CANCER CHEMOTHERAPY

Kartika Widayati Taroeno-Hariadi Division Of Hematology and Medical Oncology

Department of Internal Medicine Faculty of Medicine Universitas Gadjah MadaDR SARDJITO HOSPITAL

YOGYAKARTA

Lecture for PSIK

Definition of chemotherapy

• The use of synthetic chemical to destroy infective agents also applied to inhibit growth of malignant or cancerous cells within the body

• Route: oral, intravena, intraarterial, subcutan intraperitoneal, intravesical (Intracavity), intrathecal, topical

• New route of delivery: isolated infusion, targeted delivery, nanoparticle, minicell

Mode of delivery

• Central line• Peripherally inserted central catheter• Implantable port• Infusion pump

Intravenous chemotherapy Intrathecal chemotherapy via ommaya reservoir

Drug Delivery

Intracavity (intraperitoneal chemotherapy)

Chemotherapy delivery via PORT-A-CATH

IsoFlow drug delivery

Nanoparticle

HISTORY

Key advances in the history of cancer chemotherapy.

DeVita V T , Chu E Cancer Res 2008;68:8643-8653

©2008 by American Association for Cancer Research

Key advances in the history of cancer chemotherapy.

DeVita V T , Chu E Cancer Res 2008;68:8643-8653

©2008 by American Association for Cancer Research

PRINCIPLES OF CHEMOTHERAPY

CARCINOGENESIS

initiation

Promotion

Transformation and Proliferation

CELL CYCLE

Jillian H.Davis Department of Pharmacology Howard University

Cell cycle specific agents1.Anti metabolits2.Bleomycin3.Podophylin alkaloids4.Plan alkaloids

Cell cycle non specific agents1.Alkylating agents2.antibiotic3.Cisplatin4.Nitrosurea

Cell cycle and drug activity

Population kinetics

• Tumor growth depends on the size of the proliferating pool of cells and the number of cells dying spontaneously

• The larger the tumor mass, the greater the percentage of non dividing and dying cells, and the longer it takes for the average cell to devide.

Drugs Used in Cancer Chemotherapy

• Cytotoxic Agents– Alkylating Agents– Antimetabolites– Cytotoxic antibiotics– Plant derivatives

• Hormones– Suppress nat’l hormone secr’n or antagonize

hormone action

• Misc (mostly target oncogene products)

Indication of cancer chemotherapy

• To cure certain malignancies• To palliate symptoms• To treat asymptomatics patients: when the

cancer is aggressive and treatable, when treatment has been proved to decrease the rate of relapse and increase the disease free survival and overall survival

• To allow less mutilating surgery

CONTRAINDICATION OF CHEMOTHERAPY

• When facilitaties are inadequate to evaluate the patients’ response to therapy and to monitor and manage toxic reactions

• When the patient is not likely to survive longer even if tumor shrinkage could be accomplished

• When the patients is not likely to survive long enough to obtain benefits from the drugs

• When the patients is asymptomatic with slow growing, incurable tumors, in which case chemotherapy should be postponed untill symptoms require palliation

Responsiveness of tumors to chemotherapy

TERAPI TARGET

Molecular Targeted Therapy merupakan pendekatan terbaru terapi kanker

Karakter : Terapi ditujukan pada molekul targetMolekul target harus secara unik terekspresi pada sel-sel kankerMolekul target penting untuk mempertahankan fenotipik malignansi

1. cell-signaling targeted therapy2. Angiogenesis targeted therapy3. Protein degradation targeted therapy4. Immune modulation5. Phenotype-directed targeted therapy

OVER EKSPRESI HER-2/neu PADA KANKER

Proliferasi tidak terkontrolPotensi metastasis meningkatResisten apoptosis

TRASTUZUMAB: menghambat dimerisasi HER-2

LAPATINIB menghambat tyrosine kinase intraseluler

TERAPI TARGET CML Abnormal BCR-ABL turn on cell growth & proliferation survival invasion metastasis angiogenesis

Imatinib mesylate

TERAPI HORMON PADA KANKER

TERAPI ANTIANGIOGENESIS

Resistance to Cytotoxic Drugs

increase expression of MDR-1 gene for a cell surface glycoprotein P glycoprotein MDR-1 gen is involved in drug eflux Drug that reverse multidrug resistance include verapamil, quinidine, cyclosporin MDR increases resistance to natural products such as anthracyclins, vinca alkaloid, epipodophylotoxins

SCHEMATIC GLYCOPROTEIN

CHEMOTHERAPY SIDE EFFECTS

Anemia in cancer patients

Chemotherapy induced myelosuppression

PATHOGENESIS OF CINV

CLASSIFICATION OF CINV

Acute Occurs and resolves within 24 hours of chemotherapy

Generally peaks with 5-6 hours

Delayed Occurs 1-6 days after chemotherapy

Common with administration of cisplatin, carboplatin, cyclophosphamide, doxorubicine

Anticipatory Conditioned response after prior, inadequately controlled CINV, nausea more common than vomiting

Tavorath and Hesketh.Drug 1996;52:639

RISK FACTOR FOR CINV

TREATMENT RELATED PATIENT RELATED

Emetogenecity of single agent

Emetogenecity of regiment

High drug dose

Female

Younger age

Low / no alcohol use

Previous CINV

History of motion sickness

Hyperemesis of pregnancy

Hesketh. NEngl J Med 2008; 358:23

EMETOGENICITY

Minimal <10% Low 10-30 % Moderate 30 -90% High >90%

Alemtuzumab

Asparaginase

Bevacizumab

Cetuximab

Rituximab

Vinblastin

Vincristin

Vinorelbin

Capecitabine

5-FU

Etoposide

Fludarabine

Etoposide

Gemcitabine

Paclitaxel

Pemetrexed

Topotecan

Arsenic trioxide

Carboplatin

Cyclophos -

phamide < 1500 mg/m2

Cytarabine

Doxorubicine

Epirubicine

Ifosfamide, Oxaliplatin

Irinotecan

temozolamide

AC

Carmustine

Cisplatin

Dacarbazine

Mechloretamine

Streptozocine

Cyclophosphamide > 1500 mg/m2

Hesketh. NEngl J Med 2008; 358:23

CHEMOTHERAPY TOXICITIES based on COMMON TERMINOLOGY CRITERIA of ADVERSE EVENTS

Extravasation of anthracyclin

Day-1 Day-4 Day -8

Day-10 Day-14 Day-16

FINISH