KEMOTERAPI

Dra. Endang Martiniani M.Pharm., Apt

KANKERa/ akibat perubahan regulasi dari proliferasi, diferensiasi dan migrasi yg mrp suatu proses genetika & ada sel yg memp kemampuan proliferasi

FAKTOR PENYEBAB KANKER1. GENETIKA

Ada hub yg kuat antara bbrp peny turunan dg kanker Mis. : Familial polyposis coli colorectal adenocarcinoma Fanconi anemialeukemia akut Down's syndrome leukemia akut Mutasi gen RB1retinoblastomaosteosarcoma

2. KIMIA Rokok CA paru, larynx, bladder, mulut Asbes CA paru Aflatoxin CA hepar Aniline dyes CA ginjal, ureter, bladder

3. VIRAL HPV = human pabilloma virus Epstein - Barr virus Hepatitis B

4. FISIK = radiasi, trauma / inflamasi kronik

STADIUM DALAM KANKERSbg suatu ukuran tk keparahan penyakitIndikator prognostikSalah satu cara u/ mengetahui terapi CA rasionalU/ mambandingkan hasil terapi

STADIUM / STAGING0 : sel-sel CA dpt dihilangkan dg cara operasi / dg

prosedur non invrasineI : invasi pd drh lokal, blm ada metastaseII : penyebaran msh bersifat lokal & minimal III : sel-sel CA sdh menyebar & penyebarannya adh

ekstensif / meluasIV : metastase meluas

SIKLUS SEL CAM

G2 G1 G0

S

mitosis

Sintesa prot& RNA

Sintesa &prod enzim

Faseistirahat

Sel-selmati

Diferensiasi(maturasi mjd sel2

yg tdk membelah)

Sintesa DNA

KEMOTERAPI

cell-cycle phase non spesific eg : cyclophospamid, doxorubicin

cell-cycle phase spesific eg : MTX, FU

KEMOTERAPI : suatu terapi kanker dg menggunakan obat2 anti kanker (cytotoxic) u/ meng- hancurkan sel-sel CA

Cellcycle sel2 CA lebih lama dp sel2 normalSel2 normal : 24 - 48 jamSel2 CA : 72 - 120 jam

doneSpesifik

% su

rviv

ing

doneNon-spesifik

100%

% s

urvi

ving

KEMOTERAPI : suatu terapi kanker dg menggunakanobat2 anti kanker cytotoxic u/ menghancur-kan sel-sel CA

100%

KECAPATAN PERTUMBUHAN SEL2 CA

log

[Jum

lah

sel]

Pertumb sel2 normal

Pertumb sel2 CA

diving resting

Massa sel2 CA Massa sel2 normal

PENDEKATAN TERAPI1. Pencegahan2. Deteksi awal

mis. : - perubahan kebiasaan BAB - luka yg tidak sembuh2

- perdarahan yg tdk normal - sulit menelan / mencerna - pap smear, mammography, PASARI

3. Terapi4. Terapi paliatif

TERAPIOperasiRadio terapiKemo terapi : sitostatika, hormon, ImmunotherapyKombinasi

Pemberian sitostatika :Diberikan pd bbrp siklusDiberikan kombinasi ( 2, 3 macam obat )Dpt sbg inj bolus tiap 3-4 minggu / 3-5 hrinfus kontinu

Pemberian sitostatika bdskan Jenis kankerKerja kemoterapi relatif thd selKinetika proliferasi sel tumor dibanding jaringan normalDerajat metastaseKemungkinan u/ adanya mutasi (reisten)Usia Derajat kesehatanGangguan organ vital ( hati & ginjal )

Tujuan Pemberian Sitostatika1. Menyembuhkan (cure)2. Survival / control3. Paliatif

Cure : Bila sel2 tumor dibawah level of detection Relapse tdk tjd dlm 5-10 th sth terapi Mis. : - CA Testicular - Hodgkinsdisease - Choriocarcinoma

