KEMOTERAPI PADA PASIEN KANKER WAHYU SHOLEKHUDDIN

APA ITU KEMOTERAPI

SEL KANKER VS SEL NORMAL

Modalitas Pengobatan Kanker Terapi Kanker LokalLokal Operasi Radiasi Sistemik Kemoterapi Hormon Terapi Immunoterapi

Tujuan Pemberian Kemoterapi KuratifKuratif AjuvanAjuvan Neo Ajuvan PaliatifProlong Life

Tujuan Pemberian Kemoterapi Kemoterapi Adjuvant :  Diberikan bersama terapi yang lain ( bedah & radiasi )  Untuk menghilangkan residu mikro metastasis yang menyebabkan sel kanker tumbuh kembali Kemoterapi Neoadjuvant :  Diberikan sebelum terapi lain (pembedahan), untuk mengurangi masa tumoR  pembedahan tdk berbahaya  Dapat menghilangkan mikro metastasis Kemoterapi Paliatif  Mengurangi ukuran masa tumor  Mengatasi simptomatik : obstruksi, nyeri

Tujuan Pemberian Kemoterapi Induksi Kemoterapi : Terapi awal yang diberikan dengan tujuan untuk mereduksi sel kanker semaksimal mungkin. Diharapkan terjadi complete remission dari Induksi Kemoterapi ini. Konsolidasi / Intensifikasi : kemoterapi yang diberikan setelah remisi, untuk memperpanjang disease free survival Konsolidasi terapi biasanya menggunakan obat yang sama dengan induksi atau obat yang lain untuk intensifikasi terapi konsolidasi tetapi tidak menimbulkan cross resistance dengan induksi kemoterapi..

Tujuan Pemberian Kemoterapi Maintenance chemotherapy : Perpanjangan terapi dengan dosis rendah untuk memperpanjang durasi dari remisi dan mencapai kesembuhan. Salvage Therapy : Terapi yang diberikan setelah gagal terhadap regimen therapy yang lain. Tujuan dari salvage therapy untuk palliative

Pemilihan Terapi Kondisi Pasien Jenis Penyakit Stadium Penyakit Usia Comorbid disease Jenis kanker Lokasi organ Stadium Derajat Keganasan

MEKANISME KERJA OBAT KANKER BERDASAR SIKLUS SEL

MEKANISME KERJA OBAT KANKER PADA DNA

PENGGOLONGAN OBAT SITOSTATIKA

Golongan Kemoterapi Agen Pengalkil Cyclophosphamide Ifosfamide Chlorambucil Dacarbazine Anti-Metabolit Methotrexate (MTX) 5-Fluorouracil (5-FU) Cytarabine Gemcitabine Vinca Alkaloid Vincristine Vinorelbine Vinblastine Antibiotik Bleomycin Doxorubicin Epirubicin Mitomycin Taxane Paclitaxel Docetaxel Cabazitaxel Platinum Cisplatin Carboplatin Oxaliplatin Hormonal Tamoxifen Letrozole Anastrozole Exemestane Analog Camptothecin Topotecan Irinotecan

ALKYLATING AGENT

KLASIFIKASINAMA OBAT Nitrogen Mustards Mechlorethamine Cyclophosphamide Ifosfamide Melphalan Chlorambucil Ethylenamine and methylenamine derivatives Altretamine thiotepa Alkyl sulfonates Busulfan Nitrosoureas Carmustine Lomustine Triazenes Dacarbazine Procarbazine Temozolomide The platinum-containing antineoplastic agents Cisplatin Carboplatin Oxaliplatin ALKYLATING AGENT

ANTIMETABOLIT

KLASIFIKASINAMA OBAT Antifolates Methotrexate Pemetrexed Pralatrexate Trimetrexate Purine Analogues Azathioprine Cladribine Fludarabine Mercaptopurine Thioguanine Pyrimidine Analogues Azacitidine Capecitabine Cytarabine Decitabine Floxuridine Fluorouracil Gemcitabine Trifluridine/Tipracil

