Chemotherapy Agents 101

Transcription

1 Chemotherapy Agents 101 Jumana Ashy, Pharm D, BCOP Judith Misas, PharmD Candidate 2018 Jeremy Hutchinson, PharmD Sady Castance, PharmD September 12,

2 Learning Objectives At the end of the presentation and after performing the reading, the participant should be able to: Identify the mechanism of action of the major classes of chemotherapy and targeted agents Understand safety profile of the major classes of chemotherapy and targeted agents List the dose limiting toxicities as well as any unique toxicities of each antineoplastic agent or targeted agent. Describe the importance of combination chemotherapy agents and the different rationales for why prescribers use combination therapy agents Summarize the tumor growth hypotheses that have been used to model cancer cell death from antineoplastic therapy 2

3 Phases of the Cell Cycle 3

4 Chemotherapy agents 4

5 Principles of Chemotherapy

6

7 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 7

8 Alkylators Non-cell cycle specific: Cross-links DNA, preventing cell replication 8

9 Alkylating Chemotherapy MOA One 2-chloroethyl side chain undergoes a first-order intramolecular cyclization Results in the release of Cl- and the formation of a highly reactive ethyleniminium intermediate (aziridinium ion) 9

10 Alkylating Agents MOA (continued) Unstable aziridine ring can undergo nucleophilic attack by an electron donor (drg is an electrophile) Reaction with guanine at N-7 occurs to the greatest extent Other sites on guanine, other bases, and phosphate oxygens also can be alkylated 10

11 Alkylating Chemotherapy Drugs Nitrogen mustards Chlorambucil, Cyclophosphamide, Ifosfamide, Melphalan, Mechlorethamine hydrochloride, Bendamustine Nitroureas Carmustine, Lomustine, Semustine, Streptozocin Alkyl sulfonates Busulfan Ethylenimines Thiotepa, Hexamethylmelamine Triazenes Dacarbazine Platinum analogues Cisplatin, Carboplatin, Oxaliplatin 11

12 Cyclophosphamide (Cytoxan), Ifosfamide (Ifex), Temozolide (Temodar), Altretamine (Hexalen), Bendamustine (Treanda), Busulfan (Myleran), etc Bladder toxicity with high-doses of ifosfamide give mesna (Mesnex) to protect against hemorrhagic cystitis and ensure adequate hydration. Both cyclophosphamide and ifosfamide can cause hemorrhagic cystitis. Temozolomide crosses the BBB and is used primarily in brain cancers such as glioblastoma multiforme. Best taken on empty stomach or QHS to nausea (prophylaxis against PCP is important) 12

13 Safety/Side effects of Alkylating Agents BOXED Warnings: severe bone marrow suppression, secondary malignancy Side effects: Pulmonary toxicity with busulfan, carmustine, lomustine Neurologic toxicity such as seizures, encephalopathy (chlorambucil, ifosfamide, temozolamide, thiotepa) Skin pigmentation changes (busulfan, carmustine) Dacarbazine is highly ematogenic and can cause flu-like symptoms Impairs fertility 13

14 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 14

15 Anthracyclines Non-cell cycle specific: Work by several mechanisms, including intercalation into DNA, inhibiting topoisomerase II, and creating oxygen-free radicals that damage cells. Complex mechanism of action: Intercalate with DNA like dactinomycin Form a complex with Topoisomerase II and DNA and inhibits ability of topoisomerase II to repair broken DNA strands Generate free radicals to attack DNA through a mechanism of action involving iron Last mechanism can be blocked by exogenous antioxidants and iron chelator dexrazoxane 15

16 Anthracycline Chemotherapy Drugs 1. Doxorubicin (Adriamycin) 2. Doxorubicin liposomal (Doxil) 3. Epirubicin (Ellence) 4. Idarubicin (Idamycin) 5. Daunorubicin (Cerubidine) 6. Daunorubicin liposomal (Daunoxome) 7. Mitoxantrone (Novantrone) 8. Valrubicin (Valstar) à intravesicular bladder irrigation only! 16

