic drugs Therapeutic indications : ALL AML, CML, NHL, polycythemia vera, chronic inflammatory diseases Contraindications : Severely impaired liver functions Dose limiting toxicity : myelosuppression Side effects : Bone marrow: myelosuppression (dose-limiting), leukopenia, thrombocytopenia, anemia Gastrointestinal: moderate nausea, vomiting, loss of appetite in 25% of patients, mucositis, diarrhea, abdominal pain Liver: transient elevation of transaminases, cholestasis in 30% of patients, severe liver impairment in isolated cases, hepatic veno-occlusive disease (VOD) Kidney: reversible decrease of renal function, hyperuricemia Skin: dermatitis (rare), exanthema, hyperpigmentation, moderate alopecia Other: fever, immunosuppression Chemo : Antimetabolite ( Purine analog ). Daily 6-MP is the backbone of maintenance therapy for ALL. MOA : Cell-cycle-specific : S phase Inhibition of de novo purine synthesis and purine conversion. Dose & Administration Standard dose: 70–100 mg/m 2 /day p.o. daily (1.5–2.5 mg/kg/day) Pharmacogenomics: Patients with TPMT SNPs associated with lower enzymatic activity, either heterozygous (3-14%) or homozygous can cause moderate to severe myelosuppression when treated with conventional doses of 6-MP. Kinetic : Oral bioavailability 5-35% - Terminal t½ 0.5 - 3 h Elimination: Intrace llular activation ( metabolized to 6-thioguanine nucleotide (6-TG) Hepatic degradation by xanthine oxidase (half-life prolonged if xanthine oxidase inhibitors given, e.g., allopurinol). The enzyme, thiopurine methyltransferase ( TPMT ) catalyzes the S-methylation of thiopurine to an inactive metabolite. Biliary (80–85%) and renal (5–20%) excretion Renal excretion of active and inactive metabolites , dialyzable.

50. 3B Antimetabolites Methotrexate ( MTX ) Classification of Chemotherapeutic drugs Therapeutic indications : ALL, malignant lymphomas, meningeal leukemia, solid tumors. Bengin disorders: psoriasis vulgaris, rheumatoid arthritis. Other areas of use: immunosuppression with allogeneic stem cell transplantation Contraindications : Impaired liver & renal functions Third space, fluid deposits: pleural effusions, ascites, etc. Gastrointestinal ulcers Dose limiting toxicity Myelosuppression, pronounced mucositis, renal tubular damage Side effects : Bone M: myelosuppression (dose-limiting), leukopenia, thrombocytopenia, anemia Pulmonary: pneumonitis (rare), pulmonary fibrosis Gastrointestinal: pronounced mucositis (dose-limiting), moderate nausea / vomiting, diarrhea, gastrointestinal bleeding (rare) Liver: impaired liver function, elevated transaminases Kidney : renal tubular damage (dose-limiting), especially with acidic urine (pH < 7.0) Skin : dermatitis, erythema, exanthema, pruritus, conjunctivitis, alopecia (rare), palmar-plantar erythrodysesthesia Nervous system : reversible acute encephalopathy, leukoencephalopathy, confusion, motor and sensory disturbances, seizures, coma Other : allergic reactions, anaphylaxis, vasculitis Chemo : Antimetabolite ( a folate inhibitor ) Weekly MTX is the backbone of maintenance therapy for ALL. MOA : Cell-cycle-specific : S phase Dihydrofolate reductase ↓ → tetrahydrofolic acid formation ↓→ DNA synthesis ↓ Dose & Administration SLow-dose : 20–60 mg/m 2 /day i.v. weekly or 4–6 mg/m 2 /day p.o. on days 1–3 Medium-high dose : 500 mg/m 2 /day i.v. /2–3 weeks with leucovorin rescue High-dose : up to 12,000 mg/m 2 i.v. with leucovorin rescue. Intrathecally (maximum 15 mg absolute), orally or intramuscularly Do not give with acetylsalicylic acid, penicillin, sulfonamides, phenytoin (renal excretion ↓) . Kinetic : 50–70% plasma protein-bound, Terminal t½ 8-10 h Elimination: Hepatic inactivation by hydroxylation (20–45%), Renal and biliary excretion of unchanged drug (80%) and metabolites (20%) Folinic Acid ( Calcium Folinate, Leucovorin ): an antidote for medium-high dose