ANTITUMOR ANTIBIOTIK

PLANTA ALKALOID

Golongan ObatNama Obat Antitumour Antibiotics Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Mitoxantrone, Plicamycin, Valrubicin Plant alkaloid Vinblastine, Vincristine, Vinorelbine Vindesin Sulfat Etoposide Miscellaneous agent Mitotane, Omacetaxine, Pomalidomide, Tagraxofusp, Telotristat, Temsirolimus, Thalidomide, Venetoclax Asparaginase (Pegaspargas e), Bexarotene, Eribulin, Everolimus, Hydroxyurea, Ixabepilone, Lenalidomide, Taxane Paclitaxel Docetaxel

Protein (tyrosine kinase)inhibitors No.Zat aktifIndikasiEfek Samping 1Afatinib dimaleateTreatment of locally advanced or metastatic non-squamous NSCLC Diarrhea, stomatitis, nausea, vomiting, rash, paronychia, 2CrizotinibTreatment of ALK positive advance NSCLC Vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminase, fatigue, decreased appetite, dizziness, neuropathy

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 3AxitinibTratment of renal cell carcinoma diarrhoea, hypertension, fatigue, decreased appetite, nausea, weight decreased, dysphonia, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, haemorrhage, hypothyroidism, vomiting, proteinuria, cough, and constipation.

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 4ErlotinibTreatmet of locally advance or metastatic NSCLC with EGFR activating mutations Treatment of locally advance, unresectable or metastatic pancreatic cancer Rash, diarrhea, fatigue, keratitis, conjunctivitis, epistaxis, gastrointestinal bleeding, aliopecia, dry skin, paronychia, Folliculitis, Acne/ Dermatitis acneiform, Skin fissures

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 5GefinibTreatmet of locally advance or metastatic NSCLC who have activating mutations of the EGFR TK Anorexia, conjunctivitis,blepharitis, dry eye, haemorrhage, interstitial lung diseasae, diarrhea, vomiting, nausea, dehydration, dry mouth, skin reaction, nail disorder, alopecia, asthenia, pyrexia

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 6Imatinib mesilate Ph+ CML, GIST, Ph+ ALL, myelodysplastic/myelopr oliferative disease associated with PDGFR, systemic mastocytosis, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL), unresectable recurrent and/or metastatic DESP. Neutropenia, thrombocytopenia, anaemia, pancytopenia, febrile neutropenia, anorexia, insomnia, dizziness, paraesthesia, taste disturbance, hypoaesthesia, Eyelid oedema, lacrimation increasedi conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision, Flushing, haemorrhage

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 8Lenvatini b mesilate locally advanced or metastatic, differentiated (papillary/follicular/H rlrthle cell) thyroid carcinoma (DTC) Hypertension, diarrhea, decreased appetite, weight decreased, fatigue, nausea, proteinuria, stomatitis, vomiting, dysphonia, headache, palmar-plantar erythrodysaesthesia syndrome (PPE). 9Nilotinib HClTreatment of Ph+ CML Comiting, myalgia, alopecia, muscle spasms, decreased appetite, arthralgia, bone pain, peripheral edema, asthenia

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 10Osimertinib mesilate locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor diarrhoea, rash, Stomatitis, keratitis, Interstitial lung disease, Platelet count decreased, Leucocytes decreased, Lymphocytes decreased, Neutrophils decreased

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 11Ruxolitini b Phosphat e Myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis or post- essential thrombocythemi myelofibrosis Anaemia, thrombocytopenia, neutropenia, bruising, dizziness, headache, ALT increased, AST increased, hypercholesterolaemia 12Sorafenib tosilateAdvanced renal cell carcinoma, unresectable hepatocellular carcinoma (HCC) Diarrhoea, rash, alopecia and hand-foot skin syndrome (palmar plantar erythrodyssaesthesia syndrome)

Protein (tyrosine kinase) inhibitors No.Zat aktifIndikasiEfek Samping 13Sunitinib malateGastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (MRCC) Diarrhea, hypertension, bleeding, mucositis, skin abnormalities. 14VemurafenibUnresectable or metastatic melanoma BRAF V600 mutation positive arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis

ANTIBODI MONOKLONAL No. Zat aktifIndikasiEfek Samping 1Bevacizumab (humanised anti- VEGF monoclonal antibody) Treatment of patients with metastatic carcinoma of the colon or rectum Gastrointestinal perforations, haemorrhage, arterial thromboembolism, leucopenia, neutropenia, thrombocitopenia 2Brentuximab vedotin (antibody drug conjugate (ADC) –anti CD30 Treatment of patients with relapsed or refractory : -CD30+ Hodgkin lumphoma (HL), -systemic anaplastic large cell lymphoma (sALCL). Infection : Upper respiratory tract infection, Hematologic : neutropenia, Nervous sytem disorder: perripheral neurophaty, GI disorders: nausea, vomiting, constipation

