Application of Chemotherapy in Application of Chemotherapy in Hematology MalignanciesHematology Malignancies

林建廷林建廷Dec 4, 2007Dec 4, 2007

<<<<AttentionAttention before you prescribe the before you prescribe the chemotherapeutic regimenschemotherapeutic regimens >> >>

How much do you know about your patient?How much do you know about your patient?Disease’s factorDisease’s factor– The diagnosis? The diagnosis? – Current status? (new case, relapse, refractory) Current status? (new case, relapse, refractory)

Patient’s factorPatient’s factor– Performance status (ECOG)Performance status (ECOG)– Co-morbidity? HBV/HCV/HIV? Last MC?Co-morbidity? HBV/HCV/HIV? Last MC?– Family supportFamily support

Doctor’s factorDoctor’s factor– Previous regimen? Effect? Toxicity?Previous regimen? Effect? Toxicity?– Your plan? The possible toxicity of chemotherapy? Dose Your plan? The possible toxicity of chemotherapy? Dose

adjustment?adjustment?22

<<<<AttentionAttention before you prescribe the before you prescribe the chemotherapeutic regimenschemotherapeutic regimens >> >>

What will happen to the patient in the future?What will happen to the patient in the future?– Disease progressionDisease progression– Treatment complicationTreatment complication

Tumor lysis syndromeTumor lysis syndromeCINV (chemotherapy-induced nausea and vomiting)CINV (chemotherapy-induced nausea and vomiting)Mucositis/ diarrheaMucositis/ diarrheaInfection/ sepsis/ shockInfection/ sepsis/ shockDrug toxicityDrug toxicity

– CR/CR/ PRPR

For example:For example:– AML s/p inductional I3A7AML s/p inductional I3A7

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<<<<AttentionAttention before you prescribe the before you prescribe the chemotherapeutic regimenschemotherapeutic regimens >> >>

Tumor lysis syndromeTumor lysis syndrome– SpontaneousSpontaneous– Secondary to chemotherapySecondary to chemotherapy

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Tumor Lysis SyndromeTumor Lysis Syndrome

Important risk factors:Important risk factors:High tumor burdenHigh tumor burdenHighly chemo-sensitiveHighly chemo-sensitiveEx. Acute leukemia, high-grade NHL (Burkitt)Ex. Acute leukemia, high-grade NHL (Burkitt)

S/SS/SLDH, K, P, UA, lactic acidLDH, K, P, UA, lactic acidARF / Seizure / ArrhythmiasARF / Seizure / Arrhythmias

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Tumor Lysis Syndrome(II)Tumor Lysis Syndrome(II)

預防勝於治療預防勝於治療UAUAKKLactic acidLactic acid

Aggressive hydration if toleratedAggressive hydration if tolerated Urine alkalization, keep urine PH~7.0Urine alkalization, keep urine PH~7.0 Allopurinol/ RasburicaseAllopurinol/ Rasburicase Kalimate, HemodialysisKalimate, Hemodialysis Cytoreduction before formal chemotherapyCytoreduction before formal chemotherapy

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<<<<AttentionAttention before you prescribe the before you prescribe the chemotherapeutic regimenschemotherapeutic regimens >> >>

Chemotherapy metabolism and excretionChemotherapy metabolism and excretion– Liver/ bileLiver/ bile– KidneyKidney

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CINV (Nausea and Vomiting)CINV (Nausea and Vomiting)

High emetic potential (High emetic potential (>90%>90%))(1)Cisplatin>50 mg/m2(1)Cisplatin>50 mg/m2 (2)Dacarbazine (DTIC) (2)Dacarbazine (DTIC)(3)Nitrogen mustard(3)Nitrogen mustard (4)Streptozotocin (4)Streptozotocin(5)Cyclophosphamide>1500 mg/m2(5)Cyclophosphamide>1500 mg/m2

Moderately high emeticpotential Moderately high emeticpotential (60~90%(60~90%))(1)Carboplatin (2)Cisplatin<50mg/m2(3)Procarbazine (4)Doxorubicin(5)Cytarabine>1g/m2 (6)MTX>1g/m2

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Premedication for CINVPremedication for CINV

Anti-emesis drugs: Anti-emesis drugs: • Major: 5HT3 antagonist, steroid, NK1-Major: 5HT3 antagonist, steroid, NK1-

antogonistantogonist

• Minor: Vena, Primperan, Novamin, AtivanMinor: Vena, Primperan, Novamin, Ativan

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Vascular AccessVascular Access

