1. 1 PRINCIPLES OF ONCOLOGIC PHARMACOTHERAPY Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA

2. 2 Neoplastic Cell kinetics Tumor cells can be subdivided into three general populations: 1- cells: not dividing and terminally differentiated 2- cells: continue to proliferate 3- cells: nondividing, currently quiescent but may be recruited into the cell cycle. The kinetic behavior of dividing cells is best described by the concept of the cell cycle.

3. Cell Cycle G1, or gap, phase, in which the cell grows and prepares to synthesize DNA S, or synthesis, phase, in which the cell synthesizes DNA G2, or second gap, phase, in which the cell prepares to divide M, or mitosis, phase, in which cell division occurs.

4. Check points 1- As a cell approaches the end of the G1 phase it is controlled at a vital checkpoint, called G1/S, where the cell determines whether or not to replicate its DNA Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and ‘‘commit suicide’’ through apoptosis 2- A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase

5. Cell cycle regulatory proteins Cyclin Dependent Kinases, or CDKs, are specific enzymes that use signals to switch on cell cycle mechanisms. CDKs are activated by forming complexes with cyclins (another group of regulatory proteins only present for short periods in the cell cycle) Genetic mutations causing the malfunction or absence of one or more of the regulatory proteins at cell cycle checkpoints can result in the ‘‘molecular switch’’ being turned permanently on, permitting uncontrolled multiplication of the cell, leading to carcinogenesis, or tumor development.

6. Cell Cycle in Cancer In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates its DNA and divides. This process also includes mechanisms to ensure errors are corrected, and if not, the cells commit suicide (apoptosis). In cancer, as a result of genetic mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation.

7. How Cancer Drugs Work?

8. 8 Chemotherapeutic agents classified by mechanism of action

9. 9 “Classic” Alkylating agents Nitrogen mustards cyclophosphamide (Cytoxan, Neosar), ifosfamide (Ifex) chlorambucil (Leukeran) Estramustine (Emcyt) Melphalan (Alkeran) Thiotepa Busulfan (Myleran) Nitrosoureas: Carmustine (BiCNU) Lomustin (CeeNU) Streptozocin (Zanosar) Bendamustine (Treanda)

10. 10 Alkylating agents Impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups The most important sites of alkylation are DNA, RNA, and proteins. Depend on cell proliferation for activity but are not cell-cycle phase specific have linear dose-response curves (ie, increasing the dose increases cytotoxicity)

11. 11 Nitrosoureas Carmustine (BiCNU), Lomustin (CeeNU), Streptozocin (Zanosar) The lipophilic nature of the nitrosoureas enables free passage across membranes; therefore, they rapidly penetrate the blood- brain barrier. used for a variety of brain tumors.

12. 12 Alkylating agents Toxicities Nausea/Vomiting local vesicants skin rashes Bone marrow depression gonadal dysfunction leukemia hyperuricemia pulmonary fibrosis hemorrhagic cystitis (ifex, cytoxan) alopecia

13. 13 Alkylating agents Uses CLL, HD, NHL, AML, ALL M. myeloma ovarian cancer Prostate ca Breast ca Germ-cell testicular lung cancer mycosis fungoides sarcoma Brain tumor: GlioBlastoma Multiforme Pancreatic islet-cell, carcinoid

14. 14 Nonclassic alkylators Altretamine (Hexalen) Dacarbazine (DTIC) Procarbazine (Matulane) Temozolomide (Temodar)

15. 15 Nonclassic alkylators Toxicities Nausea and vomiting CNS toxicity, Paresthesias Bone marrow depression alopecia

16. 16 Nonclassic alkylators Uses HD (dacarbazine) Brain (Procarbazine, Temozolomide) cervical cancers Malignant melanoma (DTIC, Temozolomide) soft-tissue sarcomas (DTIC) Ovarian (Altretamine)

17. 17 Platinum complexes Cisplaplatin Carboplatin Oxaliplatin

18. 18 Platinum Inorganic heavy metal complex cell-cycle phase nonspecific inhibits the synthesis of DNA, RNA, and proteins have linear dose-response curves (ie, increasing the dose increases cytotoxicity)