ANTIBODI MONOKLONAL No.Zat aktifIndikasiEfek Samping 3Nimotuzumab (Humanized anti-EGFR monoclonal antibody) chemotherapy resistant high grade gliomas in children/ adolescent Chils, fatigue, headache, nausea, increase SGPT, vomiting 4Pembrolizumab (humanised monoclonal antibody which binds to the programmed cell death-1 (PD- 1) receptor) Treatment of patients with: -unresectable or metastastic melanoma. -advanced non small cell lung carcinoma (NSCLC) GI : nausea, dhiarrhoea, abdominal pain, vomiting Skin: rash, pruritus. Haematologic : anaemia

ANTIBODI MONOKLONAL No.Zat aktifIndikasiEfek Samping 5Pertuzumab (humanised IgG1 monoclonal antibody) Treatment of patients with HER2-positive metastatic or locally recurrent unresectable breast cancer in combination with herceptin and docetaxel. Infection: nasopharyngitis, Haematologic: neutropenia, leucopenia, anaemia, febrile neutropenia GI disorders: diarrhoea, vomiting, stomatitis, constipation, dyspepsia Nervous system disorder : neurophaty peripheral, headache, dizziness

ANTIBODI MONOKLONAL No.Zat aktifIndikasiEfek Samping 6Rituximab (human anti-CD20 monoclonal antibody) Treatment of patients with relapsed or chemoresistant low- grade or folicular, CD 20-positive, B-cell non- Hodgkin’s lymphomas Haematologic: neutropenia, leucopenia Immune sytem : angioedema GI disorders: nausea, Skin disorders : rash, pruritis, General : headache, fever, chills, asthenia

ANTIBODI MONOKLONAL No.Zat aktifIndikasiEfek Samping 7Trastuzumab (humanised IgG1 anti-HER2 monoclonal antibody) Treatment of patients with metastatic breast cancer whose tumours overexpress HER2 Infection : nasopharyngitis, Haematologic disorders: febrile neutropenia, anaemia, neutropenia, leucopenia, thrombocytopenia, Nervous system disorder: tremor, diziness, headache, paraesthesia, Eye disorders : congjuctivitis, lacrimation increased 8Secukinumab (Human IgG1/κ anti-IL-17A monoclonal antibody) the treatment of moderate to severe plaque psoriasis in adult patients Infection : Upper respiratory tract infection, oral herpes, GI disorders : diarrhoea

Other antineoplastic agents No.Zat aktifIndikasiEfek Samping Alkylating agents 1Bendamustine HClLeukemia limfositikhematological adverse kronis, Non-Hodgkinreactions (leukopenia, limfoma, Multiplethrombopenia), myelomadermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting)

Other antineoplastic agents No.Zat aktifIndikasiEfek Samping Taxanes 1CabazitaxelHormone refractoryanaemia, leukopenia, metastatic prostateneutropenia cancer previouslythrombocytopenia and treated withdiarrhoea docetaxel-containing regimen. Immunomodulators 1Fingolimod HClTreatment ofHeadache, hepatic (sphingosine 1-relapsing remittingenzyme increased, phosphatemultiple sclerosisdiarrhoea, cough, receptorinfluenza, sinusitis, back modulator)pain

Other antineoplastic agents No.Zat aktifIndikasiEfek Samping 2Bortezomib (reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome) Multiple myeloma; mantle cell lymphoma nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia

EFEK SAMPING KEMOTERAPI Mucositis Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Alopecia Pulmonary fibrosis Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis

Efek samping kemoterapi. 1.Cepat (immediate) 2.Segera (early) 3.Lambat(delayed) 4.Sangat Lambat(late effect)