17 Doxorubicin (Adriamycin), Idarubicin (Idamycin), Daunorubicin (Cerubidine), Mitoxantrone (Novantrone), Doxorubicin liposomal (Doxil), Epirubicin (Ellence), etc Very effective but limited use due to cardiac toxicity and nausea/vomiting. Monitoring required at baseline and if dose exceeds: Doxorubicin: 250 mg/m2 Daunorubicin: 320 mg/m2 Do not exceed max lifetime doxorubicin dose of mg/m2 (450 mg/m2 with mediastinal radiation) due to cardiotoxicity The cardioprotective agent dexrazoxane should be considered when cumulative doxorubicin dose > 300 mg/m2. 17

18 Doxorubicin (Adriamycin), Idarubicin (Idamycin), Daunorubicin (Cerubidine), Mitoxantrone (Novantrone), Doxorubicin liposomal (Doxil), Epirubicin (Ellence), etc Vesicants: High risk of severe tissue damage with extravasation, antidote is dexrazoxane (Totect) or dimethyl sulfoxide. Do NOT use both! Mitoxantrone is an anthracenedione similar to anthracycline in toxicity and turns body fluids blue rather than red as with other anthracyclines The liposomal products have higher incidence of hand-foot syndrome and allergic reactions 18

19 Safety/Side effects of Anthracyclines BOXED Warnings: Irreversible myocardial toxicity may occur as total dosage approaches cumulative max dose Secondary malignancy (AML or MDS) Severe myelosuppression in patients with impaired hepatic function Potent vesicant. Conventional and liposomal formulations are not bioequivalent Side effects: Alopecia, extravasation, red urine and body secretions (blue with mitoxantrone) 19

20 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 20

21 Platinum Based Compounds Non cell cycle specific: Cross-links DNA, leading to apoptosis (programmed cell death) 21

22 Platinum MOA 22

23 Platinum Based Chemotherapy Drugs 1. Cisplatin (Platinol) 2. Carboplatin (Paraplatin-AQ) 3. Oxaliplatin (Eloxatin) 23

24 Cisplatin (Platinol), Carboplatin (Paraplatin- AQ), Oxaliplatin (Eloxatin) Cisplatin: Nephrotoxicity is managed with vigorous hydration and sometimes mannitol, electrolyte wasting requires magnesium and potassium supplementation. Amifostine (Ethyol) may also be used prophylactically for renal protection. Recommend audiograms prier to each cycle to screen for ototoxicity. Manage acute and delayed nausea/vomiting with 3 drug combination antiemetic regimen. Carbolplatin: Calver Formula: Total Carboplatin Dose (mg) = (Target AUC) x (GFR + 25). Oxaliplatin: Anaphylaxis, pancreatitis, pulmonary toxicity, hepatotoxicity. Neuropathy exacerbated by exposure to cold. 24

25 Safety/Side effects of Platinum Based Compounds BOXED Warnings: Cisplatin: Anaphylactic-like reactions, cumulative renal toxicity, ototoxicity, caution against cisplatin overdose (doses > 100 mg/m2 Q3-4 weeks are rarely used) Carboplatin: Anaphylactic-like reactions, myelosuppression, nausea and vomiting Oxaliplatin: Anaphylactic-like reactions 25

26 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 26

27 Folate Antimetabolites Cell cycle specific, S-phase: Prevent DNA synthesis MTX inhibits DNA synthesis, repair, and cellular replication 1. MTX irreversibly binds to and inhibits dihydrofolate reductase 2. Inhibiting the formation of reduced folates, and thymidylate synthetase 3. Resulting in inhibition of purine and thymidylic acid synthesis, 4. Thus interfering with DNA synthesis, repair, and cellular replication. 27

28 Folate Antimetabolite Drugs 1. Methotrexate (Trexall, Rheumatrex) 2. Pemetrexed (Alimta) 3. Pralatrexate (Folotyn) 28

29 Methotrexate (Trexall, Rheumatrex), Pemetrexed (Alimta), Pralatrexate (Folotyn) Methotrexate: Lower doses used in RA and psoriasis High-dose regimens are needed to penetrate the BB and overcomes relative resistance in malignancies such as osteosarcoma. High-doses also require leucovorin or levoleucovorin rescue to toxicity. Leucovorin is the active form of folic acid, which bypasses the enzyme block of dihydrofolate reductase by methotrexate Avoid renal transport inhibitors that can elimination, resulting in MTX toxicity: aspirin, beta lactams, probenecid, and NSAIDs. Maintain proper hydration Alkalinize urine with IV sodium bicarbonate to toxicity. 29

