Application of Chemotherapy in Hematology Malignancies 林建廷 Dec 4, 2007

> > How much do you know about your patient? Disease’s factor –The diagnosis? –Current status? (new case, relapse, refractory) Patient’s factor –Performance status (ECOG) –Co-morbidity? HBV/HCV/HIV? Last MC? –Family support Doctor’s factor –Previous regimen? Effect? Toxicity? –Your plan? The possible toxicity of chemotherapy? Dose adjustment? 2

> > What will happen to the patient in the future? –Disease progression –Treatment complication Tumor lysis syndrome CINV (chemotherapy-induced nausea and vomiting) Mucositis/ diarrhea Infection/ sepsis/ shock Drug toxicity –CR/ PR For example: –AML s/p inductional I3A7 3

> > Tumor lysis syndrome –Spontaneous –Secondary to chemotherapy 4

Tumor Lysis Syndrome  Important risk factors:  High tumor burden  Highly chemo-sensitive  Ex. Acute leukemia, high-grade NHL (Burkitt)  S/S  LDH, K, P, UA, lactic acid  ARF / Seizure / Arrhythmias 5

Tumor Lysis Syndrome(II)  預防勝於治療  UA  K  Lactic acid  Aggressive hydration if tolerated  Urine alkalization, keep urine PH~7.0  Allopurinol/ Rasburicase  Kalimate, Hemodialysis  Cytoreduction before formal chemotherapy 6

> > Chemotherapy metabolism and excretion –Liver/ bile –Kidney 7

CINV (Nausea and Vomiting)  High emetic potential ( >90% ) (1)Cisplatin>50 mg/m2 (2)Dacarbazine (DTIC) (3)Nitrogen mustard (4)Streptozotocin (5)Cyclophosphamide>1500 mg/m2  Moderately high emeticpotential (60~90% ) (1)Carboplatin (2)Cisplatin<50mg/m2 (3)Procarbazine (4)Doxorubicin (5)Cytarabine>1g/m2(6)MTX>1g/m2 8

Premedication for CINV Anti-emesis drugs: Major: 5HT3 antagonist, steroid, NK1- antogonistMajor: 5HT3 antagonist, steroid, NK1- antogonist Minor: Vena, Primperan, Novamin, AtivanMinor: Vena, Primperan, Novamin, Ativan 9

Vascular Access  External devices  Peipheral cath  Central venous catheter (CVP) line  Peripherally inserted central catheters (PICC)  Implanted devices  Port-A  Hickmann 10

Catheter-related Complications  Catheter malfunction  Venous thrombosis (DVT)  Infection 11

Gastrointestinal Toxicity  Stomatitis/ mucositis (1)Methotrexate & 5-FU(2)Concomittant XRT (3)Oral rinses / anagesics / IV fluids (4)Avoid aspiration & treatment of superinfection  Diarrhea (1)IV fluids and nutritional supply (2)Oral opioid / octreotide / loperamide 12

13

Solution Normal saline : Cisplatin, Doxorubicin, Normal saline : Cisplatin, Doxorubicin, Epirubicin, Methotraxate, Vinblastine, Epirubicin, Methotraxate, Vinblastine, Melphalan (phenytoin, heparin ---) Melphalan (phenytoin, heparin ---) D5W : Oxaliplatin, Carboplatin (amphotericin D5W : Oxaliplatin, Carboplatin (amphotericin B, levophed, --) B, levophed, --) 14

Class of Chemotherapy Alkylating agent : mustargen cyclophosphamideifosfomide melphalan chloroambucil busulphan Alkylating agent : mustargen cyclophosphamideifosfomide melphalan chloroambucil busulphan Cisplatin and its analogue : carboplatin oxaliplatin Cisplatin and its analogue : carboplatin oxaliplatin Antimetabolite : methotrexate 5-FUfludarabine 2-CDA gemcitabine Ara-C 6-MP alimta Antimetabolite : methotrexate 5-FUfludarabine 2-CDA gemcitabine Ara-C 6-MP alimta Topoisomerase inhibitor : etoposide (II) irinotecan (I) topotecan (I) Adriamycin (II) Topoisomerase inhibitor : etoposide (II) irinotecan (I) topotecan (I) Adriamycin (II) Antimicrotubule : vinca alkaloid (vincristine, vinblastine, vinorelbine) taxane (paclitaxel, docetaxel) Antimicrotubule : vinca alkaloid (vincristine, vinblastine, vinorelbine) taxane (paclitaxel, docetaxel) 15

Drugs used in the treatment of leukemia/ lymphoma Antimetabolites Alkylating agents DNA binding Mitotic inhibitors Purine analogues Miscellaneous –Corticosteroid, L-asparaginase –Alfa-interferon, ATRA (Transretinoic acid) –Target therapy (Imatinib, rituximab) 16

Antimetabolites Inhibit pyrimidine or purine synthesis or incorporation into DNA Drug Side effect Drug Side effect MTX Mouth ulcer,gut toxicity 6-MP Jaundice Ara-C CNS, cerebellar toxicity, Conjunctivitis Conjunctivitis Hydroxyurea Pigmentation, nail dystrophy, Skin ulcer Skin ulcer 17

Alkylating agents Cross-link DNA, impede RNA formation Drug Side effect Cyclophosphamide Hemorrhagic cystitis, cardiomyopathy cardiomyopathy Busulphan Marrow aplasia, pulmonary fibrosis pulmonary fibrosis BCNU Renal and pulmonary toxicity 18

