DASAR – DASAR KEMOTERAPI PADA PENDERITA KANKER

DASAR – DASAR KEMOTERAPI DASAR – DASAR KEMOTERAPI PADA PENDERITA KANKERPADA PENDERITA KANKER

PELATIHAN SINGKAT TATALAKSANA KEMOTERAPI PELATIHAN SINGKAT TATALAKSANA KEMOTERAPI PADA PENDERITA KANKER PADA PENDERITA KANKER

BAGI TENAGA PARAMEDIS / PERAWAT RUMAH BAGI TENAGA PARAMEDIS / PERAWAT RUMAH SAKIT SANGLAH DENPASAR, 15 APRIL 2006 SAKIT SANGLAH DENPASAR, 15 APRIL 2006

PENDAHULUANPENDAHULUAN

MODALITAS TERAPI KANKER:MODALITAS TERAPI KANKER:

BEDAHBEDAHRADIAOTERAPIRADIAOTERAPIKEMOTERAPIKEMOTERAPITERAPI HORMONALTERAPI HORMONAL

TERAPI GENTERAPI GEN

TERAPI IMUNOLOGITERAPI IMUNOLOGI

PedahuluanPedahuluan

KEMOTERAPIKEMOTERAPI

BAGIAN INTEGRAL PENANGANAN KANKER. BAGIAN INTEGRAL PENANGANAN KANKER.

BAHAN KIMIA YG DAPAT MENGHAMBAT BAHAN KIMIA YG DAPAT MENGHAMBAT PERTUMBUHAN SEL PERTUMBUHAN SEL

KANKER.KANKER.

OBAT KERASOBAT KERAS

TATALAKSANA KHUSUSTATALAKSANA KHUSUS

PERLU PENGETAHUAN, KETERAMPILAN YANG PERLU PENGETAHUAN, KETERAMPILAN YANG MEMADAIMEMADAI

TUJUAN PEMBERIAN KEMOTERAPITUJUAN PEMBERIAN KEMOTERAPIMencapai kesembuhan (kuratif)Mencapai kesembuhan (kuratif)Mempepanjang masa bebas penyakit Mempepanjang masa bebas penyakit (DFS).(DFS).Memperpanjang lama hidup (Survival)Memperpanjang lama hidup (Survival)Memperbaiki kualitas hidup (QoL)Memperbaiki kualitas hidup (QoL)

SEBAGAI: AdjuvantSEBAGAI: Adjuvant Neoadjuvant Neoadjuvant Terapi utama Terapi utama Radiosensitizer Radiosensitizer

PRINSIP DASARPRINSIP DASAR

ASPEK ONKOLOGIASPEK ONKOLOGI ASPEK PENDERITA DAN KELUARGAASPEK PENDERITA DAN KELUARGA HASIL PENGOBATAN DAN EFEK HASIL PENGOBATAN DAN EFEK

SAMPINGSAMPING

ASPEK ONKOLOGIASPEK ONKOLOGI

Diagnosis kanker:Diagnosis kanker:Klinis, Imaging, Patologi. Klinis, Imaging, Patologi.

Marker Marker Biologi.Biologi. Stadium kankerStadium kanker Performance status (Karnofski, Performance status (Karnofski,

ECOG,WHO). ECOG,WHO). faktor risikofaktor risiko

Aspek penderita dan Aspek penderita dan keluagakeluaga

INFORMASI MENGENAI:INFORMASI MENGENAI:IndikasiIndikasiJenis, cara, siklus, lama pemberian Jenis, cara, siklus, lama pemberian

obatobat

Efek sampingEfek samping

Informed consentInformed consent

Hasil terapi dan efek Hasil terapi dan efek sampingsamping

Hasil terapi sesuai dengan tujuan Hasil terapi sesuai dengan tujuan pengobatanpengobatan

