CHEMOTHERAPY IN HEAD AND NECK CANCERS.pptx

A presentation on chemotherapy in head and neck oncology covering the role of chemotherapy in treating cancers of the head and neck, its indications, and how it is integrated with surgery and radiation therapy. It includes an overview of commonly used chemotherapy agents, such as cisplatin and 5-fluorouracil, their mechanisms of action, and different treatment protocols.

1. CHEMOTHERAPY IN HEAD AND NECK ONCOLOGY PRESENTED BY: DR. Rajat Singh Verma PG Resident Department of ENT (25/09/2024)

2. INTRODUCTION The term chemotherapy was coined by Paul Ehlrich Defined as the use of chemical compounds in treatment of neoplastic diseases so as to destroy offending cancer cells without damaging the host Anticancer drugs have been developed and used medically since the 1940s. nitrogen mustard gas, a chemical warfare agent used in the Second World War, interfered with haematopoiesis . 2

3. PRINCIPLES OF CHEMOTHERAPY Cancer is defined as the uncontrolled growth of cells coupled with malignant behaviour : invasion and metastasis It arises through a complex interaction between genetic and environmental factors, causing genetic mutations in oncogenes and tumour suppressor genes. Chemotherapy aims to exploit the resulting differences in biological and proliferative characteristics between normal and cancer cells where most cytotoxic drugs preferentially affect dividing cells in tumours . 3

4. PRINCIPLES OF TUMOUR BIOLOGY CELL CYCLE – The cell cycle is divided into a number of phases governed by an elaborate set of molecular switches. Normal non-dividing cells are in G0. When actively recruited into the cell cycle they then pass through four phases: G1: the growth phase in which the cell increases in size and prepares to copy DNA S (Synthesis): which allows doubling of the chromosomal material G2: a further growth phase before cell division M (Mitosis): where the chromosomes separate and the cell divides 4

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6. TUMOR GROWTH The kinetics of any population of tumour cells is regulated by the following: • Doubling time : the cell cycle time, which varies considerably between tissue types • Growth fraction : the percentage of cells passing through the cell cycle at a given point in time, which is greatest in the early stages • Cell loss : which can result from unsuccessful division, death, desquamation, metastasis and migration. Tumours characteristically follow a sigmoid shaped growth curve, in which tumour doubling size varies with tumour size. Tumours grow most rapidly at small volumes (Gompertzian kinetics) 6

7. TUMOR GROWTH Cell signalling - Cells respond to their environment via external signals called growth factors. These interact with cell surface receptors that activate an internal signalling cascade Metastatic spread A tumour is considered malignant when it has the capacity to spread beyond its original site and invade surrounding tissue. Mechanism of cell death - Apoptosis and necrosis. Necrotic cell death is caused by gross cell injury, and results in the death of groups of cells within a tissue. Apoptosis is a regulated form of cell death and is characterized by specific DNA changes and no accompanying inflammatory response. 7

8. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS PHASE SPECIFIC – These are effective only during a specific phase of the cell cycle: Methotrexate, cytosine arabinoside, 5-fluorouracil, 6-mercaptopurine, hydroxyurea, etc. act on S phase. Bleomycin acts on G2 phase. Vincristine and vinblastine act on M phase. L-asparaginase acts on Gl phase. 8

9. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS CELL CYCLE SPECIFIC – Most chemotherapy agents are cell-cycle-specific, meaning that they act predominantly on cells that are actively dividing They have a dose-related plateau in their cell killing ability The way to increase cell kill is therefore to increase the duration of exposure rather than increasing the drug dose 9

10. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION ALKYLATING AGENTS - These include, for example, nitrogen mustards (melphalan and chlorambucil) and oxazaphosphorines (cyclophosphamide and ifosfamide ). HEAVY METALS - These include, for example, platinum agents (carboplatin, cisplatin and oxaliplatin). Cisplatin is an organic heavy metal complex which cross-link with the DNA strands, mostly to guanine groups Carboplatin has the same platinum moiety as cisplatin Oxaliplatin contains a platinum atom complexed with oxalate. It inhibit DNA synthesis by forming interstrand and intra strand cross-linking of DNA molecules 10

11. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION ANTIMETABOLITES - compounds that bear a structural similarity to naturally occurring substances. They compete with the natural substrate for the active site on an essential enzyme or receptor. Folic acid antagonists - Methotrexate competitively inhibits dihydrofolate reductase. Dihydrofolate is essential for the generation of a variety of coenzymes. Pyrimidine analogues – resemble pyrimidine molecules and work by either inhibiting the synthesis of nucleic acids (e.g. fluorouracil), inhibiting enzymes involved in DNA synthesis (e.g. cytarabine, which inhibits DNA polymerase) or by becoming incorporated into DNA (e.g. gemcitabine), interfering with DNA synthesis and resulting in cell death 11

12. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION ANTIMETABOLITES - compounds that bear a structural similarity to naturally occurring substances. They compete with the natural substrate for the active site on an essential enzyme or receptor. Purine analogues - These are analogues of the natural purine bases and nucleotides. 6 mercaptopurine (6MP) and thioguanine are derivatives of adenine and guanine. They are then able to inhibit nucleotide biosynthesis by direct incorporation into DNA. 12

13. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION CYTOTOXIC ANTIBIOTICS - Most antitumour antibiotics have been produced from bacterial and fungal cultures (often Streptomyces species). They affect the function and synthesis of nucleic acids in different ways: Anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin ) intercalate with DNA and affect the topoisomerase II enzyme . The anthracyclines stabilize the DNA topoisomerase II complex and thus prevent reconnection of the strands. Actinomycin D intercalates between guanine and cyto sine base pairs. This interferes with the transcription of DNA Bleomycin consists of a mixture of glycopeptides that cause DNA fragmentation 13

14. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION CYTOTOXIC ANTIBIOTICS - Most antitumour antibiotics have been produced from bacterial and fungal cultures (often Streptomyces species). They affect the function and synthesis of nucleic acids in different ways: Mitomycin C inhibits DNA synthesis by cross-linking DNA, acting like an alkylating agent SPINDLE POISONS Vinca alkaloids The two prominent agents are vincristine and vinblastine, which act as mitotic spindle poisons. Taxoids Paclitaxel (Taxol) and docetaxel (Taxotere) promote assembly of microtubules and inhibits their disassembly 14

15. CLASSIFICATION OF CHEMOTHERAPEUTIC DRUGS BASED ON MECHANISM OF ACTION TOPOISOMERASE INHIBITORS - Topoisomerases are responsible for altering the 3D structure of DNA by a cleaving/unwinding/rejoining reaction. They are involved in DNA replication, chromatid segregation and transcription. The drugs are phase-specific and prevent cells from entering mitosis from G2. Topoisomerase I inhibitors (e.g. irinotecan and topetecan ). These bind to the enzyme-DNA complex, stabilizing it and preventing DNA replication Topoisomerase II inhibitors (e.g. etoposide). These stabilize the complex between topoisomerase II and DNA that causes strand breaks and ultimately inhibits DNA replication 15

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17. CHEMOTHERAPY IN HEAD AND NECK CANCERS Chemotherapy is regularly employed in the management of head and neck cancer improving organ preservation when combined with radiotherapy and has led to a reduction in rates of distant metastases. Different strategies are employed when using chemotherapy namely: SINGLE DRUG THERAPY - include metho trexate , cisplatin, carboplatin, fluorouracil, ifosfamide , bleomycin, paclitaxel, and docetaxel. Cisplatin is one of the most active drugs against squamous head and neck cancer. Duration of response is 2 to 4 months and median survival time is approximately 6 months 17

18. CHEMOTHERAPY IN HEAD AND NECK CANCERS COMBINATION THERAPY - Combination chemotherapy was introduced with the aim to improve the response rate and the survival time Cisplatin and 5-fluorouracil combination is the most common drug regimen used for palliation as well as combined modality therapy in head and neck cancers Cisplatin-based regimens are the most effective combinations for the treatment of nasopharyngeal carcinomas 18

19. CHEMOTHERAPY IN HEAD AND NECK CANCERS COMBINED MODALITY THERAPY - Although surgery and radiotherapy form the mainstay of the treatment of cancers of head and neck, majority of the advanced cases present with recurrences.. To prevent this four different approaches are undertaken: Induction or neoadjuvant chemotherapy Concomitant chemoradiation Adjuvant chemotherapy Intra-arterial chemotherapy 19