30 Methotrexate (Trexall, Rheumatrex), Pemetrexed (Alimta), Pralatrexate (Folotyn) Pemetrexed: To side effects (hematologic, mucositis, diarrhea, dermatologic): give folic acid supplements ( 1 mg PO daily), vitamin B12 (cyanobalamin) and dexamethasone Pralatrexate: Similar to above, use vitamin B12 and folate to toxicity 30

31 Safety/Side effects of Folate Antimetabolites BOXED Warnings w/ MTX: Preserved formulation not for intrathecal administration or high-dose therapy, pregnancy, SJS/TEN, diarrhea, tumor lysis syndrome, and many more Side effect: MTX: Myelosuppression, mucositis, hepatic and renal toxicity (renal is doserelated), pulmonary toxicity (rare), hand-foot syndrome, tumor lysis syndrome Pemetrexed: Renal toxicity, bone marrow suppressions, dermatologic toxicity mucositis, N/V/D Pralatrexate: Myelosuppression, mucositis, anemia, rnela oxicity, hepatic toxicity, tumor lysis syndrome, fetal harm 31

32 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 32

33 Pyrimidine Analog Antimetabolites Cell cycle specific, S-phase: Inhibits pyrimidine synthesis 33

34 Pyrimidine Analog Antimetabolites Drugs 1. Capecitabine (Xeloda) 2. Cytarabine conventional (Ara-C) 3. Cytarabine liposomal (Depocyt): for intrathecal administration 4. Fluorouracil, 5-FU (Adrucil) 5. Gemcitabine (Gemzar) 34

35 Capecitabine (Xeloda), Gemcitabine (Gemzar), Fluorouracil, 5-FU (Adrucil), Cytarabine (Ara-C), etc Capecitabine: Prodrug of 5-fluorouracil. Given PO as 2 divided doses taken 12 hours apart, take within 30 minutes after a meal Pharmacogenomic testing for dihydropyrimidine dehydrogenase (DPD) deficiency risk of severe toxicity Can INR up to 91% due to CYP 2C9 inhibition dose adjust based on severity of interaction Cytarabine (Ara-C): Cytrarabine syndrome includes fever, weakness, fatigue, skin rash, reddened eyes, bone, muscle, joint and/or chest pain - treat with corticosteroids 35

36 Capecitabine (Xeloda), Gemcitabine (Gemzar), Fluorouracil, 5-FU (Adrucil), Cytarabine (Ara-C), etc Fluorouracil, 5-FU (Adrucil): Etudex, Carac and Fluoroplex are topical formulations used for acitinic keratosis. Etudex is also used for superficial basal ell carcinoma. Pharmacogenomic testing for dihydropyrimidine dehydrogenase (DPD) deficiency risk of severe toxicity. Given with leucovorin to efficacy of 5-FU Gemcitabine: Flu-like syndrome during first 24 hours: use acetaminophen Prolonged infusion time may toxicities, use infusion rates per protocol 36

37 Safety/Side effects of Pyrimidine Analog Antimetabolites BOXED Warning: Capecitabine: INR during and up to 1 month after discontinuation; reduce warfarin dose, monitor carefully; fatal bleeding can occur Cytarabine: Bone marrow suppression (conventional formulation) Contraindications: Capecitabine: DPD deficiency, severe renal impairment (CrCl < 30 ml/min) Cytarabine: Active meningeal infection (Depocyt only) Side effects: Capecitabine: Hand foot syndrome, diarrhea, mucositis, gastritis Cytarabine: hepatotoxicity, severe N/V and peripheral neuropathy at high doses Fluorouracil: Mucositis, diarrhea, hand-foot syndrome (with continuous infusions) Gemcitabine: Myelosuppression 37

38 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Purine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 38

39 Purine Analog Antimetabolites Cell cycle specific, S-phase: Inhibits purine synthesis 39

40 Purine Analog Antimetabolites Drugs 1. Azathioprine (Imuran) 2. Mercaptopurine (Purixan) 3. Thioguanine (Tabloid) 4. Fludarabine (Fludara) 5. Pentostatin (Nipent) 6. Cladribine 40