Efek samping:Efek samping:diagnosisdiagnosispenangananpenanganan

KEMOTERAPI YANG BAIKKEMOTERAPI YANG BAIK EFEKTIFEFEKTIF AMANAMAN SPESIFIKSPESIFIK SELEKTIFSELEKTIF

CARA KERJA KEMOTERAPICARA KERJA KEMOTERAPI

BEKERJA PADA SEL YANG SANGAT AKTIFBEKERJA PADA SEL YANG SANGAT AKTIF DOSIS MAKSIMUM YANG DITOLERANSIDOSIS MAKSIMUM YANG DITOLERANSI Tingkat seluler:Tingkat seluler:

Sel proliferasiSel proliferasiSiklus selSiklus selApoptosisApoptosis

Fase spesifik atau non spesifikFase spesifik atau non spesifik Cara pemberian :IV, Oral, instilasi, perfusiCara pemberian :IV, Oral, instilasi, perfusi Terapi tunggal atau kombinasiTerapi tunggal atau kombinasi

DNA replicationP33 cdc2Cyclin A

S

G1  

M

G2

Mitosis/MiosisP34 cdc2 Cyclin B

MAP kinase

G2 controlP34cdc2 cyclin A& B

MAP kinase

Start/Restriction pointG1 ControlP33 cdc7, p34 cdc4, p33cdc6

Cyclin E & D

P53Synthesis enzyme for DNA

Taxan : microtubulin, m’blok mitosis dg m’aktivasi p34 cdc2

Doxo : merangsang p53

MG2

G1S

Bleomycin

5 Fudrara C6-Hydroxyurea

5 FUMETHOTREXATE

6-Thioguanine

6-Marcaptopurine

Mytomycin

Actinomycin D

Hydrocortisone Chalones

5 FU

VinblastineVincristineColchicineGriseofulvin

Differentiation

Phleomycin

Cyclophosphamide

Purin antagonis

Hydroxy urea

Actinomycin

Cyclophosphamide

5 Fudr .5FU, Ara C. Mitomycin,Doxorubicin Thioguanine

18-30h6-20h

0,5-1h

0.5-1h

2-10h

Doxorubicin

Alkylating agent, Antimetabolit,Mitotic inhibitor, Antibiotic

No response Early recurrence Late recurrence

Tumor detectable(clinically)

Long-term Remission Not palpable

Immune resistanceof host

(humoral&cellular)

Induction Consolidation Maintenance Cure

1012

109

106

103

(1kg)

(1 g)

(1 mg)

Number ofTumor cell

Tumor invisible(Remission)

(1 úg)

1.Objective Response Evaluation2.Subjective Response Evaluation(3). Survival

CANCER TREATMENT OUTCOME

OBJECTIVE RESPONSE EVALUATIONS

1. TUMOR SIZE : - Complete remission (CR) - Partial remission (PR) - No Changes (Stable Disease = St D) - Progressive Disease (PD)

2. Marker Tumour : - CEA, CA15-3, MCA Breast Ca - CEA, CA19-9 Pancreas Ca, Colorectal Ca - HCG Chorio Ca - PSA Prostat Ca

3. Objective-Qualitative : - Change of Clinical sign : Brain Ca-neurology sign

SUBJECTIVE RESPONSE EVALUATION

Performance status : Karnofsky / ECOG

Palliative

CURATIVE : caution of safety and side effects

DIAGNOSE of Side Effect

PHARMACOLOGYWhen Side effect become: NADIR point (degree of SE)Onset of SE, Specificity of organ target

MANAGEMENT of Side Effect

Anticipation & PreventionDose related side effect monitoringEarly treatment of side effect

SIDE EFFECT MONITORING

1. Onset of SE : - Immediately ( < 1 Hour post Chemotx) Anaphylaxsis - early (1- 48 hours ) Nausea-Vomiting profuse - delayed (2 days -2 months ) leucopenia - Late (after 2 months ) myopathy, neuropathy

2.Organ Target : Haematologic, Skin, Cardiovascular, Respiratory, Gastrointestinal, CNS.