20. CHEMOTHERAPY IN HEAD AND NECK CANCERS NEOADJUVANT CHEMOTHERAPY Neoadjuvant, or induction chemotherapy, is the use of chemotherapy prior to definitive surgery or radiotherapy in patients with locally advanced disease Response to induction chemotherapy predicts the response to radiation It does not increase the surgical/ radiotherapy complication rates and allows organ preservation and improved quality of life. Neoadjuvant chemotherapy followed by radiotherapy was found to be successful in the preserva tion of voice without decrease in the survival time according to Veteran Affairs larynx study Used in patients with locally advanced disease patients with advanced nodal disease 20

21. CHEMOTHERAPY IN HEAD AND NECK CANCERS Potential benefits of induction chemotherapy: Cytoreduction/down staging of the tumor-facilitate the use of a more conservative approach for surgical procedure or radiotherapy- the possibility of organ preservation Avoids the potential for poor drug distribution due to a compromised vascularization from surgery or radiation therapy- intact vascular bed allows for better drug delivery. Response to preoperative chemotherapy -prognostic importance of overall outcome - important in selecting patients for additional postoperative adjunctive therapy 21

22. CHEMOTHERAPY IN HEAD AND NECK CANCERS Potential adverse effects of induction chemotherapy: Developement of drug resistant cells Increased toxicity with subsequent drugs Inability of chemotherapy agent to produce significant reduction in tumor Loss of the advantage to attack micro metastases after surgery when they may exhibit more favorable cell kinetics. Proper determination of extent of surgery may be difficult 22

23. CHEMOTHERAPY IN HEAD AND NECK CANCERS CONCOMITANT CHEMOTHERAPY This involves the synchronous use of chemotherapy and radiotherapy. The rationale is that chemotherapy can sensitize tumours to radiotherapy by inhibiting tumour repopulation, preferentially killing hypoxic cells, inhibiting the repair of sublethal radia tion damage, sterilizing micrometastatic disease outside of the radiation fields and decreasing the tumour mass, which leads to improved blood supply and reoxygenation Fractionated radiotherapy, in turn, may sensitize tumours to chemotherapy by inhibiting the repair of drug-induced damage and by decreasing the size of the tumour mass 23

24. CHEMOTHERAPY IN HEAD AND NECK CANCERS CONCOMITANT CHEMOTHERAPY Major drawback is severe toxicity when multi-drugs are used. Therefore, split-course radiation is preferred that is alternate chemotherapy and radiotherapy are given to increase the tumor cell kill and decrease the tissue toxicity. 'Concomitant Chemoradiotherapy Boost' is a new app roach to chemoradiotherapy in which after the standard radiotherapy to the primary tumor and the neck, radiation fields are narrowed 24

25. CHEMOTHERAPY IN HEAD AND NECK CANCERS ADJUVANT CHEMOTHERAPY It is the course of chemotherapy given after surgery or radiotherapy to decrease the metastatic burden of the disease. The goal of this secondary treatment is palliation and rarely has long-term benefits Its advantages over induction chemotherapy are Surgery is not delayed. Induction chemotherapy can blur the tumor margins which can hamper in getting the clearance during resection. Induction treatment, if successful, will reduce the symptoms and may lead to refusal of surgery by the patient. 25

26. CHEMOTHERAPY IN HEAD AND NECK CANCERS ADJUVANT CHEMOTHERAPY Its advantages over induction chemotherapy are Surgery is not delayed. Induction chemotherapy can blur the tumor margins which can hamper in getting the clearance during resection. Induction treatment, if successful, will reduce the symptoms and may lead to refusal of surgery by the patient. After surgical debulking, there will be decrease in the population of drug resistant malignant cells 26

27. CHEMOTHERAPY IN HEAD AND NECK CANCERS INTRA ARTERIAL CHEMOTHERAPY Impaired drug delivery into the region, invaded by cancer cells, leads to poor response to chemotherapy Intra-arterial chemotherapy (IAC) is a method of delivering concentrated doses of cancer-killing medicine directly to the affected area  Intra-arterial chemotherapy is tried in advanced paranasal sinus and salivary tumors For paranasal sinus tumors, cannulation of superficial temporal artery and infusion of 5-fluorouracil only or cisplatin+ bleo mycin followed by intravenous 5-fluorouracil followed by surgery and radiotherapy has been tried and claimed to be effective. 27

28. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Methotrexate Cis-Platin/ Carboplatin Taxanes Cyclophosphamide Bleomycin 5- FU Vinca Alkaloids Monoclonal Antibodies (Targeted Therapy) Tyrosine Kinase Inhibitors 28

29. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Methotrexate This is a folic acid analog and it acts on S phase of cell cycle. It inhibits dihydrofolate reductase (DHFR) and thus decreases synthesis of tetrahydrofolic acid Alternate source of tetrahydrofolate is provided by leucovorin Leucovorin rescues cells from methotrexate toxicity, but cancer cells cannot be rescued from the lethal effects of methotrexate as they lack the transport sites for leucovorin. Dose • Mild: 40 to 60 mg/m2 weekly • Moderate: 250 to 500 mg/m2 weekly • High: 5 to 10 gm/ m2 weekly Mode of administration IV /IM/SC/ oral: 29

30. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Methotrexate Toxicity Mild stomatitis and myelosuppression Confluent mucositis Pancytopenia Abnormal LFT Exfoliative maculopapular rash Renal dysfunction, i.e. due to precipitation of methotrexate in acidic urine in high doses. 30

31. SOME COMMON AGENTS IN HEAD AND NECK CANCERS CisPlatin This is an inorganic metal compound, a bifunctional alkylating agent which binds to DNA and causes inter and intra-strand cross-linking. Dose and mode of administration : It is given intravenously with a dose of 80 to 120 mg/m2 every 3 to 4 weeks with mannitol diuresis, or is given as 24 hours continuous infusion. Toxicity Renal dysfunction: Ototoxicity occurs in the frequency of 4000 to 8000 Hz Nausea and vomiting Hematological - Neutropenia- Thrombocytopenia- Anemia - 31

32. SOME COMMON AGENTS IN HEAD AND NECK CANCERS CisPlatin Toxicity Hypomagnesemia Peripheral neuropathy is sensory more than motor Advantages Rapid response Given only once in 3 to 4 weeks Response rate 30% Duration of response 4 months 32

33. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Carboplatin This is a derivative of cisplatin and has same mechanism of action as that of cisplatin. Dose and mode of administration: 400 mg/m2 can be safely given in patients with creatinine clearance of 60mg/mL Toxicity Myelosuppression Rarely neuro-/ oto -/ renal toxicity. Due to its mild toxic effects, it can be given on OPD basis, but it is not as effective as cis-platinum. Its response rate is 24% 33

34. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Taxanes These drugs act on G2 phase. They bind to beta sub unit of tubulin and inhibits microtubule depolymerization causing cell cycle arrest Dose • Paclitaxel: 135 to 250 mg/ m2 over 3 to 24 hours every 3 weeks • Docetaxel: 60 to 100 mg/m2 bolus every 3 weeks. Toxicity: Neutropenia and infection. Growth factors GM-CSF, G-CSF shorten the neutropenic duration, therefore, decrease the risk of infection. Its response rate is 30 to 40% 34

35. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Cyclophosphamide This acts by cross-linking of DNA strands. Dose: 50 to 1500 mg/m2 3 to 4 weekly IV Toxicity Bone marrow suppression Nausea and vomiting Alopecia and ridging of nails Azoospermia and cessation of menses Acute hemorrhagic cystitis Bladder cancer-rare 35

36. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Bleomycin This is an antineoplastic antibiotic. It binds to DNA and generates 02 free radicals which cause DNA strands to breakup Dose: 10 to 20 units/m2 once or twice a week IM/IV, or 10 units/m2/24 hours, continuous infusion over 5 to 7 days. If creatinine clearance is 15 to 30 ml/min, dose is reduced by 50%, if creatinine clearance is less than 15 ml/min, dose is reduced by 75%. Toxicity Fever with chills within 24 hours. Anaphylactic reaction Alopecia 36

37. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Bleomycin Toxicity Erythema, thickening and hyperpigmentation of skin Stomatitis. Pulmonary toxicity: Pneumonitis, dry cough and rales are common. Pulmonary fibrosis and restrictive lung disease may occur at higher doses 37