19. 19 Platinum complexes Toxicities nausea and vomiting Bone marrow depression Renal toxicity peripheral neuropathy ototoxicity

20. 20 Platinum Uses Ovarian cancer (Cis, carbo) Lung ca (Cis and carbo) Head/Neck acute leukemia NHL Breast bladder uterine cervical Colorectal (oxaliplatin) Gastric and Esophageal ca

21. 21 Antimetabolites Antimetabolites are structural analogs of the naturally occurring metabolites involved in DNA and RNA synthesis. Exert their cytotoxic activity either by: competing with normal metabolites for the catalytic or regulatory site of a key enzyme or substituting for a metabolite that is normally incorporated into DNA and RNA. Most active when cells are in the S phase and have little effect on cells in the G0 phase. Most effective against tumors that have a high growth fraction.

22. 22 Antimetabolites folate analogs purine analogs pyrimidine analogs substituted ureas

23. 23 Folate analogs ( Folate antagonist) Methotrexate: Interferes with DNA synthesis, repair and cell replication Inhibits dihydrofolate reductase Pemetrexed (ALIMTA): Disrupts folate-dependent metabolic process essential for cell replication Inhibits: Thymidylate synthase dihydrofolate reductase Glycinamide ribosnucleotide formyltransferase All folate-dependent enzymes involved in biosynthesis of purine and thymidine

24. 24 Folate analogs Toxicites Mucositis GI ulceration marrow depression pulmonary fibrosis Liver toxicity rash/skin desquamation

25. 25 Folate analogs Uses ALL, CNS leukemia (MTX) Breast (MTX) head and neck Mesothelioma (Alimta) NSCLC (Alimta) Gestational trophoblastic Tumors (MTX) NHL, Burkitt’s lymphoma (MTX) Osteosarcoma (MTX)

26. 26 Purine analogs Inhibit DNA synthesis: Fludarabine Pentostatin (Nipent) Cladribine Mercaptopurine Thioguanine

27. 27 Purine analogs Toxicities Bone marrow depression Malaise pulmonary infiltrates tumor lysis syndrome Skin rash

28. 28 Purine analogs Uses CLL (fludara, pentostatin) Hairy-cell leukemia (pentostatin, cladribine) NHL (fludara) ALL AML

29. 29 Pyrimidine analogs Inhibit DNA and RNA synthesis: Fluorouracil/Adrucil (5-FU) Capecitabine (xeloda) Floxuridine Cytarabine, DepoCyt Inhibit DNA synthesis synthesis: Gemcitabine (gemzar)

30. 30 Pyrimidine analogs Toxicities Diarrhea Stomatitis/mucositis nausea and vomiting hand-foot syndrome Bone marrow depression hepatic dysfunction CNS

31. Fluorouracil/Adrucil (5-FU) Capecitabine (xeloda) Severe toxicities in pts with: DihydroPyrimidine Dehydrogenase (DPD) deficincy Thymidylate Synthase (TYMS/TS) mutation associated with reduced TS production and subsequent 5-FU toxicity

32. Tests available for 5-FU toxicity TheraGuide 5-FU: TYMS and DPYD genes mutation 25% of pts have them 60% risk of severe or life threatening toxicity OnDose (target range AUC of 20-24mg.hr/L) To optimize dosing of 5-FU To reduce 5-FU toxicity Do test at any time after 2 hr of C. I. 5FU 9/9/2015 32

33. 33 Pyrimidine analogs Uses Colorectal cancer Stomach Esophageal ca Head/Neck Breast cancer Skin cancer Leukemias

34. 34 Substituted urea Hydroxyurea Inhibits DNA synthesis in S phase

35. 35 Substituted urea Toxicity Bone marrow depression mild nausea and vomiting

36. 36 Substituted urea Uses CML Essential thrombocytosis Polycythemia vera Acute leukemia Head/Neck cancer

37. 37 Natural products (From plants, fungi, and bacteria)

38. 38 Antitumor antibiotics and Anthracyclines Bleomycin Dactinomycin Mitomycin Doxorubicin Daunorubicin liposomal daunorubicin (Doxil) Mitoxantrone

39. 39 Antitumor antibiotics and Anthracyclines Antitumor antibiotics: Bleomycin intercalates DNA at guanine-cytosine and guanine-thymine sequences, resulting in spontaneous oxidation and formation of free oxygen radicals that cause strand breakage. Anthracyclines: The anthracycline antibiotics are products of the fungus Streptomyces percetus var caesius. The anthracyclines have several modes of action. Most notable are intercalation between DNA base pairs and inhibition of DNA– topoisomerases I and II. Oxygen free radical formation from reduced doxorubicin intermediates is thought to be a mechanism associated with cardiotoxicity.