41 Azathioprine (Imuran), Mercaptopurine (Purixan), Thioguanine (Tabloid), Fludarabine (Fludara), etc Azathioprine: Widely used in transplantations to control rejection reactions It also successfully suppresses autoimmunity Mercaptopurine: Taken PO, administer on an empty stomach, and avoid concomitant milk products Used to treat acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), Crohn's disease, and ulcerative colitis Thioguanine: It is given by mouth The major concern that has inhibited the use of thioguanine has been veno-occlusive disease (VOD) and its histological precursor nodular regenerative hyperplasia (NRH) Avoiding pregnancy when on the medication is recommended for both males and females 41

42 Safety/Side effects of Purine Analog Antimetabolites BOXED Warnings: Azathioprine: Secondary malignancy (lymphoma and hepatosplenic T-cell lymphoma) Fludarabine: Bone marrow suppression, autoimmune effects, neurotoxicity, combination with pentostatin (because of fatal pulmonary toxicity), administered under the supervision of a qualified physician Pentostatin: Administered under the supervision of a qualified physician, the use of higher doses than those specified is not recommended (20 to 50 mg/m2 in divided doses over 5 days) Side effects: Bone marrow suppression and vomiting 42

43 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 43

44 Taxanes M-phase specific: Inhibit microtubule function and angiogenesis (dysfunctional microtubule bundling). Elimination of taxanes is reduced when given immediately after administration of cisplatin or carboplatin. Give taxanes first. 44

45 Taxane Drugs 1. Paclitaxel (Taxol) 2. Docetaxel (Taxotere) 3. Cabazitaxel (Jevtana) 45

46 Paclitaxel (Taxol), Docetaxel (Taxotere), Cabazitaxel (Jevtana), etc Paclitaxel: Paclitaxel albumin-bound (Abraxane) has less hypersensitivity reactions Anaphylaxis, hypersensitivity reaction (78%) due to polyoxyethylated castor oil solvent systems, can be severe in 2-4% of patients. Pre-treat with dexamethasone, diphenhydramanine and H2RA (not needed with Abraxane) Do not extravasate Will INR if on warfarin Docetaxel: Hypersensitivity (40-50%) due to polysorbate 80 solvent system Cardio-pulmonary side effects (41-70%) include fluid retention. Pre-treat with dexamethasone to fluid retention Cabazitaxel: Hypersensitivity (40-50%) due to polysorbate 80 solvent system. Pre-treat with antihistamines and corticosteroids ** For all taxanes, use non-pvc IV bag and tubing due to leaching of DEHP** 46

47 Safety/Side effects of Taxanes BOXED Warnings: Docetaxel: Neutropenia, edema, hepatic disease Cabazitaxel: Neutropenia, hypersensitivity Side effects: Paclitaxel: Myelosuppression, peripheral neuropathy Docetaxel: Myelosuppression, fluid retention, peripheral neuropathy Cabazitaxel: Myelosuppression, peripheral neuropathy 47

48 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 48

49 Vinca Alkaloids M-phase specific: Inhibit microtubule function (destabalizers). 49

50 Vinca Alkaloid Drugs 1. Vincristine (Vincasar) 2. Vincristine liposomal (Marqibo) 3. Vinblastine (Velban) 4. Vinorelbine (Navelbine) 50

51 Vincristine (Vincasar), Vinblastine (Velban), Vinorelbine (Navelbine) Vincristine: Max single dose: 2 mg weekly in most protocol These agents are vesicants. Best to administer with a central line. Avoid extravasation as tissue damage may occur. Use warm compress and hyaluronidase if extravasation occurs IV only, accidental intrathecal is fatal Vincristine is NOT myelosuppressive, vinblastine and vinorelbine are myelosuppressive 51

52 Safety/Side effects of Vinca Alkaloids BOXED Warnings: Extravasation, intrathecal administration (fatal), vincristine conventional injection and liposomal injection are not interchangeable Side effects: Cumulative (dose-dependent) peripheral neuropathy Paresthesias Gastroparesis Constipation, paralytic ileus Neurological toxicity. risk of falls SIADH, rash, alopecia, tumor lysis syndrome, LFTs 52

53 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 53

54 Molecular Function of Topoisomerase

55 Topoisomerase I inhibitors S-phase specific: Block the coiling and uncoiling of the DNA helix. Topoisomerase I facilitates single strand breaks followed by relegation (putting the DNA strands back together) 55