Survival / control :- bila cure tdk memungkinkan- agar sel - sel CA berhenti berkembang- quality of life ( QOL ) dg sisa - sisa sel CA- surgery / radiotherapi dilanjutkan kemoterapi- respon awal tjd ttp sering timbul relapse- mis. : CA mammal Small cell lung CA Non Hodgkin's Pymphoma

Paliatif : - CA sdh terminal- kemo u/ memperbaiki gejala CA shg QOL- Tdk diharapkan tjdnya remisi- Sitostatika hanya u/ partial remisi gejala klinis membaik- Pertimbangan pd intensitas & durasi terapi tetap QOL

ADJUVANT CHEMOTHERAPY Tujuan cure rate dg membasmi sel2 tumor yg

tersisa sth dilakukan terapi primer (mis.: op, rad) U/ CA yg sdh menyebar u/ control CA Mencegah pertumbuhan sel-sel CA sth op / rad

( level of detection )

ADJUVANT CHEMO

Jml sel tumor 0-103

Tujuan : menyembuhkan

s/d 75 % penderita bebas dr sel2 tumor

Short term toxicity : highlong term toxicity : low

CONVENTIONAL CHEMO

Jml sel tumor 0-109

Tujuan : survival/paliatif( kadang2 cure )

Tdk ada pend yg bebas dr sel tumor

Toksisitas dpt diterima

INTENSIFICATIONTerapi diberikan sth terapi awal yg tdk terlalu intensifStd terapi u/ penderita :

yg memp. respon bagus pd terapi awalkemungkinan besar memp long term remissionkemungkinan u/ sembuh

Penderita pd klasifikasi tsb diberikan terapi yg lbh intensif Transplantasi sumsum tulang diberikan kmd

CONSOLIDATIONSth 1x complate remission didapatkanDiberikan u/ kemungkinan cure rate

MAINTENANCEu/ pend dg resiko relapse tinggi pd saat remisiLong term & dosis rendah

SALVAGE THERAPYu/ tujuan penyembuhan sth terapi awal gagal

NEO ADJUVANT / PRIMARYSbg bag dr terapi kuratifKemoterapi diberikan sebelum operasi / radiasiUntuk mengecilkan sel CA shg mudah diambilDiterapkan bila

CA cenderung bersifat lokalCA diketahui responsif thd sitostatika pd stadium lanjut

Cara Pemberian Kemo :Intra vena - IntrathecalTablet / kapsul - IntracavityIntra muscular - CreamSubcutan

KLASIFIKASI SITOSTATIKAAlkylating agents

nitrogen mustard : mustine HCl, cyclophosphamide, ifosfamide, chlorambucilnitrosoureas : lomustine, carmustine, streptozineplatinum/metal salts : cisplatin, carboplatinalkyl sulfonate : busulfan

Natural Productsmitotic inhibitor : vinblastin, vincristinmicrotubule polymer stabilizer : paclitaxel, doxitaxelpodophyllum derv : etoposideantibiotic : doxorubicin/Adriamycin, daunorubicin, bleomycin, mitomycinenzyme : asparaginase

Anti-metabolitesfolic acid analog : methrotrexatepyrimidine analog : fluorouracilcytidine analog: cytarabine, gemcitabinepurine analog : mercaptopurine, fludarabinehydroxyurea

Vinca alkaloids : vincristine, vinblastineEpidophyllotoxins : etoposide, teniposide

Carboplatin : ovarian Ca, cervix Ca, endometrium Ca, Ca of head & neck, breast Ca, lung CaCisplatin : idem, brain tumors, NHL Carmustine : Hodgkin’s & non-Hodgkin’s, MM, lymphoma, colorectal, stomach & liver Ca, brain tumorsCyclophosphamide : Hodgkin’s & non-Hodgkin’s, neuroblastoma, Ca ovary, breast Ca, MMBleomycin : endometrium Ca, Ca ovary, Ca kidney/bladder, Kaposi’s sarcoma, soft tissue sarcomaDaunorubicin : ANLL, ALL, CML, NHL, Kaposi’s sarcoma, neuroblastoma