DNA binding Binding to DNA and interfere with mitosis Drug Side effect Anthracyclines Cardio toxicity Daunorubicin Daunorubicin Adriamycin Adriamycin Mitoxantrone Mitoxantrone Idarubicin Idarubicin Bleomycin(DNA break) Pulmonary fibrosis 19

Mitotic inhibitor Spindle damage, absent metaphase Drug Side effect Vincristine(Oncovin) Neuropathy Vinblastine Vinblastine Vindesine Vindesine 20

Purine analogues Inhibit adenosine deaminase or other purine pathways Drug Side effect Fludarabine Immune suppression, AIHA 2-CDA Renal and neurotoxicity 21

Miscellaneous Corticosteroid : Lymphoblast lysis Peptic ulcer,diabetes,osteoporosis,psychosis Peptic ulcer,diabetes,osteoporosis,psychosis L-Asparaginase: Deprive cells of asparagine Hypersensitivity, low albumin and coagulation factors, pancreatitis Hypersensitivity, low albumin and coagulation factors, pancreatitis VP-16: Mitotic inhibitor Oral ulcer Oral ulcer Alfa-interferon: activate RNAase & natural killer activity Flu-like symptom, thrombocytopenia, leukopenia Flu-like symptom, thrombocytopenia, leukopenia ATRA: Induce differentiation Liver dysfunction,skin hyperkeratosis, leukocytosis, ATRA syndrome Liver dysfunction,skin hyperkeratosis, leukocytosis, ATRA syndrome 22

Alkylating agent Cyclophosphamide and Ifosphamide: Early Hemorrhagic cystitis Early Hemorrhagic cystitis Mesna and keep high urine output –Mesna dose = 1.0 to 1.5  dose of Cyclophosphamide and Ifosphamide (before, after 4hr/ 8hr) 23

24

Methotrexate (1) Toxicity : Myelosuppression Mucositis Renal toxicity and liver toxicity Neurotxicity : systemic : acute cerebral dysfunction intrathecal : acute arachnoiditis subacute arachnoididitis chronic encephalopathy Only one drug for serum level 25

Methotrexate(2) Hydration : 12 hours before MTX, hrs after stopping MTX, keep u/o cc/day Urine alkalinization : keep PH>7.0 LV rescue : hours after finishing MTX, 10-15mg (60-100mg) iv q6h Keep LV rescue to MTX < 0.05μmol/ L. Keep LV rescue to MTX < 0.05μmol/ L. 26

High dose Ara-C: –Cerebellar toxicity (ataxia) –skin rash –conjunctivitis Prophylactic steroid use for skin rash and conjunctivitis Ara-C 27

Vincristine Vincristine (Oncovin): –Peripheral neuropathy –Autonomic neuropathy (ileus) –“NO” bone marrow suppression –Total dose: 2mg in one cycle 28

Doxorubicin Doxorubicin –CHF (DCM): irreversible –Dose-responsive effect rare if cumulative dose < 450 mg/m rare if cumulative dose < 450 mg/m 2 550mg/m2  7% 600mg/m2  15% 700mg/m2  30% –EKG, Cardiac echo f/u 29

L-Asparaginase L-Asparaginase: hydrolyzes asparagine into aspartic acid, kills cells that cannot synthesize asparagine L-asparagine : nonessential amino acid lack of synthesis in lymphoid malignancy lack of synthesis in lymphoid malignancy  AE  Allergy rxn/ pancreatitis/ hyperglycemia/ dyslipidemia/ coagulopathy  Testing dose  “NO” bone marrow suppression 30

Complications of Treatment  Extravasation  Anaphylaxis  Myelosuppression  GI toxicity  Tumor lysis syndrome  Interstitial pneumonitis  Hemorrhagic cystitis 31

Class of Skin Toxicity Vesicants : Vesicants : Anthracycline : Doxorubicin, Epirubicin Vinca alkaloid : Vincristine, Vinblastine Mitomycin-C Anthracycline : Doxorubicin, Epirubicin Vinca alkaloid : Vincristine, Vinblastine Mitomycin-C Irritants : Etoposide, BCNU, DTIC, Cisplatin Paclitaxel, Mitoxantrone Irritants : Etoposide, BCNU, DTIC, Cisplatin Paclitaxel, Mitoxantrone 32

Guidelines for Administration of Vesicant Drugs 1.Ensure patency of a peripheral line (Keep visualization) 2.Avoid dorsal hands or near joints 3.Avoid limbs with impaired circulation 4.Central line in preferred, especially for continuous infusion 5. Test the line in advance 6.Patient’s sensation / Observe local condition 33

Management of Extravasation Stop injection Stop injection Extract drug before removing the Extract drug before removing the catheter, Avoid pressure on the site catheter, Avoid pressure on the site Heat pack : Vinblastine, Vincristine Heat pack : Vinblastine, Vincristine Cold pack : others Cold pack : others Surgery : consult surgeon in persistent Surgery : consult surgeon in persistent pain (>72 hours) or local necrosis pain (>72 hours) or local necrosis Antidote Antidote 34

Antidotes for Extravasation of Cytotoxic Drugs Anthracycline Ice packs DMSO MitomycinDMSO Mechlorethamine(CDDP) Sodium thiosulfate Vinca alkaloid (Etoposide) Warm packs Hyaluronidase Paclitaxel Ice packs Hyaluronidase 35

Other things you should watch out Body weight and urine output Vital signs Intake and nutrition Oral cavity and self-hygiene Blood CBC, DC and biochemistry (Sugar and K) Blood CBC, DC and biochemistry (Sugar and K + ) Mood and emotional change 36