51. Classification of Chemotherapeutic drugs Leucovorin Rescue 2 Folinic Acid ( Calcium Folinate, Leucovorin ): an antidote for medium-high dose methotrexate

52. 3C Antimetabolites Cytarabine ( AraC ) Classification of Chemotherapeutic drugs Therapeutic indications : AML, ALL, CML in blast crisis, NHL Contraindications : Impaired liver & renal functions, pre-existing CNS disease Dose limiting toxicity : myelosuppression Side effects : Bone M: myelosuppression (dose-limiting), leukopenia, thrombocytopenia, anemia Pulmonary: with high-dose therapy acute pulmonary toxicity, pulmonary edema, ARDS (“acute respiratory distress syndrome”) → intensive care unit necessary Gastrointestinal: nausea / vomiting, mucositis, diarrhea, loss of appetite. Rarely with high-dose therapy, pancreatitis, ulcers, bowel necrosis, esophagitis Liver: transient elevation of transaminases, cholestasis Skin : alopecia, dermatitis, erythema, exanthema, keratitis Nervous system : peripheral and central neurotoxicity. Cerebral and cerebellar disorders, especially in older patients (> 60 years) and with high-dose therapy. With intrathecal administration: acute arachnoiditis, leukoencephalopathy Other : fever, myalgia, arthralgia, bone,muscle pain, flu-like symptoms, conjunctivitis Chemo : Antimetabolite ( Pyrimidine analog ) MOA : Cell-cycle-specific : S phase Incorporated into DNA, inhibition of DNA polymerases , DNA synthesis ↓ Dose & Administration Low-dose AraC: 10–20 mg/m 2 /day s.c. daily, for 21 days Medium-dose AraC: 100 mg/m 2 twice a day i.v. on days 1–7 or 200 mg/m2/day c.i.v. on days 1–7 High-dose AraC: 1,000–3,000 mg/m 2 twice a day i.v. on days 1–6, with prophylactic administration of dexamethasone i.v. and as eye drops Intrathecal (40–50 mg absolute) or intramuscular administration possible Kinetic : Initial t½ 12 m - Terminal t½ 2 h Elimination: Intracellular phosphorylation to active ara-CMP and ara-CTP, Hepatic degradation into inactive metabolites (ara-U, ara-UMP) by deamination, Renal excretion of metabolites

53. Topoisomerase I inhibitors ( Irinotecan, Topotecan ) 04 Classification of Chemotherapeutic drugs Therapeutic indications : M etastatic colorectal cancer Others: gastrointestinal tumors, lung cancer, ovarian cancer, cervical cancer, sarcoma ( RMS ) Contraindications : Pre-existing diarrhea, acute infections Side effects : BM: myelosuppression , neutropenia, eosinophilia , thrombocytopenia, anemia Cardiovascular: thromboembolic events (rare) Gastrointestinal: nausea, vomiting, loss of appetite, delayed and in some cases severe diarrhea with mucositis (5–10 days after administration) in 10–20% of patients Liver: transient elevation of transaminases Kidney: reversible decrease of renal function, microscopic hematuria Skin: alopecia, erythema Other: Acute cholinergic syndrome: within 24 h of administration Delayed diarrhea : > 24 h of administration Chemo ( Irinotecan ) : Camptothecin analog, topoisomerase I inhibitor MOA : Cell-cycle-specific : G2/M phase Inhibition of topoisomerase I , DNA religation ↓↓ → DNA strand breaks and DNA intercalation Dose & Administration ( Standard dose ): 250–350 mg/m 2 /day i.v. on day 1, every 3 weeks 100–125 mg/m 2 /day i.v. on days 1, 8, 15, 22, every 6 weeks Kinetic: Half-life: t½ 14 - 18 h . ubiquitous distribution, enters CSF , 3 rd space fluid (pleural effusions, ascites) Metabolism: intracellular activation by carboxylesterase to active metabolite SN-38, hepatic degradation to inactive metabolites, biliary and renal excretion of active and inactive metabolites . Dose limiting toxicity : Myelosuppression - diarrhea Acute cholinergic syndrome Acute diarrhea, occures within 24 h of administration) Especially with doses >300 mg/m 2. It is often accompanied by other symptoms of cholinergic excess, such as abdominal cramping, rhinitis, lacrimation, and salivation. Treat with atropine 0.25–1mg.