External devicesExternal devices Peipheral cathPeipheral cath Central venous catheter (CVP) lineCentral venous catheter (CVP) line Peripherally inserted central catheters (PICC)Peripherally inserted central catheters (PICC)

Implanted devicesImplanted devices Port-APort-A HickmannHickmann

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Catheter-related ComplicationsCatheter-related Complications

Catheter malfunctionCatheter malfunction Venous thrombosis (DVT)Venous thrombosis (DVT) InfectionInfection

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Gastrointestinal ToxicityGastrointestinal Toxicity

Stomatitis/ mucositisStomatitis/ mucositis

(1)Methotrexate & 5-FU(1)Methotrexate & 5-FU (2)Concomittant XRT(2)Concomittant XRT

(3)Oral rinses / anagesics / IV fluids(3)Oral rinses / anagesics / IV fluids

(4)Avoid aspiration & treatment of superinfection(4)Avoid aspiration & treatment of superinfection

DiarrheaDiarrhea

(1)IV fluids and nutritional supply(1)IV fluids and nutritional supply

(2)Oral opioid / octreotide / loperamide(2)Oral opioid / octreotide / loperamide

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SolutionSolution

Normal salineNormal saline : : Cisplatin , Doxorubicin , Cisplatin , Doxorubicin ,

Epirubicin , Methotraxate , Vinblastine , Epirubicin , Methotraxate , Vinblastine ,

Melphalan (phenytoin , heparin ---) Melphalan (phenytoin , heparin ---)

D5WD5W : : Oxaliplatin , Carboplatin (amphotericin Oxaliplatin , Carboplatin (amphotericin

B , levophed , --) B , levophed , --)

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Class of ChemotherapyClass of Chemotherapy Alkylating agent :Alkylating agent :

mustargen cyclophosphamidemustargen cyclophosphamideifosfomide melphalan chloroambucil ifosfomide melphalan chloroambucil busulphan busulphan

Cisplatin and its analogue : Cisplatin and its analogue : carboplatincarboplatin oxaliplatin oxaliplatin

Antimetabolite :Antimetabolite :methotrexatemethotrexate 5-FU 5-FU fludarabine 2-CDA fludarabine 2-CDA gemcitabine Ara-C 6-MP alimtagemcitabine Ara-C 6-MP alimta

Topoisomerase inhibitor :Topoisomerase inhibitor :etoposide (II)etoposide (II) irinotecan (I) irinotecan (I)topotecan (I) Adriamycin (II)topotecan (I) Adriamycin (II)

Antimicrotubule :Antimicrotubule : vinca alkaloid (vincristine , vinblastine , vinca alkaloid (vincristine , vinblastine ,

vinorelbine)vinorelbine) taxane (paclitaxel , docetaxel)taxane (paclitaxel , docetaxel)1515

Drugs used in the treatment of Drugs used in the treatment of leukemia/ lymphomaleukemia/ lymphoma

AntimetabolitesAntimetabolites

Alkylating agentsAlkylating agents

DNA bindingDNA binding

Mitotic inhibitorsMitotic inhibitors

Purine analoguesPurine analogues

MiscellaneousMiscellaneous– Corticosteroid, L-asparaginaseCorticosteroid, L-asparaginase– Alfa-interferon, ATRA (Transretinoic acid)Alfa-interferon, ATRA (Transretinoic acid)– Target therapy (Imatinib, rituximab)Target therapy (Imatinib, rituximab)

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AntimetabolitesAntimetabolites

Inhibit pyrimidine or purine synthesis or Inhibit pyrimidine or purine synthesis or incorporation into DNAincorporation into DNA

Drug Side effectDrug Side effectMTX Mouth ulcer,gut toxicityMTX Mouth ulcer,gut toxicity

6-MP6-MP Jaundice Jaundice

Ara-C CNS, cerebellar toxicity, Ara-C CNS, cerebellar toxicity,

ConjunctivitisConjunctivitis

HydroxyureaHydroxyurea Pigmentation, nail dystrophy, Pigmentation, nail dystrophy,

Skin ulcerSkin ulcer

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Alkylating agentsAlkylating agents