3.Level/degree of SE (IUCC,WHO, ECOG) : - grade 0-2 : tolerable ( safety enough ) - grade 3 (severe) : must be alert (Yellow light), need treatment ± - grade 4 (life threatening) : Hazard, early and adequate treatment

PROFILE EPISODE of FEBRIL NEUTROPENI

Chemotherapy day

Chemotherapy day

nadir1 6 11 16 21 26

FEBRILE NEUTROPENIAFEBRILE NEUTROPENIA

CRITERIA :

• NEUTROPENIA :

absolute count of neutrophill in circulating blood < 2000 cells/mm3

• FEVER :

body temperature > 38.50C in 3 x measurement per 24 hours

CRITERIA :

• NEUTROPENIA :

absolute count of neutrophill in circulating blood < 2000 cells/mm3

• FEVER :

body temperature > 38.50C in 3 x measurement per 24 hours

DEGREE OF NEUTROPENIADEGREE OF NEUTROPENIA

• Mild : 2000 – 1000 cells/mm3• Moderate : 1000 – 500 cells/mm3• Severe : < 500 cells/mm3

• Mild : 2000 – 1000 cells/mm3• Moderate : 1000 – 500 cells/mm3• Severe : < 500 cells/mm3

TREATMENT of FEBRIL NEUTROPENI

Empiric antibacterial

Empiric antibacterial

Chemotherapy day

Chemotherapy day

nadir

G-CSFSterile room

Hiperpigmentation (Fluorouracil )

Management Side Effect

1. ANTIDOTUM to specific agent : - Antidotum of MTX : Calcium leucovorin, Ca Lefofolinat - Cardiomyopathy prophylaxis – Doxorubicin > 450 mg/m2 * Dexrazosane 10 mg – Doxorubicin 1 mg

2. Dose modification : - Toxicity grade 3 and 4 : decrease dose 25% - 50%

3. Supportive Drugs : - Haemopoetic GF : G-CSF, GM-SF, IL-3, Epo - Component Blood transfuse - Selective antibiotic

4. Sterile Room technology

Three types of CINV: Three types of CINV:

Acute nausea vomiting (12-24h)Acute nausea vomiting (12-24h) Delayed nausea vomiting (up to 5 Delayed nausea vomiting (up to 5

days)days) Anticipatory nausea vomiting (result Anticipatory nausea vomiting (result

from patient’s expectation from patient’s expectation (anticipation) of NV.(anticipation) of NV.

Risk factors for CINV:Risk factors for CINV:

Patients risk factors:Patients risk factors:AgeAgeGenderGenderHistory of NVHistory of NVHistory of alcohol use.History of alcohol use.

Drug risk factors (see table)Drug risk factors (see table) Procedural risk factors (RINV).Procedural risk factors (RINV).

Markman M. CCJM 2002;69(8):609-617.Markman M. CCJM 2002;69(8):609-617.

Emetogenic potential of antineoplastic agents Emetogenic potential of antineoplastic agents

High risk High risk Moderate riskModerate risk Low riskLow risk Altretamine Altretamine Docetaxel Docetaxel Bleomycin Bleomycin CarboplatinCarboplatin Etoposide Etoposide Busulfan Busulfan Carmustine Carmustine Fluorouracil Fluorouracil Chlorambucil Chlorambucil Cisplatin Cisplatin Gemcitabine Gemcitabine

Fludarabine Fludarabine Cyclophosphamide Cyclophosphamide Mitomycin Mitomycin Hydroxyurea Hydroxyurea (high-dose)(high-dose) Paclitaxel Paclitaxel Melphalan Melphalan Cytarabine Cytarabine Vinblastine Vinblastine Dacarbazine Dacarbazine Vincristine Vincristine Doxorubicin Doxorubicin Vinorelbine Vinorelbine Epirubicin Epirubicin Ifosfamide Ifosfamide MitoxantroneMitoxantrone Streptozocin Streptozocin

Hesketh PJ, Kris MG, Grunberg SM, et al. J Clin Oncol. 1997;15:103-109Hesketh PJ, Kris MG, Grunberg SM, et al. J Clin Oncol. 1997;15:103-109

Emetogenic Potential of Single Chemotherapy AgentsEmetogenic Potential of Single Chemotherapy Agents

LeveLevell

Frequency of Frequency of Emesis (%)Emesis (%)