54. Classification of Chemotherapeutic drugs What is the mechanism and clinical applications for irinotecan induced diarrhea (IID)? 2 Severe delayed diarrhea: The pathophysiological mechanism of IID. Irinotecan is converted to SN38 then to SN38G. Most of SN38 & SN38G, are excreted along with bile and the fecal route. In the intestinal lumen, SN38G can be converted back to SN38. It causes direct damage to the intestinal mucosa and subsequently delayed diarrhea. Severe delayed diarrhea prophylaxsis and treatment Cephalosporin used to eliminate bacteria in the gut to prevent the conversion of SN38G to active SN38 Activated Charcoal has ability to attract and expel ingested toxins from the GIT. Salvage treatment Loperamide (an opioid) slows gut peristalsis, increases gut transit time and promotes fluid reabsorption. Octreotide is a synthetic somatostatin analogue that decreases hormone secretion (e.g., vasoactive intestinal polypeptide), reduces motility and pancreatic secretions and increases water absorption. Jie Xu, Lu Xie, Xin Sun and Wei Guo. Irinotecan-Induced Diarrhea during a Protracted Administration Schedule for Pediatric Sarcomas - Mechanisms and Clinical Applications . http://clinicsinoncology.com/2022 | Volume 7 | Article 1953

55. 05 Topoisomerase II inhibitors ( Doxorubicin, Liposome-encapsulated Doxorubicin ) Classification of Chemotherapeutic drugs Chemo : topoisomerase II inhibitor (glycoside antibiotic) MOA : Cell-cycle-specific : S/G2 phase Inhibition of topoisomerase II , generation of free oxygen radicals → DNA strand breaks and DNA intercalation Dose & Administration: Standard dose : 45–75 mg/m 2 /day every 21–28 days, 10–20 mg/m 2 /day i.v. weekly High-dose : 90–150 mg/m 2 /day (ATTN: only in transplant centers) Liposome-encapsulated doxorubicin : 20–50 mg/m 2 /day i.v. every 3–4 weeks Kinetic: Half-life: t½ 21 - 90 h - 70% plasma protein-bound. Metabolism: hepatic degradation to active (doxorubicinol) and inactive metabolites, aglycon formation. Biliary (50%) and renal (< 10%) excretion Therapeutic indications : AML, ALL, Lymphoma (HL, NHL) Solid tumours : wilms, sarcoma, lung, ovarian, breast, bladder, thyroid cancers. Contraindications : Cardiac disease (arrhythmias, myocardial infarction, coronary heart disease, HF) Severely impaired liver function, acute infections Side effects : BM: myelosuppression , neutropenia, eosinophilia , thrombocytopenia, anemia Cardiovascular: cardiotoxicity (dose-limiting) Acute cardiotoxicity: ECG changes, arrhythmias, ischemia, infarction Chronic cardiotoxicity: congestive cardiomyopathy with decreased LVEF Gastrointestinal: nausea / vomiting, mucositis, stomatitis, diarrhea (rare) Skin: exanthema, urticaria, alopecia, delayed tissue reaction in a previously irradiated site ( radiation recall reaction ), nail changes, hyperpigmentation (rare); reversible erythrodysesthesia with liposome-encapsulated doxorubicin Local toxicity ( extravasation ): causes severe necrosis Other: fever, allergic reactions, red urine Dose limiting toxicity: Myelosuppression, cardiotoxicity Risk factors for cardiotoxicity: Pre-existing cardiac disorders, Age < 15 or > 60 years, Rapid bolus injection, Mediastinal radiation, Total dose of 400–550 mg/m 2