40. 40 Antitumor antibiotics and Anthracyclines Toxicities vesication (local tissue necrosis) nausea and vomiting diarrhea, stomatitis cardiotoxicity (anthracyclines) Pneumonitis (bleomycin) pulmonary fibrosis (bleomycin) anaphylaxis (bleomycin) hyperpigmentation alopecia bone marrow depression red urine (doxo) blue urine and sclera (mitoxantrone) hand-foot syndrome (Doxil)

41. 41 Anthracycline: Cardiotoxicity Heart less able to detoxify free radical low catalase in heart high iron in heart anthracycline inactivate glutathione peroxidase

42. 42 Anthracycline: Cardiotoxicity Cumulative doses: Doxorubicin Toxic > 550mg/m 450-500mg/m = 1-10% CHF risk safe dose <360mg Daunorubicin 700mg/m idarubicin 180mg/m mitoxantrone 120mg/m Epirubicin 900mg/m (zinocard) safe dose <720mg Doxil 500-550 mg/m = 11% CHF

43. 43 Antitumor antibiotics and Anthracyclines: Uses Breast Ovarian cancer Testicular cancer Hodgkin’s AML, ALL, NHL Gestational trophoblastic Tumors Ewing’s sarcoma SCLC Kaposi’s sarcoma

44. 44 Epipodophyllotoxins Etoposide (VP-16) Teniposide

45. 45 Epipodophyllotoxins Etoposide is a semisynthetic epipodophyllotoxin extracted from the root of Podophyllum peltatum (mandrake). M-phase specific It inhibits topoisomerase II activity by stabilizing the DNA–topoisomerase II complex This process ultimately results in the inability to synthesize DNA, and the cell cycle is stopped in the G1 phase.

46. 46 Epipodophyllotoxins Toxicities Bone marrow depression MDS, Leukemia Nausea and vomiting Diarrhea Alopecia Skin rash

47. 47 Epipodophyllotoxins Uses Testicular SCLC NSCLC HD, NHL, AML GTT

48. 48 Microtubule agents Taxanes: Docetaxel (taxotere) Paclitaxel (taxol) Nanoparticle Albumin-bound Cabazitaxel (Jevtana)

49. 49 Taxanes Semisynthetic derivatives of extracted precursors from the needles of yew tree. Unlike the vinca alkaloids, which cause microtubular disassembly, the taxanes promote microtubular assembly and stability M-phase specific: therefore blocking the cell cycle in mitosis. Docetaxel is more potent than paclitaxel in enhancing microtubular assembly and also induces apoptosis

50. 50 Microtubule agents Toxicities Bone marrow depression Fluid retention Hypersensitivity Peripheral neuropathy, Paresthesias Skin changes Nails changes Alopecia Myalgias

51. 51 Microtubule agents Uses Breast (ixempra, Halaven) NSCL Prostate Ovarian head and neck Esophagus Stomach Cervical Kaposi’s sarcoma Uterine bladder

52. 52 Vinca alkaloids Vinblastine Vincristine Vinorelbine

53. 53 Vinca alkaloids Derived from the periwinkle plant Vinca rosea. bind rapidly to the tubulin. M-phase specific The binding occurs in the S phase polymerization of microtubules is blocked, resulting in impaired mitotic spindle formation in the M phase.