Chemotherapeutic Chemotherapeutic

AgentsAgents

55 > 90> 90 Carmustine > 250 mg/mCarmustine > 250 mg/m22

Cisplatin >=50 mg/mCisplatin >=50 mg/m22

Cyclophosphamide >1,500 mg/mCyclophosphamide >1,500 mg/m22

Dacarbazine Dacarbazine

Mechlorethamine Mechlorethamine

Streptozocin Streptozocin

44 60 – 9060 – 90 Carboplatin Carboplatin

Carmustine <=250 mg/mCarmustine <=250 mg/m22

Cisplatin <50Cisplatin <50 mg/mmg/m22

Cyclophosphamide >750 mg/mCyclophosphamide >750 mg/m22 <=1,500 mg/m <=1,500 mg/m22

Cytarabine >1 g/mCytarabine >1 g/m22

Doxorubicin >60 mg/mDoxorubicin >60 mg/m22

Methotrexate >1,000 mg/mMethotrexate >1,000 mg/m22

Procarbazine (oral)Procarbazine (oral)

33 30 – 6030 – 60 Cyclophosphamide >=750 mg/mCyclophosphamide >=750 mg/m22

Cyclophosphamide (oral)Cyclophosphamide (oral)

Doxorubicin 20-60 mg/mDoxorubicin 20-60 mg/m22

Epirubicin <=90 mg/mEpirubicin <=90 mg/m22

Hexamethylmelamine (Oral)Hexamethylmelamine (Oral)

Idarubicin Idarubicin

IfosfamideIfosfamide

Methotrexate 250-1,000 mg/mMethotrexate 250-1,000 mg/m22

Mitoxantrone <15 mg/mMitoxantrone <15 mg/m22

22 10 – 3010 – 30 DocetaxelDocetaxel

EtoposideEtoposide

5-Fluorouracil >1,000 mg/m5-Fluorouracil >1,000 mg/m22

Gemcitabine Gemcitabine

Methotrexate >50 mg/mMethotrexate >50 mg/m22 to <250 mg/m to <250 mg/m22

MitomycinMitomycin

PaclitaxelPaclitaxel

11 < 10< 10 Bleomycin Bleomycin

Busulfan Busulfan

Chlorambucil (oral)Chlorambucil (oral)

2-Chlorodexyadenosine2-Chlorodexyadenosine

FludarabineFludarabine

HydroxyureaHydroxyurea

Methotrexate <=50 mg/mMethotrexate <=50 mg/m22

L-phenylalanine mustard (oral)L-phenylalanine mustard (oral)

Thioguanine (oral)Thioguanine (oral)

Vinblastine Vinblastine

VincristineVincristine

VinorelbineVinorelbine

The neuronal pathway of The neuronal pathway of CINVCINV

Vomiting center in the medulla (lateral Vomiting center in the medulla (lateral reticular formation)reticular formation)

Chemoreceptor Trigger Zone (CTZ) Chemoreceptor Trigger Zone (CTZ) area prostrema 4area prostrema 4thth ventricle. ventricle.

Neurotransmitters: dopamin, Neurotransmitters: dopamin, serotonin, neurokinin and their serotonin, neurokinin and their receptors.receptors.

Nuroreceptors in Enterochromaffin cell Nuroreceptors in Enterochromaffin cell GI tract.GI tract.

Enterochromaffin sel

3ACTZ

Gut-wall

Emetic Center

Emetic mechanism due to chemotherapy and radiotherapy

Vagal afferent nerve terminal

(seretonin)r.5-HT3A

Chemotherapy/RadiotherapyOpiat /stimulus

r.5-HT3B

r.

Emetogenic stimulus

ondansetron

Complication of CINVComplication of CINV

DehydrationDehydration Electrolyte imbalanceElectrolyte imbalance Aspiration pneumoniaAspiration pneumonia Very distressing for patients Very distressing for patients

choosing discontinue potentially choosing discontinue potentially curative therapy.curative therapy.

Economic burdenEconomic burden

Treatment of CINVTreatment of CINV

Preventing CINV is more effective Preventing CINV is more effective than treating itthan treating it

Anti emetic drugs:Anti emetic drugs:Serotonin-receptor antagonist Serotonin-receptor antagonist

(5-HT3 (5-HT3 receptor antagonist).receptor antagonist).CorticosteroidCorticosteroidOthersOthers

corticosteroids potentiate seretonin-corticosteroids potentiate seretonin-receptor antagonist.receptor antagonist.