38. SOME COMMON AGENTS IN HEAD AND NECK CANCERS 5-Fluorouracil It competes with enzyme thymidylate synthetase by displacing uracil and thus inhibits the formation of thymidine causing decrease in DNA synthesis Dose • 10 to 15 mg/kg/week IV, or • 400 to 500 mg/m2 daily for 5 days IV as a loading dose, followed by 400 to 500 mg/m2 weekly IV, or • 1 gm/ m2 / day as continuous infusion for 5 days and repeated 3 to 4 weekly. Toxicity Myelosuppression Nausea, vomiting, diarrhea Alopecia, hyperpigmentation, maculopapular rash Most common drug used in combination with cisplatin 38

39. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Vinca Alkaloids (Vincristine & Vinblastin ) They disrupt microtubular spindle formation and thereby cause mitotic arrest Dose • Vincristine (oncovin) 1 to 1.5 mg/m2 once or twice a month IV. • Vinblastine ( velban ) 5 mg/m2 weekly IV Toxicity Vincristine Neurotoxicity: It causes sensory, motor and peripheral neuropathy. Hoarseness and it increases, if the drug is not stopped. Constipation 39

40. SOME COMMON AGENTS IN HEAD AND NECK CANCERS Vinca Alkaloids (Vincristine & Vinblastin ) Toxicity Vincristine Alopecia Vinblastine Myelosuppression Myalgia Alopecia. 40

41. NOVEL THERAPIES FOR THE FUTURE TARGETED THERAPY Targeted therapy aims to specifically act on a well-defined target or biologic pathway that, when inactivated, causes regression or destruction of the malignant process The therapies are mainly targeted against the follow ing properties of cancer cells (Hanahan, et al. 2000) Growth factor independence Ability to recruit a dedicated blood supply Avoidance of apoptosis Insensitivity to antigrowth signals Reactivation of telomerase Ability to invade adjacent normal tissues and metastasize 41

42. NOVEL THERAPIES FOR THE FUTURE MONOCLONAL ANTIBODIES Monoclonal antibodies can be derived from a variety of sources: murine – mouse antibodies chimeric – part mouse/part human antibodies humanized – engineered to be mostly human human – fully human antibodies. There are several proposed mechanisms of action of monoclonal antibodies as anticancer agents.These include: induction of apoptosis blocking of the receptors needed for cell proliferation/ function , etc 42

43. NOVEL THERAPIES FOR THE FUTURE MONOCLONAL ANTIBODIES Examples include – cetuximab, monoclonal antibody developed against EGFR TARGETED SMALL MOLECULES Gefitinib ( Iressa ) and erlotinib ( Tarceva ) are orally active epidermal growth factor receptor tyrosine kinase inhibi tors (EGFR-TKI) that block the EGFR signalling cascade, thereby inhibiting the growth, proliferation and survival of many solid tumours 43

44. NOVEL THERAPIES FOR THE FUTURE CETUXIMAB It is a human-murine chimeric monoclonal antibody against EGFR ( epidermal growth factor receptor) Overexpression of the receptor without gene ampli fication appears to be the dominant process in squa mous cell cancer or head and neck cancer Cetuximab targets these receptors and has shown antiproliferative effect, direct cytotoxicity anti-angiogenic actions and potentiation of cytotoxic effects of chemo- and radiotherapy Similar EGFR antibodies which have entered clinical trials are zalutumumab and panitumamab . 44

45. NOVEL THERAPIES FOR THE FUTURE GEFTINIB - Low molecular weight tyrosin kinase inhibitor (TKI), specific for EGFR. LAPATINIB- Oral dual TKI acts against both EGFR (c ErbB-1, HER-1) and c-ErbB-2 (HER-2/neu). 1500 mg/ day with chemoradiation in locally advanced SCC of head and neck. BEVACIZUMAB - Humanized MAB to VEGFR ligand (vascular endothelial growth factor). Acts as an anti angiogenic agent. 45

46. NOVEL THERAPIES FOR THE FUTURE Tyrosine Kinase Inhibitors T yrosine kinases are transmembrane  glycoproteins that regulate cell proliferation, differentiation, and singnalling Activity of tyrosine kinases implicated in many cancers and other proliferative disease such as atherosclerosis and psoriasis Chief example is imatinib . 46

47. CHEMOPROTECTIVE AGENTS Chemoprotective agents are substances that help protect normal, healthy tissues from the harmful effects of chemotherapy without reducing the effectiveness of the treatment against cancer cells These agents are often used to minimize chemotherapy-induced toxicities in various organs, such as the heart, kidneys, and bone marrow 47