Cross-link DNA, impede RNA formationCross-link DNA, impede RNA formation

DrugDrug Side effect Side effectCyclophosphamideCyclophosphamide Hemorrhagic cystitis, Hemorrhagic cystitis,

cardiomyopathycardiomyopathy

Busulphan Busulphan Marrow aplasia, Marrow aplasia,

pulmonary fibrosispulmonary fibrosis

BCNUBCNU Renal and pulmonary toxicity Renal and pulmonary toxicity

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DNA bindingDNA binding

Binding to DNA and interfere with mitosisBinding to DNA and interfere with mitosis

DrugDrug Side effect Side effectAnthracyclinesAnthracyclines Cardio toxicity Cardio toxicity

DaunorubicinDaunorubicin

AdriamycinAdriamycin

MitoxantroneMitoxantrone

IdarubicinIdarubicin

Bleomycin(DNA break)Bleomycin(DNA break) Pulmonary fibrosis Pulmonary fibrosis

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Mitotic inhibitorMitotic inhibitor

Spindle damage, absent metaphaseSpindle damage, absent metaphase

DrugDrug Side effect Side effectVincristine(Oncovin)Vincristine(Oncovin) Neuropathy Neuropathy

VinblastineVinblastine

VindesineVindesine

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Purine analoguesPurine analogues

Inhibit adenosine deaminase or other purine Inhibit adenosine deaminase or other purine pathwayspathways

DrugDrug Side effect Side effectFludarabineFludarabine Immune suppression, AIHA Immune suppression, AIHA

2-CDA2-CDA Renal and neurotoxicity Renal and neurotoxicity

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MiscellaneousMiscellaneousCorticosteroidCorticosteroid: : Lymphoblast lysisLymphoblast lysis

Peptic ulcer,diabetes,osteoporosis,psychosisPeptic ulcer,diabetes,osteoporosis,psychosis

L-AsparaginaseL-Asparaginase: Deprive cells of asparagine: Deprive cells of asparagine

Hypersensitivity, low albumin and coagulation factors, Hypersensitivity, low albumin and coagulation factors, pancreatitispancreatitis

VP-16VP-16: Mitotic inhibitor: Mitotic inhibitor

Oral ulcerOral ulcer

Alfa-interferonAlfa-interferon: activate RNAase & natural killer activity: activate RNAase & natural killer activity

Flu-like symptom, thrombocytopenia, leukopeniaFlu-like symptom, thrombocytopenia, leukopenia

ATRAATRA: Induce differentiation: Induce differentiation

Liver dysfunction,skin hyperkeratosis, leukocytosis, ATRA Liver dysfunction,skin hyperkeratosis, leukocytosis, ATRA syndromesyndrome

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Alkylating agentAlkylating agent

Cyclophosphamide and Ifosphamide:Cyclophosphamide and Ifosphamide:

Early Early Hemorrhagic cystitisHemorrhagic cystitis

Mesna and keep high urine outputMesna and keep high urine output– Mesna dose = 1.0 to 1.5 Mesna dose = 1.0 to 1.5 dose of dose of

Cyclophosphamide and Ifosphamide (beforeCyclophosphamide and Ifosphamide (before , , after 4hr/ 8hr)after 4hr/ 8hr)

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Methotrexate (1)Methotrexate (1)

Toxicity : Toxicity : Myelosuppression Myelosuppression Mucositis Mucositis Renal toxicity and liver toxicity Renal toxicity and liver toxicity Neurotxicity : Neurotxicity : systemic : acute cerebral dysfunction systemic : acute cerebral dysfunction intrathecal : acute arachnoiditis intrathecal : acute arachnoiditis

subacute arachnoididitis subacute arachnoididitis chronic encephalopathy chronic encephalopathy

Only one drug for serum level Only one drug for serum level

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Methotrexate(2)Methotrexate(2)

Hydration : 12 hours before MTX , 24-48 hrs Hydration : 12 hours before MTX , 24-48 hrs after stopping MTX , keep u/o 1500-2000cc/dayafter stopping MTX , keep u/o 1500-2000cc/day Urine alkalinization : keep PH>7.0Urine alkalinization : keep PH>7.0

LV rescue : 12-24 hours after finishing MTX, LV rescue : 12-24 hours after finishing MTX, 10-15mg (60-100mg) iv q6h 10-15mg (60-100mg) iv q6h

Keep LV rescue to MTX < Keep LV rescue to MTX < 0.050.05μμmol/ L.mol/ L.