Hormon & hormone antagonist androgen : fluoxymesteronecorticosteroid : prednison, dexamethasoneestrogen : diethylstilbestrolprogestin : megestrol acetate, medroxyprogesterone acetateestrogen antagonist : tamoxifen LHRH : leuprolide, goserelin

Miscellaneous agent :substituted urea : hydroxyureamethylhydrazine derv : procarbazinesteroid synthesis inhibitor : aminoglutethimide

Asparaginase :almost all types of leukemiaEtoposide : ALL, ANLL, breast Ca, prostate Ca, Hodgkin’s & non-Hodgkin’s, neuroblastoma, lung Ca, bladder Ca, Kaposi’s sarcomaVinblastine : Hodgkin’s & non-Hodgkin’s, Ca of testis, breast Ca, Kaposi’s sarcoma, choriocarcinomaVincristine : ANLL, ALL, Hodgkin’s & non-Hodgkin’s, rhabdomyosarcoma, MM, Ca cervix, head & neck Ca, kidney

Cytarabine : almost all types of leukemiaFluorouracil : Ca colon, rectum pancreas, breast Ca, Ca cervix, endometrium, ovary, Ca prostate, bladder, lung, liverHydroxyurea : CML, melanoma, Ca head & neck, Ca ovary, cervix, prostate, MMMercaptopurine : ANLL, ALL, CML, NHLMTX : choriocarcinoma, Ca cervix, ovary, prostate, testis, kidney, breast Ca, ALL, ANLL, NHL, MM, Ca esophagus, stomach

EFEK SAMPING SITOSTATIKA1. Supresi Sumsum Tulang Belakang (BM)

a. Infeksi bakteri, fungi atau viusNeutropeniaSebab lain : perubahan sistem imun k/ sel2 tumorperubahan permukaan kulit / mukosamalnutrisiKuman patogen :- streptococcus pneumoniae - H. influenzae- sthapylococcus epidermidis - E-coli- Pseudomonas aeruginosa - G(-) & G(+)- jamur (candida sp, aspergillus)- virus (herpes simplex, CMV, varicella, zoster, adeno virus)

b. Thrombocytopeniac. Anemia

2. Nausea & Vomiting dpt dose limiting tox3. Diare, konstipasi4. Mouth ulcer mucous membrane ulceration5. Allopecia6. Cachexia

ANEMIAPenyebab utama : kemoterapiPenyebab lain : malnutrisi, blood loss, inflitrasi marrow k/ tumor, prod eritropoietinEtiologi dr blood loss hrs diketahui. Blood loss mens bleeding, thrombositopenia, GI bleedingCisplatin, cytarabine, paclitaxel plg seringFaktor resiko : kondisi klinis , multiple metastase, geriatri, gangg jantung, malnutrisi, Hb di siklus awal kemoterapiTerapi : transfusi SDM, recombinant Epo

terapi supportive

NEUTROPENIAANC < 1500 sel/mm3 resiko infeksi ANC = (neutrophil + band)/100 x WBCPrognosa infeksi derajat neutropeniaTimbul opportunistic inf t.u. dr endogenous orgn.Strategi :1. Memicu sistem imunR/ granulocyte colony-stimulating factors (G-CSF)

Gejala Klinis InfeksiSuhu > 38oCMengginggil

InflamasiGatal RR

General malaiseBengkak

Sakit kepalaTdk dpt menganggukUrinary +/- rasa sakit

Batuk +/- sputumtendernes

2. Mempertahankan barrier tubuh yg alami

Menghindari injeksi sedpt mungkinMenghindari catheter sedpt mungkin higienitas di drh oral, rektum, uretra, vagina, jari tangan & kakiKumur dg lar antiseptik / chorhexidine Hindari enema, supp, termometer rektumBila konstipasi : laksatif, stool softenersMembersihkan drh injeksi dg antiseptik

3. Mempertahankan integritas mukosa intestin

Mkn dg Low-microbial containedHigh-fiber diet tgt jenis CA dan kondisi klinis PxHigh in calories, protein, vitaminCukup fluid intakeNutrisi mgn glutamin, fiber, albuminKumur chlorhexidine

