DASAR DASAR KEMOTERAPI PADA PENDERITA KANKER

PELATIHAN SINGKAT TATALAKSANA KEMOTERAPI PADA PENDERITA KANKER BAGI TENAGA PARAMEDIS / PERAWAT RUMAH SAKIT SANGLAH DENPASAR, 15 APRIL 2006

PENDAHULUAN

MODALITAS TERAPI KANKER: BEDAH RADIAOTERAPI KEMOTERAPI TERAPI HORMONAL

TERAPI GEN TERAPI IMUNOLOGI

Pedahuluan
KEMOTERAPI BAGIAN INTEGRAL PENANGANAN KANKER. BAHAN KIMIA YG DAPAT MENGHAMBAT PERTUMBUHAN SEL KANKER. OBAT KERAS TATALAKSANA KHUSUS

PERLU PENGETAHUAN, KETERAMPILAN YANG MEMADAI

 TUJUAN

PEMBERIAN KEMOTERAPI

Mencapai kesembuhan (kuratif) Mempepanjang masa bebas penyakit (DFS). Memperpanjang lama hidup (Survival) Memperbaiki kualitas hidup (QoL) SEBAGAI: Adjuvant Neoadjuvant Terapi utama Radiosensitizer

PRINSIP DASAR
ASPEK

ONKOLOGI ASPEK PENDERITA DAN KELUARGA HASIL PENGOBATAN DAN EFEK SAMPING

ASPEK ONKOLOGI
Diagnosis

kanker: Klinis, Imaging, Patologi. Marker Biologi. Stadium kanker Performance status (Karnofski, ECOG,WHO). faktor risiko

Aspek penderita dan keluaga

INFORMASI MENGENAI: Indikasi Jenis, cara, siklus, lama pemberian obat Efek samping Informed consent

Hasil terapi dan efek samping

Hasil

terapi sesuai dengan tujuan pengobatan Efek samping: diagnosis penanganan

KEMOTERAPI YANG BAIK

EFEKTIF AMAN SPESIFIK SELEKTIF

CARA KERJA KEMOTERAPI

BEKERJA PADA SEL YANG SANGAT AKTIF DOSIS MAKSIMUM YANG DITOLERANSI Tingkat seluler: Sel proliferasi Siklus sel Apoptosis Fase spesifik atau non spesifik Cara pemberian :IV, Oral, instilasi, perfusi Terapi tunggal atau kombinasi

DNA replication P33 cdc2Cyclin A

S
Start/Restriction point G1 Control P33 cdc7, p34 cdc4, p33cdc6 Cyclin E & D MAPkinase

P53
Synthesis enzyme for DNA

G1

G2

MAPkinase

G2 control

P34cdc2 cyclin A&B

Mitosis/Miosis P34 cdc2 Cyclin B Taxan : microtubulin, mblok mitosis dg maktivasi

Doxo : merangsang p53

p34 cdc2

Phleomycin

5 FU

Bleomycin Cyclophosphamide
Actinomycin

Vinblastine Vincristine Colchicine Griseofulvin

0,5-1h
Differentiation Hydrocortisone Chalones

0.5-1h G2 M
2-10h

Purin antagonis

Hydroxy urea Cyclophosphamide

Actinomycin D

G1

6-20h 18-30h

Mytomycin
6-Marcaptopurine 6-Thioguanine

Doxorubicin

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

5 Fudr ara C 6-Hydroxyurea

Alkylating agent, Antimetabolit,Mitotic inhibitor, Antibiotic

5 FU METHOTREXATE

Number of Tumor cell

No response
1012 (1kg)

Early recurrence

Late recurrence

109 (1 g)

Tumor detectable (clinically)

106 (1 mg) Tumor invisible (Remission) 103

Long-term Remission Not palpable

(1 g)

Immune resistance of host (humoral&cellular)

Induction

Consolidation

Maintenance

Cure

CANCER TREATMENT OUTCOME

1.Objective Response Evaluation 2.Subjective Response Evaluation (3). Survival

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

SIDE EFFECT MONITORING

DIAGNOSE of Side Effect
PHARMACOLOGY When Side effect become: NADIR point (degree of SE) Onset of SE, Specificity of organ target

MANAGEMENT of Side Effect

Anticipation & Prevention Dose related side effect monitoring Early treatment of side effect

1. Onset of SE : -Immediately(<1HourpostChemotx)Anaphylaxsis -early(1-48hours)Nausea-Vomitingprofuse -delayed(2days-2months)leucopenia -Late(after2months)myopathy,neuropathy 2.Organ Target:Haematologic,Skin,Cardiovascular, Respiratory,Gastrointestinal,CNS. 3.Level/degree of SE(IUCC,WHO,ECOG): -grade0-2:tolerable(safetyenough) -grade3(severe):mustbealert(Yellowlight),needtreatment -grade4(lifethreatening):Hazard,earlyandadequatetreatment

PROFILE EPISODE of FEBRIL NEUTROPENI

11

nadir

16

21

26

Chemotherapy day

Chemotherapy day

FEBRILE 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

DEGREE OF NEUTROPENIA

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

TREATMENT of FEBRIL NEUTROPENI

Empiric antibacterial

nadir
Empiric antibacterial G-CSF Sterile room

Chemotherapy day

Chemotherapy day

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:

Acute

nausea vomiting (12-24h) Delayed nausea vomiting (up to 5 days) Anticipatory nausea vomiting (result from patients expectation (anticipation) of NV.