48. CHEMOPROTECTIVE AGENTS AMIFOSTINE Used for : Protection against radiation-induced xerostomia (dry mouth) and chemotherapy-induced toxicities (especially with cisplatin). Mechanism : A cytoprotective agent that scavenges free radicals and detoxifies harmful metabolites produced during chemotherapy. Protects : Kidneys (nephrotoxicity), salivary glands (from radiation), and bone marrow. Specific Chemotherapy Drugs : Cisplatin, radiation therapy 48

49. CHEMOPROTECTIVE AGENTS MESNA (2 – MERCAPTOETHANE SULFONATE SODIUM) Used for : Prevention of hemorrhagic cystitis (bladder toxicity) induced by chemotherapy. Mechanism : Binds to and neutralizes the toxic metabolites of alkylating agents, particularly acrolein. Protects : Bladder from toxicity caused by chemotherapy agents like cyclophosphamide and ifosfamide . Specific Chemotherapy Drugs : Ifosfamide , cyclophosphamide 49

50. CHEMOPROTECTIVE AGENTS DEXRAZOXANE Used for : Prevention of cardiotoxicity associated with anthracycline chemotherapy. Mechanism : Acts as a chelating agent by binding to iron and preventing the formation of free radicals, which can damage heart tissue. Protects : The heart (from cardiomyopathy). Specific Chemotherapy Drugs : Doxorubicin, epirubicin (anthracyclines) 50

51. CHEMOPROTECTIVE AGENTS LEUCOVORINE (FOLINIC ACID) Used for : As a rescue agent to reduce toxicity from methotrexate and enhance the efficacy of fluorouracil (5-FU). Mechanism : Provides a source of reduced folate, helping to rescue normal cells from the effects of folic acid antagonists like methotrexate. Protects : Bone marrow, gastrointestinal lining (prevents mucositis), and other rapidly dividing cells from folate deficiency. Specific Chemotherapy Drugs : Methotrexate, fluorouracil (5-FU). 51

52. CHEMOPROTECTIVE AGENTS PALIFERMIN Used for : Reducing the incidence and severity of mucositis (inflammation and ulceration of the mucous membranes) in patients undergoing chemotherapy or radiation therapy. Mechanism : A keratinocyte growth factor that promotes the growth and repair of mucosal cells in the mouth and gastrointestinal tract. Protects : Oral mucosa (from mucositis). Specific Chemotherapy Drugs : Often used in high-dose chemotherapy for bone marrow transplantation. 52

53. CHEMOPROTECTIVE AGENTS GLUTATHIONE Used for : Reducing neurotoxicity and other toxicities associated with platinum-based chemotherapy. Mechanism : A potent antioxidant that neutralizes free radicals and detoxifies harmful chemotherapy metabolites. Protects : Kidneys, nerves (neuropathy), and bone marrow. Specific Chemotherapy Drugs : Cisplatin, carboplatin. 53

54. CHEMOPROTECTIVE AGENTS SODIUM THIOSULFATE Used for : Prevention of nephrotoxicity and ototoxicity associated with platinum-based chemotherapy (especially in children). Mechanism : Neutralizes the toxic effects of platinum-based chemotherapy by providing a substrate for conjugation and elimination. Protects : Kidneys (nephrotoxicity) and ears (ototoxicity). Specific Chemotherapy Drugs : Cisplatin 54

55. CHEMOPROTECTIVE AGENTS COLONY STIMULATING FACTORS (CSF) Granulocyte colony-stimulating factor (G-CSF) (e.g., Filgrastim , Pegfilgrastim ) and Granulocyte-macrophage colony-stimulating factor (GM-CSF) . Used for : Prevention and treatment of neutropenia (low white blood cell count), reducing the risk of infection during chemotherapy. Mechanism : Stimulates the production of neutrophils in the bone marrow. Protects : The bone marrow (from neutropenia and infection risk). Specific Chemotherapy Drugs : Various myelosuppressive agents, such as those used in solid tumors and hematologic cancers. 55

56. CHEMOPROTECTIVE AGENTS N- ACETYLCYSTINE Used for : Protecting against hepatic and renal toxicity . Mechanism : Acts as an antioxidant and replenishes intracellular glutathione levels, helping to detoxify harmful metabolites. Protects : Liver and kidneys. Specific Chemotherapy Drugs : Used in conjunction with high-dose chemotherapy that can cause liver damage 56

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