56. 06 Antibiotic ( Bleomycin ) Classification of Chemotherapeutic drugs Chemo : Antibiotic, isolated from a strain streptomyces verticllus MOA : Cell-cycle-specific : G2/M phase DNA strand breaks , inhibition of DNA ligase, DNA intercalation. Dose & Administration Standard dose : 15–30 mg absolute, 1–2×/week, Administration : i.v. / i.a. / s.c. or I.M, intrapleural With intracavitary administration (pleural effusion, pericardial effusion, urinary bladder) 30–180 mg absolute Kinetic: Initial t½ 30 min, terminal t½ 2–5 h Elimination: cytochrome P450-dependent hepatic activation, intracellular degradation (50%) by aminohydrolase ( low levels in lung and skin → organotoxic ), renal excretion of unchanged drug (50%) and metabolites Therapeutic indications : Testicular cancer, HL, NHL, squamous cell carcinoma S olid tumors, instillation (malignant effusions) Contraindications : Pre-existing lung disease (especially COPD), previous lung radiation, assisted ventilation with increased O2 concentration Severely impaired liver or renal function Side effects : Bone marrow: mild myelosuppression Pulmonary: dose-limiting interstitial pneumonitis and pulmonary fibrosis in up to 10% of cases with cough, dyspnea, hypoxia. Cumulative toxicity especially with total doses > 300 mg, increased in patients aged < 15 years and > 65 years Gastrointestinal : nausea / vomiting, loss of appetite, mucositis, diarrhea Skin: dose-dependent in 50% of patients: alopecia, erythema, urticaria, exanthema, striae, hyperpigmentation, edema, hyperkeratoses, nail changes, pruritus Local toxicity: phlebitis, pain at injection site Other: flu-like symptoms (fever, chills, myalgia). In 1% of patients allergic reactions up to anaphylaxis. Raynaud’s syndrome Dose limiting toxicity Interstitial pneumonitis and pulmonary fibrosis Risk factors for toxicity: Total cumulative dose of ≥ 400 units Renal insuficiency Radiation therapy (chest) Cigarette smoking Exposure to high partial pressure of o 2

57. Plant Products (Anti-microtubule drugs) ( Vincristine ) 07 Classification of Chemotherapeutic drugs Dose limiting toxicity : neurotoxicity Chemo : alkaloid extracted from Vinca rosea, mitotic inhibitor MOA : Cell-cycle-specific : G2 /M phase Binds to tubulin → ↓ formation microtubules → mitotic arrest Inhibition of DNA-dependent RNA polymerases → RNA synthesis ↓ Dose & Administration Standard dose : 1.0–1.4 mg/m2/day i.v. on day 1, maximum single dose 2 mg Kinetic: Half-life: initial t½ < 5 min, terminal t½ 23–85 h Metabolism : hepatic metabolism, biliary excretion (>70–80%), minor renal excretion Therapeutic indications : Lymphomas, leukemias, Solid tumors (e.g., breast cancer, lung cancer, sarcomas, Wilms’ tumor, neuroblastoma, brain tumours) Contraindications : Impaired liver function, hepatic radiation, manifest neuropathies, constipation Side effects : BM: mild myelosuppression , espechially neutropenia Cardiovascular: cardiovascular disorders, hypertension, hypotension Pulmonary: interstitial pneumonitis/bronchospasm (esp. when given in combination with mitomycin C) GIT : constipation / ileus, nausea / vomiting, mucositis, pancreatitis (rare) Kidney : polyuria (ADH secretion ↓), dysuria, urinary retention (bladder atony) Skin : moderate alopecia, erythema CNS : peripheral neurotoxicity (cumulative, dose-limiting ), autonomic neurotoxicity, in some cases cranial nerve deficits and central nervous system disorders: hypesthesia, paresthesias, motor disorders, areflexia, in rare cases paralysis, ataxia, ileus, optic atrophy/blindness, seizures Local toxicity ( extravasation → phlebitis, necrosis) Other: muscle spasms/ pain in mandible, neck, back, limbs, fever (rare)