54. 54 Vinca alkaloids Toxicities Bone marrow depression nausea and vomiting ileus Peripheral neuropathy Alopecia Stomatitis myalgias hepatic insufficiency

55. 55 Vinca alkaloids Uses ALL, NHL (Vincristine) HD (Vinblastine) NSCLC (Vinorebine) Gestational trophoblastic tumors Testicular Breast mycosis fungoides Kaposi’s sarcoma bladder and renal cancers

56. New Microtubule agents Eribulin (Halaven) Eribulin (Halaven) Ixabepilone (Ixemra) Ixabepilone (Ixemra) Uses Uses Breast cancer Breast cancer 56

57. 57 Camptothecin analogs Irinotecan (camptosar, CPT-11) Topotecan (Hycamtin) semisynthetic analogs of the alkaloid camptothecin, derived from the Chinese ornamental tree Camptotheca acuminata inhibit topoisomerase I and interrupt the elongation phase of DNA replication

58. 58 Camptothecin analogs Diarrhea nausea and vomiting anorexia, weight loss Bone marrow depression Irintecan: Severe toxicities in pt with UGT1A1 gene mutation

59. 59 Camptothecin analogs Uses Colorectal cancer (CPT-11) SCLC (CPT-11, Topo) Ovarian (Topo)

60. 60 Enzymes Asparaginase

61. 61 Enzymes Toxicities Allergic reactions (fever, chills, anaphylaxis) Skin rash Nausea vomiting, anorexia Liver dysfunction CNS depression Coagulopathy

62. 62 Enzymes Uses ALL AML

63. 63 Targeted Therapies

64. 1. 1. Monoclonal antibodies (MAbs) 2. 2. Small-molecules 64

65. 65 Monoclonal antibodies (MAbs) Uses begin in late 1990s The number of new agents in this class is growing exponentially

66. 66 Monoclonal antibodies (MAbs) Rituximab (Rituxan), anti-CD20 (approved in 1997) Trastuzumab (Herceptin), anti-Her2-neu Alemtuzumab (Campath), anti-CD52 Bevacizumab (Avastin) (anti-VEGF) (approved in 2004) Cetuximab (Erbitux) (anti-EGFR) (approved in 2004) Down regulation of EGFR pathway Reverse tumor response to chemo (CPT-11) Vectibix (humanized anti-EGFR) (approved in 2006) Lapatinib (Tykerb) Her2 neu and EGFR inhibitor ONTAK (Denileukin, Diftitox) Diphtheria toxin domains bound to human IL-2 MYLOTARG (gemtuzumab) anti-CD33 Ipilimumab (Yervoy), blocks CTLA-4

67. 67 Monoclonal antibodies (MAbs) Indictaions: CLL (Rituxan, Campath) B-NHL (Rituxan) T-cell NHL (Ontak) Breast cancer (Herceptin, Tykerb) Colorectal (Avastin, Erbitux, Vectibix) Head/Neck (Erbitux) NSCLC (Avastin) GBM (Avastin) Melanoma (Yervoy)

68. Bevacizumab (Avastin) (anti-VEGF) 68

69. 69 Monoclonal antibodies (MAbs) A.E. Infusion reactions Allergy/Anaphylaxis Acneform skin rash/pruritus tumor lysis syndrome opportunistic infections (campath) GI perforations (avastin) wound-healing complications (avastin) hypertension/hypertensive crisis (avastin) Proteinurea (Avastin) Cardiotoxicity (Herceptin, Tykerb) Severe immune-mediated reaction (Yervoy)

70. 70 Small-molecules Imatinib mesylate (Gleevec), TK inhibitor Dasatinib (SPRYCEL), TK inhibitor Dasatinib (SPRYCEL), TK inhibitor (300-1000 potent than imatinib) (300-1000 potent than imatinib) Nilotinib, Tasigna, TK inhibitor Nilotinib, Tasigna, TK inhibitor 20-50 potent than imatinib 20-50 potent than imatinib not effective in T3151 mutant not effective in T3151 mutant Gefitinib (Iressa, EGFR inhibitor) Erlotinib (Tarceva, EGFR inhibitor) Bortezomib (Velcade, proteasome inhibitor) Sunitinib (sutent, multi-VEGFR, KIT) Sorafenib (Nexifar, multi-VEGFR, KIT) Temsirolimus (Torisel, mTOR inhibitor Everolimus (AFINITOR), mTOR inhibitor Everolimus (AFINITOR), mTOR inhibitor Pazopanib (Votrient), multikinase inhibitor Pazopanib (Votrient), multikinase inhibitor Crizotinib (Xalkori), TK inhibitor Crizotinib (Xalkori), TK inhibitor Vemurafenib (Zelboraf ), TK inhibitor Vemurafenib (Zelboraf ), TK inhibitor