56 Topoisomerase I inhibitor Drugs 1. Irinotecan (Camptosar) 2. Topotecan (Hycamtin) 56

57 Irinotecan (Camptosar), Topotecan (Hycamtin) Irinotecan: Acute diarrhea is a cholinergic symptom, treat with atropine. Delayed diarrhea is treated with loperamide (up to 24 mg daily) Pharmacogenomic testing: Those who are homozygous for the UGT1A1*28 allele are at an risk for neutropenia, dose adjust as needed Topotecan: Used typically as a second line agent for cervical, ovarian, or small cell lung cancer 57

58 Safety/Side effects of Topoisomerase I inhibitors BOXED Warnings: Bone marrow suppression Side effects: Irinotecan: Diarrhea, myelosuppression, mucositis, acute cholinergic syndrome, LFTs Topotecan: Myelosuppression, alopecia, dyspnea, infertility 58

59 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 59

60 Topoisomerase II inhibitors G2-phase specific: Bock the coiling and uncoiling of the DNA helix by facilitating single strand breaks followed by religation 60

61 Topoisomerase II inhibitor Drugs 1. Etoposide (Vepesid) 2. Teniposide (Vumon) 61

62 Etoposide (Vepesid), Teniposide (Vumon) Vepesid capsules require refrigeration IV administration can cause hypotension due to rapid infusion rate, infuse slowly over at least minutes. Precipitation may occur, to risk: use a large volume infusion for etoposide concentrations > 0.4 mg/ml, administer all teniposide concentrations within 4 hours of preparation Irritant: use hyaluronidase and warm compresses to treat extravasation Etoposide IV:PO ratio is 1:2, if total dose is > 400 mg, administer BID ** Use non-pvc IV bag and tubing due to leaching of DEHP** 62

63 Safety/Side effects of Topoisomerase II inhibitors BOXED Warnings: Bone marrow suppression Side effects: Myelosuppression, hypotension, bronchospasms, secondary malignancies Dose limiting myelosuppression-primarily leukopenia. Additional toxicities include nausea and vomiting (with oral dosing), alopecia 63

64 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 64

65 Epothilone M-phase specific: Microtubule stabilizer enhancing polymerization of tubules halting cell division; Mechanism similar to taxanes 65

66 Epothilone Drugs 1. Ixabepilone (Ixempra) 66

67 Ixabepilone (Ixempra) Hypersensitivity due to Cremophor EL (polyoxyethylated castor oil solvent), requires pre-treatment with antihistamines +/- steroids Use micron filter **Use non-pvc IV bag and tubing due to leaching of DEHP** 67

68 Safety/Side effects of Epothilone BOXED Warnings: Hepatic disease Contraindications: Hypersensitivity to castor oil, neutropenia, thrombocytopenia, hepatic disease Side effects: Myelosuppression, neuropathy, fatigue 68

69 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 69

70 Miscellaneous Agents 1. Tretinoin (Alitrans Retinoic Acid, ATRA) 2. Arsenic Trioxide 3. L-Asparaginase (Elspar) 4. Asparaginase (Erwinaze) 5. Pegaspargase (Oncaspar) 6. Bleomycin 7. Mitomycin (Mutamycin) 70

71 Tretinoin (Alitrans Retinoic Acid, ATRA), Arsenic Trioxide, L-Asparaginase (Elspar), Asparaginase (Erwinaze), Bleomycin, Mitomycin (Mutamycin) Tretinoin: Retinoids (Vitamin A analogs) proliferation and differentiation of APL cells First line therapy for acute promyelocytic leukemia (APL) Pregnancy Category D Retinoic Acid-Acute Promyelocytic Leukemia (RA-APL) differentiation syndrome: Fever Dyspnea Weight gain Edema Pulmonary infilfrates Pericardial/pleural effusions Treat with dexamethasone 71

72 Tretinoin (Alitrans Retinoic Acid, ATRA), Arsenic Trioxide, L-Asparaginase (Elspar), Asparaginase (Erwinaze), Bleomycin, Mitomycin (Mutamycin) Arsenic trioxide: apoptosis of APL cells and damages fusion protein PML-RAR alpha Second line therapy for acute promyelotic leukemia (APL) QT prolongation: monitor ECG, avoid concurrent QT prolonging agents, keep Mg2+, Ca2+, and K+ within normal range. APL Differentiation Syndrome If acute vasomotor reactions (lightheadedness, dizziness, or hypotension) occur, prolong infusion 72