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High dose Ara-C: High dose Ara-C: – Cerebellar toxicity (ataxia)Cerebellar toxicity (ataxia)– skin rashskin rash– conjunctivitis conjunctivitis

Prophylactic steroid use for skin rash and Prophylactic steroid use for skin rash and conjunctivitisconjunctivitis

Ara-CAra-C

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VincristineVincristine

Vincristine (Oncovin): Vincristine (Oncovin): – Peripheral neuropathyPeripheral neuropathy– Autonomic neuropathy (ileus)Autonomic neuropathy (ileus)– ““NO” bone marrow suppressionNO” bone marrow suppression

– Total dose: 2mg in one cycleTotal dose: 2mg in one cycle

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DoxorubicinDoxorubicin

DoxorubicinDoxorubicin– CHF (DCM): irreversibleCHF (DCM): irreversible– Dose-responsive effectDose-responsive effect

rare if cumulative dose < 450 mg/mrare if cumulative dose < 450 mg/m2

550mg/m2 550mg/m2 7% 7%

600mg/m2600mg/m2 15% 15%

700mg/m2700mg/m2 30% 30%

– EKG, Cardiac echo f/uEKG, Cardiac echo f/u

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L-AsparaginaseL-Asparaginase

L-Asparaginase: hydrolyzes asparagine into L-Asparaginase: hydrolyzes asparagine into aspartic acid, kills cells that cannot synthesize aspartic acid, kills cells that cannot synthesize asparagineasparagine

L-asparagine : nonessential amino acid L-asparagine : nonessential amino acid

lack of synthesis in lymphoid malignancylack of synthesis in lymphoid malignancy

AEAE Allergy rxn/ pancreatitis/ hyperglycemia/ Allergy rxn/ pancreatitis/ hyperglycemia/ dyslipidemia/ coagulopathydyslipidemia/ coagulopathy

Testing dose Testing dose ““NO” bone marrow suppressionNO” bone marrow suppression

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Complications of TreatmentComplications of Treatment

ExtravasationExtravasation AnaphylaxisAnaphylaxis MyelosuppressionMyelosuppression GI toxicityGI toxicity Tumor lysis syndromeTumor lysis syndrome Interstitial pneumonitis Interstitial pneumonitis Hemorrhagic cystitisHemorrhagic cystitis

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Class of Skin ToxicityClass of Skin Toxicity

Vesicants :Vesicants : Anthracycline : Doxorubicin , EpirubicinAnthracycline : Doxorubicin , Epirubicin

Vinca alkaloid : Vincristine , VinblastineVinca alkaloid : Vincristine , VinblastineMitomycin-C Mitomycin-C

Irritants :Irritants : Etoposide , BCNU , DTIC , CisplatinEtoposide , BCNU , DTIC , CisplatinPaclitaxel , MitoxantronePaclitaxel , Mitoxantrone

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Guidelines for Administration of Guidelines for Administration of Vesicant DrugsVesicant Drugs

1.1.Ensure patency of a peripheral line (Keep Ensure patency of a peripheral line (Keep visualization)visualization)

2.Avoid dorsal hands or near joints2.Avoid dorsal hands or near joints

3.Avoid limbs with impaired circulation3.Avoid limbs with impaired circulation

4.Central line in preferred, especially for 4.Central line in preferred, especially for continuous infusioncontinuous infusion

5. Test the line in advance5. Test the line in advance

6.Patient’s sensation / Observe local condition6.Patient’s sensation / Observe local condition

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Management of ExtravasationManagement of Extravasation

Stop injectionStop injection

Extract drug before removing the Extract drug before removing the

catheter, catheter, Avoid pressure on the siteAvoid 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 necrosispain (>72 hours) or local necrosis

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Antidotes for Extravasation Antidotes for Extravasation of Cytotoxic Drugsof Cytotoxic Drugs

AnthracyclineAnthracycline Ice packsIce packs DMSODMSO

MitomycinMitomycin DMSODMSO

MechlorethamineMechlorethamine

(CDDP)(CDDP)Sodium Sodium

thiosulfatethiosulfate

Vinca alkaloidVinca alkaloid

(Etoposide)(Etoposide)

Warm packsWarm packs HyaluronidaseHyaluronidase

PaclitaxelPaclitaxel Ice packsIce packs HyaluronidaseHyaluronidase

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Other things you should watch outOther things you should watch out

Body weight and urine outputBody weight and urine output

Vital signsVital signs

Intake and nutritionIntake and nutrition

Oral cavity and self-hygieneOral cavity and self-hygiene

Blood CBC, DC and biochemistry (Sugar Blood CBC, DC and biochemistry (Sugar and Kand K+))

Mood and emotional change Mood and emotional change

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