71. 71 Tyrosine Kinase Inhibitors Uses NSCLC (Iressa, Tarceva, Xalkori) CML (Gleevec) Ph +ve ALL (Gleevec) GIST (Gleevec) Multiple myeloma (Velcade) Zelboraf (Met Melanoma, BRAF v600E +) Zelboraf (Met Melanoma, BRAF v600E +)

72. 72 Targeted therapies Toxicities Edema and fluid retention (Gleevec) Myalgias (Gleevec) diarrhea Nausea and vomiting (Gleevec) Myelosuppression (Sutent, Sorafenib) Liver toxicity (Gleevec) Acne-form skin rash (EGFR inhibitors) Hand foot syndrome (Sutent) peripheral neuropathy (Velcade) thrombocytopenia (Velcade)

73. Autologous Cellular Immunotherapy 73

74. PROVENGE Sipuleucel-T (Provenge) is the first FDA- approved autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic met HRPC Sipuleucel-T (Provenge) is the first FDA- approved autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic met HRPC Provenge induces immune response against PAP Provenge induces immune response against PAP Provenge is produced by taking cells from a patient's tumor, and incorporating them into a vaccine consisting of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) and the Dendreon PAP-GM-CSF fusion protein Provenge is produced by taking cells from a patient's tumor, and incorporating them into a vaccine consisting of the patient's own blood cells (autologous, with dendritic cells thought to be the most important) and the Dendreon PAP-GM-CSF fusion proteinautologous dendritic cellsPAPGM-CSFfusion proteinautologous dendritic cellsPAPGM-CSFfusion protein 74

75. Endocrine therapy Female Female Antiestrogens Antiestrogens Tamoxifen Tamoxifen Fulvestrant (Faslodex) Fulvestrant (Faslodex) A.Is. A.Is. Anastrozole (Arimidex) Anastrozole (Arimidex) Lotrozole (Femara) Lotrozole (Femara) Exemestine (Armasin) Exemestine (Armasin) Megestrol Megestrol Male Male LHRH LHRH Leupromide Leupromide Goserelin (Zoladex) Goserelin (Zoladex) Abiraterone (Zytiga), inhibit androgen synthesis. Inhibits CYP17 Abiraterone (Zytiga), inhibit androgen synthesis. Inhibits CYP17 Degarelix (gonadotropin-releasing hormone receptor inhibitor) Degarelix (gonadotropin-releasing hormone receptor inhibitor) Antiandrogines Antiandrogines Bicalutamide (Casodex) Bicalutamide (Casodex) Nilutamide Nilutamide Flutamide Flutamide 75

76. Principles of Chemotherapy 76

77. 77 Chemotherapy Ideal Timing Neoadjuvant/preoperative Adjuvant/postoperative When to start ? about 3-6 wks from date surgery For how long ?????!!!!! (3 – 6 m) Palliative

78. 78 Dose Calculation Dosage calculated according to BSA (most of chemo drugs) According to the weight (Avastin) AUC (Carboplatin)

79. 79 Principles of Combination Chemotherapy Known active single agents should be selected Drugs with different mechanisms of action and with additive or synergistic cytotoxic effects Drugs with different dose-limiting toxicities Drugs should be used at their optimal dose and schedule Drugs should be given at consistent intervals Treatment-free period should be as short as possible to allow for recovery for the most sensitive normal tissues Drugs with different patterns of resistance should be used to minimize cross-resistance

80. 80 Principles of Combination Chemotherapy Advantage: Maximize cell kill while minimizing host toxicities May increase the range of drug activity against tumor cells with endogenous resistance to specific types of therapy May prevent or slow the development of newly resistant tumor cells. Disadvantage: Toxicities and complications Cost