58. 08 Classification of Chemotherapeutic drugs Miscellaneous ( L-Asparaginase, PEG-Asparaginase ) * Chemo : Enzyme derived from Escherichia coli or Erwinia carotovora. Covalently linked with polyethylene glycol to form PEG-asparaginase. E. coli asparaginase : Hypersensitivity reaction seen in 35% of patients, 10% of those reactions are life-threatening anaphylaxi), PEG-asparaginase : A prolonged half-life, Increases efficacy and reduces the possibility of antibody generation, and Erwinia asparaginase : A lower rate of allergic reactio n, Used in who had previously experienced an allergy to PEG-asparaginase Dose & Administration L-Asparaginase 5,000–20,000 IU/m2/day i.v. or IM for 10–20 days PEG-asparaginase: 2,500 IU/m2/day i.v. or IM every 14 days MOA : Intravascular depletion of asparagine (hydrolysis of L-asparagine → L-asparaginic acid and ammonia) Normal cells induce asparagine synthetase (ASNS) (convert aspartic acid to asparagines) Leukemic blasts are devoid of ASNS. Therapeutic indications : ALL, AML, NHL, CML in lymphatic blast crisis, CLL Kinetic : t½ 8–30 h , t½ prolonged to 3–6 days with PEG-asparaginase Elimination: metabolic degradation (proteolysis) Side effects : Allergic reactions up to anaphylactic shock. Moderate nausea / vomiting (60%), mucositis Impaired liver function, elevated transaminases (50% of patients) Kidney: transient increase of serum creatinine and uric Pancreatitis, hyperglycemia, impairment of clotting factor synthesis (especially fibrinogen and antithrombin III), Thromboembolic events, hemorrhage Contraindications : Known intolerance Pancreatitis Impaired liver function, pre-existing coagulation disorders * Lin Mei, Evelena P . rt al. Pharmacogenetics predictive of response and toxicity in acute ymphoblastic leukemia therapy . 2015 Dose limiting toxicity severe allergic reaction, thrombotic events

59. Wishing

60. Reality

61. Objectives Antineoplastic agents & Cell cycle Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

62. Objectives The role of pharmacogenomics in shaping chemotherapy portocols Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4 3

63. Proper diagnosis shapes treatment Benefits The role of pharmacogenomics in shaping chemotherapy portocol

64. The role of pharmacogenomics in shaping chemotherapy portocols Hereditary syndromes * 3

65. The role of pharmacogenomics in shaping chemotherapy portocols Hereditary syndromes Second, we need dose modification according to each syndrome: Down syndrome with ALL (reduce methotrexate dose) Fanconi syndrome should avoid alkylating agents Ataxia telangiectasia and nijmegen breakage syndrome ( DNA douple starded break disorders like) * Upfront ↓ of high dose methotrexate (>1 g/m 2 ) to 2/3 of the dose is recommended for all patients A 50% reduction of the cyclophosphamide/ifosphamide dosage upfront Radiotherapy should be omitted from any treatment scheme. 3 * Pastorczak A, Attarbaschi A, Bomken S, Borkhardt A, van der Werff ten Bosch J, Elitzur S, Gennery AR, Hlavackova E, Kerekes A, Křenová Z, Mlynarski W. Consensus recommendations for the clinical management of hematological malignancies in patients with DNA double stranded break disorders. Cancers. 2022 Apr 14;14(8):2000.

66. The role of pharmacogenomics in shaping chemotherapy portocols Pharmaco genomics * Lin Mei, Evelena P . rt al. Pharmacogenetics predictive of response and toxicity in acute ymphoblastic leukemia therapy . 2015 3 Drug Gene Effect 6-MP TPMT Myelossupression Brain tumour ITPA Drug clearance, toxicity Drug Gene Effect MTX RFC-1/SLC19A1 Resistance SLCOIBI GI toxicity, drug clearance MTHFR MTX level, neurotoxicity, relapse TTMS Relapse Drug Gene Effect VCR CYP3A5 Neurpathy CEP72 Drug Gene Effect Steroid XIAP, TBL1ZR1 Resistance CRHR1, ACP1 Osteoporosis IL-10, GST Drug efficacy Drug Gene Effect TKIs IKZF1 Heterogeneous response CYP3A4/5 Drug efficacy CYP2D6*4 Adverse effect