73 Tretinoin (Alitrans Retinoic Acid, ATRA), Arsenic Trioxide, L-Asparaginase (Elspar), Asparaginase (Erwinaze), Bleomycin, Mitomycin (Mutamycin) L-Asparaginase (Elspar): derived from E. coli Deprives leukemia cells of asparagine which is an essential amino acid in leukemia Asparaginase (Erwinaze): derived from Erwinia chrysanthemi FDA approved for patients who develop allergic reactions to the E. coli derived asparaginase Pegaspargase (Oncaspar): modified form of L-asparaginase conjugated with polyethylene glycol The pegylated form allows for every 2 week dosing and incidence of allergic reactions Monitor fibrinogen 73

74 Tretinoin (Alitrans Retinoic Acid, ATRA), Arsenic Trioxide, L-Asparaginase (Elspar), Asparaginase (Erwinaze), Bleomycin, Mitomycin (Mutamycin) Bleomycin: Intercalating agent blocking topoisomerase II Due to risk of anaphylactoid reaction, a test dose may be given to lymphoma patients May pre-medicate with acetaminophen to incidence of fever or chills risk of pulmonary fibrosis when given with G-CSF (filgrastim). Recommended not using G-CSF on days of bleomycin administration Not myelosuppressive Maximum lifetime dose of 400 units due to pulmonary toxicity risk Mitomycin: derived from Stepromyces caespitosus Free radical formation and alkylator Vesicant, do not extravasate. Antidote is dimethyl sulfoxide (DMSO) and cool compresses Mitomycin IV solutions are a hazy blue or purple color 74

75 Safety/side effects of Miscellaneous Agents BOXED Warnings: Tretinoin: RA-APL differentiation syndrome, leukocytosis, pregnancy Arsenic trioxide: RA-APL differentiation syndrome, ECG abnormalities Bleomycin: Pulmonary fibrosis, anaphylaxis Mitomycin: Bone marrow suppression, hemolytic-uremic syndrome Side effects: Arsenic trioxide: QT prolongation L-Asparaginase: Hypersensitivity reactions, pancreatitis, prolonged PT/INR/PTT Bleomycin: Hypersensitivity reaction, pulmonary reaction (10%) such as pneumonitis 75

76 Chemotherapy Agents Alkylating Agents Anthracyclines Platinum-Based Compounds Folate Antimetabolites Pyrimidine Analog Antimetabolites Taxanes Vinca Alkaloids Topoisomerase I inhibitors Topoisomerase II inhibitors Epothilone Miscellaneous Agents Monoclonal Antibodies 76

77 Monoclonal Antibodies Over-expression targeted: Inhibit growth factors that are promoting cancer cell growth 77

78 Nomenclature - mab = monoclonal antibody O = mouse U = human Xi = chimera E = hamster I = primate A = rat Zu = humanized 78

79 Monoclonal Antibody Agents 1. Bevacizumab (Avastin) 2. Trastuzumab (Herceptin) 3. Ado-Trastuzumab Emtansine (Kadcyla) 4. Pertuzumab (Perjeta) 5. Cetuximab (Erbitux) 6. Panitumumab (Vectibix) 7. Rituximab (Rituxan) 8. Blinatumomab (Blincyto) 79

80 Bevacizumab (Avastin), Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla), Pertuzumab (Perjeta), Cetuximab (Erbitux), Panitumumab (Vectibix), Rituximab (Rituxan) Bevacizumab: Binds to VEGF-A Angiogenesis inhibitor: limits tumor s blood supply Impairs wound healing: stop at least 28 days before elective surgery and may restart bevacizumab 28 days after surgery Monitor blood pressure and urinalysis prior to each dose Used with other agents in numerous types of cancer but a high cost for modest benefit 80