Risk factors for CINV:

Patients

Age Gender History of NV History of alcohol use. Drug risk factors (see table) Procedural risk factors (RINV).

risk factors:

Emetogenic potential of antineoplastic agents

High risk Altretamine Carboplatin Carmustine Cisplatin Cyclophosphamide (high-dose) Cytarabine Dacarbazine Doxorubicin Epirubicin Ifosfamide Mitoxantrone Streptozocin Moderate risk Docetaxel Etoposide Fluorouracil Gemcitabine Mitomycin Paclitaxel Low risk Bleomycin Busulfan Chlorambucil Fludarabine Hydroxyurea Melphalan Vinblastine Vincristine Vinorelbine

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

Emetogenic Potential of Single Chemotherapy Agents

Level
5

Frequency of Emesis (%)

> 90 Carmustine > 250 mg/m2 Cisplatin >=50 mg/m2 Cyclophosphamide >1,500 mg/m2 Dacarbazine Mechlorethamine Streptozocin

Chemotherapeutic Agents

60 90

Carboplatin Carmustine <=250 mg/m2 Cisplatin <50 mg/m2 Cyclophosphamide >750 mg/m2 <=1,500 mg/m2 Cytarabine >1 g/m2 Doxorubicin >60 mg/m2 Methotrexate >1,000 mg/m2 Procarbazine (oral) Cyclophosphamide >=750 mg/m2 Cyclophosphamide (oral) Doxorubicin 20-60 mg/m2 Epirubicin <=90 mg/m2 Hexamethylmelamine (Oral) Idarubicin Ifosfamide Methotrexate 250-1,000 mg/m2 Mitoxantrone <15 mg/m2 Docetaxel Etoposide 5-Fluorouracil >1,000 mg/m2 Gemcitabine Methotrexate >50 mg/m2 to <250 mg/m2 Mitomycin Paclitaxel Bleomycin Busulfan Chlorambucil (oral) 2-Chlorodexyadenosine Fludarabine Hydroxyurea Methotrexate <=50 mg/m2 L-phenylalanine mustard (oral) Thioguanine (oral) Vinblastine Vincristine Vinorelbine

30 60

10 30

< 10

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

The neuronal pathway of CINV

Vomiting

center in the medulla (lateral reticular formation) Chemoreceptor Trigger Zone (CTZ) area prostrema 4th ventricle. Neurotransmitters: dopamin, serotonin, neurokinin and their receptors. Nuroreceptors in Enterochromaffin cell GI tract.

Emetic mechanism due to chemotherapy and radiotherapy

Chemotherapy /Radiotherapy Opiat /stimulus

EmeticCenter
r.5-HT3B

Enterochromaffi n sel

r.5-HT3A

(seretonin)

CTZ

r.

3A

Vagal afferent nerve terminal

Gut-wall

Emetogenic stimulus

on

da nse tro n

Complication of CINV
Dehydration Electrolyte

imbalance Aspiration pneumonia Very distressing for patients choosing discontinue potentially curative therapy. Economic burden

Treatment of CINV
Preventing

treating it Anti emetic drugs: Serotonin-receptor antagonist (5-HT3 receptor antagonist). Corticosteroid Others corticosteroids potentiate seretoninreceptor antagonist.

CINV is more effective than

Serotonin-receptor antagonists
DRUG DOSAGE

Dolasetron

100 mg IV (single dose) 100 mg orally (single dose) Granisetron 1-2 mg IV (single dose) 1 or 2 mg orally (single dose) Ondansetron 8 mg IV (single dose) 16-24 mg orally (single dose) or 8 mg orally twice daily Others (Tropisetron, Itasetron)

Other agents used to prevent and treat Chemotherapy-induced emesis

DRUG DOSAGE

Dexamethasone Lorazepam Metoclopramide Haloperidol Dronabinol Prochlorperazine

20 mg IV over 5 minutes (single dose) 20 mg orally (single dose) 0.5-2 mg IV every 4-6 hours as needed 0.5-2 mg orally every 6 hours as needed 2-3 mg/kg IV every 2 hours 2-3 mg/kg orally every 2-3 hours 1-2 mg IV every 4-6 hours 1-2 mg orally every 4-6 hours 5 mg/m2 orally every 4 hours 10-20 mg IV every 3-4 hours 5-10 mg orally every 4-6 hours 25 mg suppository every 6 hours

Regimens to prevent delayed chemotherapy-induced emesis

DRUG DOSAGE

Metoclopramide 30-40 mg orally twice a day plus dexamethasone 8 mg orally twice a day (both for 3 days) Ondansetron 8 mg orally twice a day plus dexamethasone 8 mg orally twice a day (both for 3 days)

Tepat indikasi : kemoterapi tepat dipilih berdasar titik tangkap kerjanya berdasar patogenesis kanker sehingga dapattercapaitujuan: 1.kuratif 2.mencapaibebaspenyakit(DFS)yanglebihlama 3.neoadjuvant(Mikrometastasis,mengecilkanvolumetumor preoperasi-downstaging) 4.mempertahankanataumeningkatkanquality of life (terapipaliatif)

Tepat jenis obat:sebaiknya lebih spesifik, selektif, mempunyai Response rate tinggi, established, dan dapat dijangkau oleh penderita Tepat dosis obat:sesuaiMaximum Tolerated Dose ( Risk group ) Tepat cara pemberian obat:oral, IV, bolus, infusion dsb yang penting :penderitanyaman , 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

TERIMAKASIH SEMOGA BERMANFAAT