81. ROUTE How chemotherapy given? 81

82. 82 Chemotherapy Toxicities

83. Vesicant Chemotherapy Antitumor Antibiotics Antitumor Antibiotics doxorubicin, daunorubicin, mitomycin, idarubicin, epirubicin and actinomycin doxorubicin, daunorubicin, mitomycin, idarubicin, epirubicin and actinomycin Mechlorethamine Mechlorethamine nitrogen mustard nitrogen mustard Vinca Alkaloids Vinca Alkaloids vinblastine, vinorelbine and vincristine vinblastine, vinorelbine and vincristine Taxanes Taxanes paclitaxel, docetaxel, and Abraxanene paclitaxel, docetaxel, and Abraxanene Others Others amsacrine, VP16, streptozocin, oxaliplatin ifex, cisplatin, dacarbazine, mitoxantrone carmustine amsacrine, VP16, streptozocin, oxaliplatin ifex, cisplatin, dacarbazine, mitoxantrone carmustine 83

84. Extravasations vesicant chemotherapy as medication that can cause damage to cells and tissues if it leaks into subcutaneous tissue. Vesicant drugs may continue to cause tissue death months after the extravasation occurs. Treatment: Elevation of the arm Cold compresses Warm compresses (Vinca Alkaloids) Antitumor Antibiotics) Steroid inj (Antitumor Antibiotics) hyaluronidase local inj (Taxane, Vinca alkaloid) hyaluronidase local inj (Taxane, Vinca alkaloid) isotonic sodium thiosulfate local inj (Mechlorethamine) isotonic sodium thiosulfate local inj (Mechlorethamine) Dexrazoxane/Totecd (anthracycline) Dexrazoxane/Totecd (anthracycline) IV diff sites within 6hr of extravasation, repeat in 24 and 48hr IV diff sites within 6hr of extravasation, repeat in 24 and 48hr

85. 85 Neuotoxicity vinka alkaloid Constipation = 50% reduct. Paresthesia=DC Cisplatin Ototoxicity Oxaliplatin Avoid cold Calcium + Mg supliment Cytarabine Neuro check Taxol Neuropathy = 20% reduct. Glutamine 10gm tidx4d, 24hr after taxol

86. 86 Chemotherapy Dose-Adjustment

87. 87 Renal Dysfunction Cisplatin Cr Cl 30-60=50% <30=omit VP-16 CrCl >50=ok 10-50=25% <10=50% Cytoxan CrCl >50=ok 10-50=25% <10=50% MTX (cr1.5-2=50%,cr >2=hold) CrCl>60=ok 30-60=50% <30=omit Bleomycin CrCl>60=ok 10-60=25%red, <10=50% Topotecan CrCl > 60=ok 10-60=50% <10=omit Carboplatin Ifex Carmustine Fludarabine Hydroxurea Streptozocin Cladrabine Thiotepa 6-MP IL-2 Mitomycin-C Procarbazine L-asparaginase CrCl<60=omit Ara-C Daunorubicin Cr >3=50%

88. 88 Hepatic Dysfunction Adria/Doxil bil 1.5-3=50% bil 3.1-5= 75% red bil>5=omit Daunorubicin/Idarubicin bil 1.5-3=25% 3-5=50% >5 =omit Mitoxantrone bil>3=25%red Taxotere: Bil>ULN or AST/ALT>1.5ULN+ ALP>2.5ULN=omit Taxol Bil 1.5-3,AST60-180: No formal recommondation bil>5,AST>180=omit Vincr/Vinbl bil<1.5,AST<60=No red bil1.5-3,AST60-180=50% bil>3,AST>180=omit CPT-11 Cytoxan Dactinomycin VP-16 bil1.5-3,AST60-180=50% bil>3,AST>180=omit Casodex/Flutamide bil>3=reduction 5-FU bil>5=omit MTX bil3-5=25%,AST>180red bil>5=omit Vinorelbine bil<2=No red bil2-3=50% bil3-5=75%red bil>5=omit

89. 89 Miscellaneous Cardiac Adria >300mg/m2 Zinocard: Adria = 10:1 Mucositis MTX, 5-FU, Adria = 50% reduction Bleomycin 450mg --> 3-5% pneumonitis/fibrosis PFT/c-xray; prior to each cycle hold for >10% drop in DLco/VC