4. Mengurangi koloni environmental microorganisms

PRINSIP MANAGEMENT FEBRILE NEUTROPENIA

Broad spectrum AB bila : ANC < 500/mm3, suhu >38.5oC, 3x kenaikan suhu menuju > 38oCKultur & sensitivitas dr catheterMonitor thd secondary infectionsFever > 1 minggu teruskan AB + terapi antifungalAB hentikan bila ANC > 500/mm3 , psn dg resiko rendahMycostatin cream bila candidiasis di mulutPrecautions u/ mempertahankan higienitas

THROMBOCYTOPENIA

Platelet < 100.000 sel/mm3

K/ chemoterahpy induces myelosuppresion dose-limitingside effectCarboplatin, carmustine, cyclophosphamide, lomustine, mitomycin, doxorubicin, daunorubicin, vincristin, dactinomycinPlt < 50.000 sel/mm3 resiko bleedingPlt < 10.000 sel/mm3 GI bleed, CNS bleed, resp tract hemorrhage

Gejala :BruisingPetechiaePurpuraHypermenorrheaHematemesisMelenaEpistaxisHematuria

Terapi : transfusi platelet

GASTROINTESTINAL TOXICITYNausea, vomiting antiemetic therapy3 pola N-V akut, delayed, anticipatoryAkut dlm 24 jam pertama sth kemoterapiDelayed tjd stlh > 24 jam pertama kemoterapi, durasi 1-7 hari, puncak hr ke-3Delayed dpt tjd msk terapi u/ akut efektifAnticipatory tjd sebelum kemoterapi

terapiTgt emetogenic potential dr kemoterapiMod – highly serotonin antagonist iv / PPI iv + dexamethasone ivMod serotonin antagonist po, PPILow risk prochloperazine, serotonin antagonist, PPICorticosteroid efektif bila kombinasi dg anti-emetik yg lainDelayed emesis highly emetogenic chemo

STOMATITISHigienitas oralBisa muncul sekitar 7 hari sth kemotx diberikanBleomycin, daunorubicin, doxorubicin, 5-FU, busulfan, etoposide, , 6-mercaptopurine, vinblastine, vincristineFaktor resiko : dosis, siklus, kombinasi kemotx, fungsi liver & heparProfilaksis : kumur chlorhexidine, saline, NabicTerapi : salep myconazole

DIARE

Penyebab : anxiety, diet, terapi, infeksi, radiasi, tumor, obstruksi, kemotx.Cytarabine, 5-FU, hydroxyurea, MTX, Pencegahan :hindari mkn yg mengiritasi & menstimulasimkn & mnm kaya K (kentang, pisang, asparagus)Hindari produk susuTerapi : karbon aktif

KONSTIPASIMkn tinggi serat (sayuran, buah, gandum)Minum air putih 8 gelas/h Olah raga ringanMinuman hangat u/ merangsang aktifitas ususStool softener, laksatifm bulk forming agent (Metamucil, laktulosa)Hindari antikolinergik, preparat Fe, diuretik, fenotiazine, antidepresan

CACHEXIA

Hilangnya nafsu mkn berat badanPenyebab :perubh di GIT fatigueES terapi perubh hormonalinfeksi faktor psikologiantibiotik, analgesik rasa sakitkomplikasi dr penyakitTerapi : Megace

RENAL TOXICITYCyclophosphamide, ifosfamide toksisitas pd bladder (hemorraghic toxicity)antidote : mesnapencegahan : hydration solution w/ NSMTX toksisitas pd tubuluspencegahan : hydration, cukup urinasi antidote : leucovorinMitomycin Nitrosureas : toksisitas pd tubulus & glomerular

PULMONARY TOXICITY

Sering tjd bleomycin, carmustine, mitomycinJarang tjd cyclophosphamide, doxorubicin, MTX, vinblastine, vincristineTerapi : corticosteroid & simptomatik