67. The role of pharmacogenomics in shaping chemotherapy portocols 6-Mercaptopurine (6-MP) * Pharmacogenomic The enzyme, thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine to an inactive metabolite . These genes are co-dominantly inherited , containing nonsynonymous SNPs, leading to significant differences in enzyme activity and important clinical consequences. Patients with TPMT SNPs associated with lower enzymatic activity , either heterozygous (3-14%) or homozygous can cause moderate to severe myelosuppression when treated with conventional doses of 6-MP. Homozygosity for the TPMT deficient SNP can result in greater risk for radiation-induced brain tumors and chemotherapy-induced acute myeloid leukemia, although these patients tend to have a lower rate of relapse rate. * Lin Mei, Evelena P . rt al. Pharmacogenetics predictive of response and toxicity in acute ymphoblastic leukemia therapy . 2015 3 Drug Gene Effect 6-MP TPMT Myelossupression Brain tumour ITPA Drug clearance, toxicity

68. Objectives Patient and family education Principles of chemotherapy & drug resistance 1 2 3 Classification/Mechanism of action Be familiar with the potential common side effects of chemotherapy The role of pharmacogenomics in shaping chemotherapy portocols Patient and family education Explore your role during/post chemotherapy 4

69. Smart doctor Manger Expert Health Advocator Collaborator Communicator Educator H Mustafa Selim, MD 

70. Message Always put yourself in the others shoes. If you feel that it hurts you, it probably hurts the person too .

71. Patient and family education Home safety after chemotherapy treatment After receiving chemotherapy, patient and his caregiver(s) need to take special care to prevent contact with patient body fluids ( urine, stools, sweat, mucus, blood, vomit, and those from sex ) .

72. Patient and family education Home safety after chemotherapy treatment

73. Some of these products can change how chemotherapy works. So need proper communication before starting chemotherapy Patient and family education Can I take minerals, dietary supplements, or herbs while I get chemotherapy? Common Q from patients Some people think that severe side effects mean that chemotherapy is working well, or that no side effects mean that chemotherapy is not working. ( wrong ) Through → physical exams and medical tests (such as blood tests and imaging) √√√ How will I know if chemotherapy is working?

74. Bring a family member or trusted friend to your medical visits. Make a list of your questions before each appointment. Ask all your questions (There is no such thing as a stupid question). If you do not understand an answer, keep asking until you do. Take notes (You can write them down) . Tell your doctor or nurse about any side effects you are having. Ask for printed information about your type of cancer and chemotherapy. Find out how to contact your doctor or nurse in an emergency. Patient and family education Educate your patients about Tips for meeting

75. Know your options, understanding the disease, the available treatments, possible side effects and any extra costs. Record the details Ask questions, If you are confused or want to check anything Consider a second opinion It’s your decision, to accept or refuse any treatment Patient and family education Educate your patients about Tips for ways to Making treatment decisions by patients

76. Patient and family education Educate your patients about Tips for feeling during chemotherapy It is normal to have a wide range of feelings while going through chemotherapy. You may feel: frustrated, helpless, lonely, anxious, depressed, afraid, angry.

77. Patient and family education Educate your patients about Relax : Find some quiet time and think of yourself in a favorite place. Breathe slowly or listen to soothing music. Exercise (light exercise such as walking, swimming, riding a bike, and doing yoga) . Talk with others. Join a support group (these groups allow you to meet others with the same problems) . Tips for coping with these feelings during chemotherapy?

78. Patient and family education Educate your patients about What are side effects? How long do side effects last? What can be done about side effects?

79. Patient and family education Common side effects Tumor Lysis Syndrome Anemia, bleeding, Infection, Appetite changes, Nausea and vomiting , Constipation, Diarrhea, Mouth and throat changes, Skin and nail changes, Eye changes, Fatigue, Flu-like symptoms, Fluid retention, Hair loss, Infertility, Secondary malignancy, Nervous system changes (neuropathy, Pain), Urinary, kidney, or bladder changes. Hepatotoxicity, Cardiotoxicity, Ototoxicity, pulmonary toxicity

80. Patient and family education Common side effects classifications

81. Thank y u