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Chemotherapy

Chemotherapy. Chemotherapy. History General approaches Preparation Commonly used agents mechanism of action indications toxicity. Ancient practices. Medieval times. 19 th Century. 20 th Century. Different approaches to using chemotherapy. Combination chemotherapy

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Chemotherapy

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  1. Chemotherapy

  2. Chemotherapy • History • General approaches • Preparation • Commonly used agents • mechanism of action • indications • toxicity

  3. Ancient practices

  4. Medieval times

  5. 19th Century

  6. 20th Century

  7. Different approaches to using chemotherapy Combination chemotherapy Neoadjuvant chemotherapy Adjuvant chemotherapy Dose intensity Rescue

  8. Combination chemotherapy Works better than single agents. Most effective when each agent has a different mechanism of cell kill. prednisone → apoptosis vincristine → mitotic spindle inhibitor doxorubicin → DNA intercalator Best if there are non-overlapping toxicities prednisone → weight gain, HTN, ulcer, diabetes vincristine → peripheral neuropathy doxorubicin → myelosuppression

  9. vincristine • ↓ • ↑ • methotrexate

  10. Combination chemotherapy works! • Ewing sarcoma • vincristine + doxorubicin + cyclophosphamide (VAC) • ifosfamide + etoposide (IE) • VAC alone 50% overall survival • VAC/IE 70% overall survival

  11. Neoadjuvant chemotherapy • Therapy given prior to definitive local therapy • chemotherapy →surgery • →

  12. Adjuvant therapy • Therapy given after local therapy • Dose intensity • Philosophy that “more is better” • Rescue • Giving agents to protect the patient from toxicity of treatment • Methotrexate → leucovorin rescue • Cyclophosphamide → MESNA • High dose chemotherapy → stem cell infusion

  13. Preparation

  14. Main classes of chemotherapy Alkylating agents Antimetabolites Antitumor antibiotics Plant products Miscellaneous agents

  15. Alkylating agents • Cyclophosphamide • Ifosfamide • Melphalan • Nitrosoureas (BCNU/CCNU) • Carboplatin • Cisplatin • Procarbazine • Temozolomide

  16. Mechanism of action • Covalently links alkyl group to DNA and creates cross-links

  17. Cyclophosphamide • Indications • Leukemia: ALL • Lymphoma: Hodgkins and non-Hodgkins • Solid tumors: neuroblastoma • rhabdomyosarcoma • Ewing sarcoma • Brain tumors: medulloblastoma • infant brain tumors

  18. Cyclophosphamide • Dosing and delivery • Dosing: low-dose: 50 – 100mg PO • medium dose: 250 – 750mg/m2 IV • high dose: 1000 – 4000 mg/m2 IV • Delivery: give with IV fluids (> 125 ml/m2/hr) • for doses > 1000mg/m2 give MESNA

  19. Cyclophosphamide • Toxicity • Short term • Nausea and vomiting • Hair loss • Myelosuppression • Hemorrhagic cystitis • Long term • Sterility • Second malignancies

  20. Cisplatin • Indications • Leukemia: no • Lymphoma: no • Solid tumors: neuroblastoma • osteosarcoma • germ cell tumors • hepatoblastoma • Brain tumors: medulloblastoma • infant brain tumors

  21. Cisplatin • Dosing and delivery • Dosing: 20 – 40mg/m2 IV once a day for 5 days • 75 – 100 mg/m2 IV as a single dose • Delivery: give with IV fluids (> 125 ml/m2/hr) • add mannitol

  22. Cisplatin • Toxicity • Short term • Severe nausea and vomiting • Delayed nausea and vomiting • Hair loss • Mild myelosuppression • Long term • Sterility • Hearing loss • Renal toxicity • Second malignancies

  23. Anti-metabolitesDrugs that interfere with specific biochemical pathways • Methotrexate • Thiopurines • Cytosine arabinoside (ara-C) • Fluorouracil

  24. Methotrexatemechanism of action Dihydrofolate reductase inhibitor Results in inhibition of purine production

  25. Methotrexate • Indications • Leukemia: ALL • Lymphoma: non-Hodgkins • Solid tumors: osteosarcoma • Brain tumors: infant brain tumors