Immediate : Efek samping yang terjadi dalam waktu beberapa jam sampai beberapa hari setelah kemoterapi. Contoh : Nausea/Vomiting, local tissue necrosis, Phlebitis, Hyperuricemia, Skin rash, anaphylaxis, demam&menggigil (bleomycin), hypotension (etoposide), hypertension (Procarbazine). Early : Efek samping yang terjadi dalam waktu beberapa hari sampai beberapa minggu setelah kemoterapi. Contoh:Alopecia, Stomatitis, Leukopenia,Thrombocytopenia, Diarrhea,Hypercalcemia Hypomagnesemia (esterogen), (cisplatin),DIC(asparaginase), Hyperglycemia(corticosterid),ototoxicity(cisplatin), Conjungtivitis (Methotrexate, Ara-C) Onset Efek Samping Kemoterapi

Delayed : Efek samping yang terjadi dalam waktu beberapa minggu sampai beberapa bulan setelah kemoterapi. Contoh : Anemia, Aspermia, Hepatocellular damage, Hyperpigmentation, pulmonary fibrosis. Peripheral neuropathy (vincristine), Cardiac necrosis (cyclophosphamide), Cholestatic jaundice (6-MP) Late : Efek samping yang terjadi dalam waktu beberapa bulan sampai beberapa tahun setelah kemoterapi. Contoh : Sterility, Premature menopause, Acute leukemia, Lymphoma, solid tumor. Hepatic cirrhosis (Mtx.), Osteoporosis (Corticosteroid), Cataracts(busulfan)

Emetogenic Potential Chemotherapy High Emetogenic Cisplatin Dacarbazine Daunorubicin Doxorubicin (moderate to high dose) Cyclophosphamide (high dose) Moderate Emetogenic Mitomycin-C Doxorubicin (low dose) Cyatarabine Methotrexate (high dose) Carboplatin Mitoxantrone Ifosfamide

Antiemetic for CINV Serotonin binds to 5HT3 receptors  efektif untuk ANTIEMETIK Dapat diberikan sebagai profilaksis 5HT3 inhibitor tidak efektif untuk delayed N/V Neuropeptide substance P  NK1-receptor antagonist : aprepitant mempunyai efektifitas yang baik untuk delayed N/V Kortikosteroid  dexametason sebagai kombinasi pada 5HT3 inhibitor.

Mielosupresi Hampir semua senyawa sitotoksik bersifat mielosupresif. Titik nadir hari ke Leukopenia/Neutropenia: Risiko tinggi infeksi Anemia Trombositopenia : Fatique, lemas, oksigen  : Risiko tinggi perdarahan Pemberian GC-SF untuk mencegah perburukan mielosupresi pada pasien pasca kemoterapi.

Infeksi pada pasien kanker :  Aggressive chemotherapy terutama pada kasus – kasus hematology cancer menyebabkan neutropenia.  Komponen sel darah putih (WBC) terutama Neutrophil jumlahnya berkurang.  Pada Absolute Neutrophil Count (ANC ) < 0.5 x 10 9 /L pasien berresiko tinggi terkena infeksi.  Pada beberapa penelitian menunjukkan infeksi adalah penyebab kematian pada sebagian besar kasus ALL dan sebagian dari kasus Lymphoma.  Empirical therapy antibiotik dapat mengurangi resiko tersebut.

Demam (Febrile) Demam dapat disebabkan oleh obat chemotherapy, blood transfusion, Infeksi, atau sel kanker (pada leukemia). Pada umumnya yang sering terjadi dan berbahaya adalah Infeksi. Senyawa chemotherapy yang menyebabkan demam : Doxorubicin, L-Asparaginase, Azathioprine, Bleomycin, Cyclophosphamide, Ara-C, Dacarbazine, Dactinomycin, 6-MP, Methotrexate, Vincristine, Vinblastine.

Jika suhu tubuh >38.5 o C dan jumlah neutrophil dibawah 1000, empirik AB harus dilakukan. Infeksi dapat disebabkan oleh bakteri gram positif dan gram negatif.

Pulmonary Toxicity : Bleomycin Fatal toxicity 1-2 %. Risk Factor : Age > 70, concomitant radiotherapy, concurrent cyclophosphamide, previous exposure to Bleomycin. S/S : Dry cough, Dyspnea, tachypnea, fever, Cyanosis. Outcome : with minimal changes, may recover if drug discontinue Death occurs if hypoxemia present. Mitomycin C Incidence % Risk Factor : Previously mitomycin therapy. S/S : Progressive dyspnea, nonproductive cough, chest pain Outcome : 40% die of progressive pulmonary insufficiency. 60% recover after stopping mitomycin.