81 Bevacizumab (Avastin), Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla), Pertuzumab (Perjeta), Cetuximab (Erbitux), Panitumumab (Vectibix), Rituximab (Rituxan) Trastuzumab: HER2/neu over-expression required for use Synergistic efficacy with some chemotherapeutics but avoid use with anthracyclines due to cardiotoxicity Pharmacogenomics: trastuzumab binds to and reverses effects of overactive HER2 receptors. HER2 gene is over-expressed in ~25% of early-staged breast tumors. Must be 2+ by immunohistochemical (IHC) testing to respond/use this drug Obtain MUGA or ECHO at baseline and during treatment Not interchangeable with ado-trastuzumab emansine Ado-Trastuzumab Emtansine: HER2/neu over-expression required for use Kadcyla is a conjugate of trastuzumab linked to DM-1, a highly potent anti-microtubule derivative of maytansine which provides targeted delivery Pharmacogenomics: HER 2 gene over-expression required for use Use 0.22 micron filter Obtain MUGA or ECHO at baseline and during treatment Do not confuse with conventional trastuzumab; not interchangeable 81

82 Bevacizumab (Avastin), Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla), Pertuzumab (Perjeta), Cetuximab (Erbitux), Panitumumab (Vectibix), Rituximab (Rituxan) Pertuzumab: HER2/neu over-expression required for use Pharmacogenomics: HER2 gene over-expression Obtain MUGA or ECHO at baseline and during treatment Cetuximab: EGFR positive expression correlates with better response rates. K-ras mutation indicates poor response; requires EGFR positive and K-ras wildtype Pharmacogenomics: Must test for EGFR and K-ras mutations before treatment Premedicate with diphenhydramine for at least the first dose Presence of rash correlates with high survival rate 82

83 Bevacizumab (Avastin), Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla), Pertuzumab (Perjeta), Cetuximab (Erbitux), Panitumumab (Vectibix), Rituximab (Rituxan), Blinatumumab (Blincyto) Panitumumab: Same EGFR and K-ras issues as cetuximab Pharmacogenomics: Must test for EGFR and K-ras mutations before treatment Presence of rash correlates with a higher survival rate Rituximab: Targets CD20 antigen on B lymphocytes, killing the cancer and releasing cytokines Must be administered in hospital or clinic to monitor for infusion reactions which may occur within minutes, and may include: urticarial, hypotension, angioedema, hypoxia, bronchospasms, acute respiratory distress, etc. Administer diphenhydramine and acetaminophen prior to infusion 83

84 Bevacizumab (Avastin), Trastuzumab (Herceptin), Ado-Trastuzumab Emtansine (Kadcyla), Pertuzumab (Perjeta), Cetuximab (Erbitux), Panitumumab (Vectibix), Rituximab (Rituxan), Blinatumumab (Blincyto) Blinatumumab: Bispecific CD19-directed CD3 T-cell engager (BiTE) Indicated for treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL Administered as continuous infusion for 4 weeks without panned interruption, with 2 week break For cycle 1 only: administer 9 μg/day on days 1 7 and 28 μg/day on days 8 28; patients require inpatient setting for first 9 days a) Patients with high tumor burden may receive dexamethasone 10 mg/m2/day (max = 24 mg/day) x 5 days prior to day 1 For cycle 2 only: administer 28 μg/day on days 1 28; patients require inpatient setting for first 2 days For cycles 3 and beyond: administer 28 μg/day on days 1 28; no minimum inpatient setting required Paucity of data for administering doses other than 9 or 28 μg/day at any point during 5 cycles 84

85 Safety/side effects of Monoclonal Antibodies BOXED Warnings: Trastuzumab: Heart failure, severe infusion-related reactions (may give acetaminophen, diphenhydramine, corticosteroids or meperidine for management) Ado-Trastuzumab Emtansine: Heart failure, hepatotoxicity, embryo-fetal death and birth defects Pertuzumab: Cardiac failure, embryo-fetal death and birth defects Cetuximab: Severe infusion reactions, cardiopulmonary arrest Panitumumab: Dermatologic toxicities Rituximab: Hepatitis B reactivation, severe infusion reactions, fatal mucocutaneous reactions, PML from JC vitus Blinatumumab: Cytokine Release Syndrome (CRS), Neurotoxicit 85

86 Safety/side effects of Monoclonal Antibodies Side effects: Trastuzumab: Cardiomyopathy Ado-Trastuzumab Emtansine: Cardiac dysfunction, constipation Pertuzumab: Cardiomyopathy Cetuximab: Acne-like rash, magnesium and calcium wasting Panitumumab: Acne-like rash, magnesium and calcium wasting Rituximab: Infusion reaction, tumor lysis syndrome, risk of opportunistic infections Blinatumumab: Cardiac toxicity, pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, and constipation 86