  26. Methotrexate • Dosing and delivery • Dosing: low-dose: 20 – 100mg/m2 PO/IM/IV • medium dose: 1-4 gm/m2 IV • high dose: 8-12 gm/m2 IV • Delivery: caution with the medium – high doses! • give with IV fluids (> 125 ml/m2/hr) • fluids should be alkaline (40 – 75 mEq/l NaHCO3) • leucovorin rescueis REQUIRED

  27. Methotrexate • Toxicity • Short term • Nausea and vomiting • Hair loss • Myelosuppression • Mucositis • Renal damage • encephalopathy • Long term • no major problems

  28. Anti-tumor antibiotics • Anthracyclines • Doxorubicin • Daunomycin • Idarubicin • Mitoxantrone • Bleomycin • Dactinomycin

  29. Doxorubicinmechanism of action intercalate into DNA DNA breaks oxidative damage

  30. Doxorubicin • Indications • Leukemia: ALL, AML • Lymphoma: Hodgkins, non-Hodgkins • Solid tumors: Wilms tumor • neuroblastoma • soft tissue sarcoma • Ewing sarcoma • osteosarcoma • Brain tumors: no

  31. doxorubicin • Dosing and delivery • Dosing: 25 – 75 mg/m2 IV • Delivery: usually give IV push over a few minutes • Cumulative doses exceeding 300- 360 mg/m2 is not recommended

  32. Doxorubicin • Toxicity • Short term • Nausea and vomiting • Hair loss • Myelosuppression • Mucositis • Skin burns due to extravasation • Long term • cardiomyopathy

  33. Dactinomycin (Actinomycin D)mechanism of action intercalate into DNA DNA breaks blocks DNA transcription

  34. Actinomycin D • Indications • Leukemia: no • Lymphoma: no • Solid tumors: Wilms tumor • rhabdomyosarcoma • Ewing sarcoma • Brain tumors: no

  35. Actinomycin D • Dosing and delivery • Dosing: 15 - 45 micrograms/m2 IV • Delivery: usually give IV push over a few minutes

  36. Actinomycin D • Toxicity • Short term • Nausea and vomiting • Hair loss • Myelosuppression • Mucositis • Skin burns due to extravasation • Radiation recall • Serious • veno-occlussive disease of the liver • Long term

  37. Plant products Vincristine Vinblastine VP-16 (etoposide)

  38. Vincristinemechanism of action Mitotic spindle inhibitor

  39. Vincristine • Indications – just about everything! • Leukemia: ALL • Lymphoma: Hodgkins, non-Hodgkins • Solid tumors: Wilms tumor • neuroblastoma • rhabdomyosarcoma • Ewing sarcoma • hepatoblastoma • Brain tumors: medulloblastoma • low grade astrocytoma • infant brain tumors

  40. vincristine • Dosing and delivery • Dosing: 1.5 - 2 mg/m2 IV • Generally maximum dose is 2mg • Often given weekly • Delivery: usually give IV push over a few minutes

  41. vincristine • Toxicity • Short term • Hair loss (+/-) • No myelosuppression • No nausea or vomiting • peripheral nerve toxicity • jaw, back, leg, abdominal pain • constipation • Skin burn due to extravasation • Long term • no major problems

  42. VP-16mechanism of action Topoisomerase inhibitor

  43. VP-16 • Indications • Leukemia: ALL, AML • Lymphoma: Hodgkins, non-Hodgkins • Solid tumors: Wilms tumor (high risk) • neuroblastoma • rhabdomyosarcoma • Ewing sarcoma • germ cell tumors • Brain tumors: ependymoma • CNS germinoma • infant brain tumors

  44. VP-16 • Dosing and delivery • Dosing: 100 - 150 mg/m2 IV • usually given once a day for 3 – 5 days • Oral dosing: 50 mg/m2/d x 21 days • Delivery: IV dosing given over 1 – 2 hours

  45. VP-16 • Toxicity • Short term • Hair loss (+/-) • Myelosuppression • Nausea, vomiting • Allergic reaction • Long term • second malignancy

  46. Miscellaneous Asparaginase Prednisone

  47. Targeted therapy

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