Serotonin-receptor antagonistsSerotonin-receptor antagonists

DRUGDRUG DOSAGE DOSAGE

Dolasetron Dolasetron 100 mg IV (single dose)100 mg IV (single dose)

100 mg orally (single dose)100 mg orally (single dose)

Granisetron Granisetron 1-2 mg IV (single dose)1-2 mg IV (single dose)

1 or 2 mg orally (single dose)1 or 2 mg orally (single dose)

OndansetronOndansetron 8 mg IV (single dose)8 mg IV (single dose)

16-24 mg orally (single dose)16-24 mg orally (single dose)

or 8 mg orally twice daily or 8 mg orally twice daily

Others (Tropisetron, Itasetron)Others (Tropisetron, Itasetron)

Other agents used to prevent and treatOther agents used to prevent and treat

Chemotherapy-induced emesisChemotherapy-induced emesis

DRUGDRUG DOSAGE DOSAGE

Dexamethasone Dexamethasone 20 mg IV over 5 minutes (single dose)20 mg IV over 5 minutes (single dose)

20 mg orally (single dose)20 mg orally (single dose)

Lorazepam Lorazepam 0.5-2 mg IV every 4-6 hours as needed0.5-2 mg IV every 4-6 hours as needed

0.5-2 mg orally every 6 hours as 0.5-2 mg orally every 6 hours as neededneeded

MetoclopramideMetoclopramide 2-3 mg/kg IV every 2 hours2-3 mg/kg IV every 2 hours

2-3 mg/kg orally every 2-3 hours 2-3 mg/kg orally every 2-3 hours

Haloperidol Haloperidol 1-2 mg IV every 4-6 hours 1-2 mg IV every 4-6 hours

1-2 mg orally every 4-6 hours1-2 mg orally every 4-6 hours

DronabinolDronabinol 5 mg/m5 mg/m22 orally every 4 hours orally every 4 hours

Prochlorperazine Prochlorperazine 10-20 mg IV every 3-4 hours 10-20 mg IV every 3-4 hours

5-10 mg orally every 4-6 hours 5-10 mg orally every 4-6 hours

25 mg suppository every 6 hours 25 mg suppository every 6 hours

Regimens to prevent delayedRegimens to prevent delayedchemotherapy-induced emesischemotherapy-induced emesis

DRUGDRUG DOSAGE DOSAGE

Metoclopramide Metoclopramide 30-40 mg orally twice a 30-40 mg orally twice a day day

plus dexamethasoneplus dexamethasone 8 mg orally twice a day 8 mg orally twice a day (both for 3 days)(both for 3 days)

Ondansetron Ondansetron 8 mg orally twice a day 8 mg orally twice a day plus dexamethasoneplus dexamethasone 8 mg orally twice a day 8 mg orally twice a day

(both for 3 days)(both for 3 days)

Tepat indikasi : kemoterapi tepat dipilih berdasar titik tangkap kerjanya berdasar patogenesis kanker sehingga dapat tercapai tujuan : 1.kuratif 2.mencapai bebas penyakit (DFS) yang lebih lama 3.neoadjuvant (Mikrometastasis,mengecilkan volume tumor preoperasi-down staging) 4.mempertahankan atau meningkatkan quality of life (terapi paliatif)

Tepat cara pemberian obat : oral, IV, bolus, infusion dsb yang penting : penderita nyaman , tidak takut dan dengan kesadaran sendiri ingin melanjutkan kemoterapi Tepat monitoring efek obat : - penilaian hasil / respons terapi - kemampuan hidup (quality of life) dan - efek samping obat

Tepat jenis obat : sebaiknya lebih spesifik, selektif, mem- punyai Response rate tinggi, established, dan dapat dijangkau oleh penderita

Tepat dosis obat : sesuai Maximum Tolerated Dose ( Risk group )

TERIMAKASIHSEMOGA BERMANFAAT