Nephro Toxicity : Methotrexate : Monitor serum level untuk menentukan leucovorin rescue.  Dosis jika Creatinine Clearance < 60 ml/min Cyclophosphamide : Creatinine clearance < 25 ml/min   dosis 50% Cisplatin : Creatinine clearance < 50 ml/min   dosis 50% Carboplatin : CrCl ml/min : dosis 250 mg/m 2 CrCl ml/min : dosis 200 mg /m 2 CrCl < 15 ml/min : sebaiknya tidak diberikan Bleomycin : CrCl < 25 ml/min   dosis 50% - 75% Etoposide : CrCl < 20 ml/min diberikan 75% dari dosis standar

Hepatotoxicity : Manifestasi Hepatotoksik : Me  enzym liver : asparaginase, carmustine, cytarabine, dacarbazine, mercaptopurine, methotrexate, mitomycin. Jaundice : Azathioprine, Busulfan, Mercaptopurine Hepatic Fibrosis : Azathioprine, Cyclophosphamide Necrosis Hepar : Asparaginase, azathioprine, Cyclophosphamide, Methotrexate. Bilirubin > 5 hentikan penggunaan : 5-Fu, Cyclophosphamide, Methotrexate, daunorubicin, adriamycin, vinblastine, vincristine. SGOT >180 : Cyclophosphamide, Methotrexate 75% dosis, Daunorubicin 50% dosis, Doxorubicin 25% dosis, Vincristine dan vinblastine hentikan penggunaannya.

dermatotoxicity Vesikan: vincristin, antracyclin Handfoot syndrome: 5 FU, Xelloda Rash :BCNU,Gemzar,procarbazine Photosensitive :DTIC,mitomycin Kuku berubah:cyclof, doxo,FU Hiperpigmentasi: doxo,5FU,

Kardiotoksisitas. Pada antracyclin paling sering, obat lain juga bisa al.cisplatin, Cyclophosphamide,dll Akut : aritmia, perubahan EKG Kronik : kardiomiopati Late : CHF

Neurological Side-effect : Vincristine : Peripheral neuropathy, seizure, nerve paresis Vinblastine: Peripheral neuropathy, seizure, nerve paresis Cisplatin: Tinnitus, deafness, peripheral neuropathy Asparaginase: Lethargy, confusion Cyclophosphamide : drowsiness, lethargy Methotrexate: Fits, encephalopathy Taxan

Gastro Intestinal Toxicity Mucositis: doxorubicine,mtx, bleomycin,5 FU Diare:5-fu, Cpt 11, mtx.,ara-c. Konstipasi: kadang kala bukan diare tetapi konstipasi

Mucositis : Senyawa chemotherapy yang sering menyebabkan mucositis : Methotrexate : efek  pada infus yang lama, penurunan fungsi ginjal, dan radiasi. 5-Fu : efek  pada dosis tinggi,  frekwensi, arterial infusion. Actinomycin-D : sangat sering menyebabkan mucositis terutama jika bersamaan dengan radiasi. Doxorubicin : efek  pada liver disease, dan radiasi Bleomycin : mucositis hebat + ulcerative

Nyeri pada pasien kanker Nyeri pada pasien kanker bisa disebabkan karena : -Perkembangan sel kanker -Terapi kanker ( chemotx., radiasi, surgery ) -Penyakit yang timbul sebagai efek samping terapi. -Sama sekali tidak berhubungan dengan kanker. Nyeri sebagai efek samping dari kemoterapi sering terjadi pada pemberian vinca alkaloid. Rasa nyeri dan panas ( burning ) terjadi pada kaki dan tangan. Post steroid therapy pada hodgkin’s disease menimbulkan nyeri pada sendi bahu dan lutut. Mucositis sebagai efek samping chemotx. Menyebabkan nyeri pada saat pasien makan, minum, dan berbicara.

PENUTUP Pemberian kemoterapi pada pasien kanker harus melibatkan multi disiplin Penetapan diagnosis yang pasti diperlukan untuk menentukan modalitas terapi Monitoring pemberian kemoterapi diperlukan untuk melihat potensial efek samping yang terjadi dan efikasi pengobatan

TERIMA KASIH