87 Key point to Chemotherapy treatment Systemic Chemotherapy is the main treatment available for disseminated malignant disease Progress in chemotherapy resulted in cure for several tumors Chemotherapy usually require multiple cycles 87

88 Modes of Chemotherapy Primary Chemotherapy-chemotherapy is used as the sole anti-cancer treatment in a highly sensitive tumor types Example-CHOP for non-hodgkins Lymphoma Adjuvant chemotherapy-treatment is given after surgery to mop up microscopic residual diseas Example-Adriamycin, cyclophosphamide for breast cancer Neoadjuvant Chemotherapy-treatment is given before surgery to shrink tumor and increase chance of successful resection Example-Adriamycin, ifosfamide for osteosarcoma Concurent Chemotherapy-treatment is given simultaneous to radiation to increase sensitivity of cancer cell to radiation Example-Cisplatin, 5-FU XRT for head and neck cancer 88

89 Cancer Chemotherapy Principles The Silver Bullet isn t out there. Conventional chemotherapy targets have been the cell cycle, microtubules, and DNA Combination chemotherapy improves responses over single agent, but dose intensity must be maintained. 89

90 Importance of Combination Chemotherapy 90

91 Summary In theory, chemotherapy medications make ideal combination agents because they target the underlying cancer biology while usually avoiding the common adverse events associated with traditional chemotherapy. 91

92 The Basics of Combination Chemotherapy 92

93 Log Kill Hypothesis: Skipper Schabel model A model for the effect of cytotoxic chemotherapy on tumor size. It states that a given dose of chemotherapy kills the same fraction of tumor cells regardless of the size of the tumor at the time of treatment. 93

94 Skipper Schabel model The Skipper Schabel model does not accurately represent the entire clinical reality The log-kill model presumes that growth is exponential between treatment doses and does not vary as a function of tumor size Clinical experience with several solid tumors does not support this model The observations that cure is rare for patients with advanced cancer, and that many patients with early stage cancer recur despite treatment suggest that this model does not completely predict or explain tumor cytokinetics. 94

95 Modern Theories 95

96 Synergy/additive effects Examples: Tamoxifen: When used in combination, is additive and sometimes synergistic Herceptin: A monoclonal antibody to her 2/neu is synergistic with doxorubicin and paclitaxel. Her 2/neu (erbb2) is present on the cancer cell surface of 25% of the patients with breast cancer. Toxicities may also be substantial, however. Herceptin in combination with doxorubicin increased cardiac toxicity. A lesser risk of cardiac toxicity may exist when herceptin is included in taxol combinations 96

97 Synergy/additive effects CHOP: The addition of a complement-fixing monoclonal antibody, rituximab, to cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone (CHOP) chemotherapy in non-hodgkin's lymphoma increases response without an increase in toxicity. Vincristine + prednisone: Represent a long-established combination that is highly potent for ALL. All-trans-retinoic acid (ATRA) and arsenic trioxide interact with acute progranulocytic leukemia cells with resultant differentiation and remission. Cure, however, requires the addition an anthracycline. 97

98 Tumor Cell Heterogeneity and Drug Resistance Heterogeneity among tumor cells increases the number and diversity of potential target sites for chemotherapy and the need for combining therapeutic agents. Drug resistance may be either an acquired or inherited. Mechanisms of drug resistance include: Altered drug transport systems, metabolism, and target enzymes; Inability to repair drug-induced damage; Insensitivity to drug-induced apoptosis. 98

99 Cytokinetics The use of repeated cycles allows the recovery of normal tissues 99

100 Modulation Nontoxic agents improve the therapeutic index of an established chemotherapeutic agent By reducing normal tissue toxicity, such as leucovorin (LCV) for methotrexate, Enhancing antitumor efficacy, such as 5-FU and LCV in metastatic and adjuvant colon cancer studies 100

101 Reference Shord SS, Medina PJ. Chapter 104. Cancer Treatment and Chemotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; /content.aspx?bookid=689&sectionid= Accessed July 31,

102 Questions? 102