Principle of Chemotherapy

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Principle of Chemotherapy



History of Cancer Chemotherapy(I)

� The modern era of cancer chemotherapy :

mustard gas(BM & LN hypoplasia) in world

war II

� First clinical use of nitrogen mustard :

lymphoma by Gilman at Yale, 1940s

� First induced remission using aminopterin :

childhood leukemia by Farber at Harvard



History of Cancer Chemotherapy(II)

� First chemotherapy used to cure a solid tumor :

gestational trophoblastic carcinoma, in 1955

� Development of combination chemotherapy :

childhood acute leukemia andH

odgkin¶sdisease, in 1960s



Pharmacodynamics� Dose-limiting toxicity

� Maximal tolerated dose

� Drug selectivity



Drug Resistance� De novo resistance

tumor cells are initially unresponsive to

chemotherapy

� Acquired resistance

tumor cells are initially responsive to

chemotherapy but resistance developswith continued therapy



Goldie and ColdmanH

ypothesis

� In 1979, de novo resistance

genomic instability of tumor cells

-> spontaneous mutation within the

population

-> development of drug resistant cells

before exposure to anticancer agents



Mechanisms of Single Agents Drug Resistance

� Defects in drug transport

ex) MTX resistance in loss of a folate transport protein

� Defects in drug-activating enzymeex) cytarabine resistance in decreased deoxycytidine

kinase

� Increased drug inactivation

ex) increase cytidine deaninase

� Imcrease target enzyme

ex) amplification of dihydrofolate reductase gene

� Alterations in target structure

ex) tubulin alteration-vincristine, taxol resistance



Mechanisms of Multiple Drug Resistance

� MDR-1 gene amplification

: increase expression of p-glycoprotein

: anthracycline, vinca alkaloid, epipodophyllotoxin

� Altered expression of topoisomerase II

: anthracycline, epipodophyllotoxin

� Increase toxicity of glutathione detoxification

: alkylating agents, anthracycline

� Decrease apoptosis



Dose Intensity� Dose intensity

: amount of drug delivered per unit of time

(mg/m2/week)

� Relative dose intensity (RDI)

: amount of drug delivered per unit of time

relative to an arbitrary chosen standard

single agent



Requirements for Chemotherapy

� Biopsy-proven residual or metastatic

disease

� Indicator lesion

� Satisfactory performance score and

nutrition

� Informed consent

� Normal bone marrow, renal, hepatic

function



Patient Selection(I)

� Physiologic age

: age-related alterations

disease-related changes

� Nutrition

: 1,500 - 2,000 calories daily

enteral or parenteral feeding



Performance Score

Symptomatic, in

bed >50% of day, butnot bedridden

40-503

bedridden20-304

Symptomatic, in bed

< 50% of day

60-702

Symptomatic, fully

ambulatory

80-901

Asymptomatic1000

DefinitionKARNOFSKY(%)ZUBROD



Patient Selection(II)� Obesity

: curative intent -actual BWt. or ideal BWt.

palliative intent - ideal BWt.

� Prior therapy

: less probability of response to second-line

therapy



Patient Selection(III)� Organ function

: dose modification or elimination

: BM , renal, cardiac, pulmonary

� Coexisting illness: modify the choice of chemotherapeutic

agent



Drug Selection

� Single agents

: MTX, interferon, cladribine

� Combination therapy

� Chemohormonal therapy

: prednisone in ALL treatment

� Biologic response modifiers

: interferon , IL-2

� Differentiating agents

: all-trans retinoic acid



Route of Administration� Intravenous

: injection or continuous infusion

� Oral

� Subcutaneous

� Intraarterial

� Body cavity



Dose Modification for

Chemotherapy(I)(% of dose to be given)

Granulocyte

0000<50,000

050505050,000-

99,000

05075100>100,000

<1,0001,000-1,4991,500-1,999>2,000

Platelet count

� Hematologic

toxicity



Dose Modification for Chemotherapy(II)

50NCNCNCCytoxanOmitOmit50NCMTX

507575NCMitomycin

Creatinin clearance

OmitomitomitNCNitrosurea

OmitOmit50NCCisplatin

507575NCBleomycin

<10ml/min10-30ml/min30-60ml/min>60ml/min

Drug

� Nephrotoxicity



Dose Modification for Chemotherapy(III)

5-FUCTX,

MTX

Vincrstine,

VP-16

AdriamycinsGOT*

Omitomitomitomit>5.0

10075omit50>1803.1-5.0

100100507560-1801.5-3.0

100100100100<60<1.5

Drug

BilirubinÛ

� Hepatotoxicity

Û mg/dl * IU



Response Criteria of Chemotherapy

� Complete response

� Partial response

� Stable disease

� Progressive disease



Evaluation of Response

� Adjuvant chemotherapy

: set number of cycles

� Palliative therapy

: every 2 or 3 cycles



Principles of Combination Chemotherapy

� Independent single-agent activity

� different mechanism of action

� Different dose-limiting toxicity

� Non-cross resistance

� Given maximal dose� Administer in shortest interval



Adjuvant Chemotherapy� Systemic treatment after local treatment

of primary tumor

� Endpoints

: relapse-free survival

overall survival



Principles of Adjuvant Chemotherapy

� Effective chemotherapy regimen

available

� Known tumor removed by surgery

� Started as soon as possible

postoperatively

� Given in maximally tolerated doses

� Continued for a limited time period



Cancers Effectively Treated by

Adjuvant Chemotherapy� Colorectal cancer(III)

� Ovarian cancer(III)

� Breast cancer

� Osteosarcoma

� Testicular cancer� Wilm¶s tumor



Neoadjuvant Chemotherapy� Chemotherapy as the initial treatment to

patients who presents with localized

cancer for which there is an alternativetreatment



Cancers Effectively Treated by

Neoadjuvant Chemotherapy� Soft tissue sarcoma

� Osteosarcoma

� Anal cancer

� Bladder cancer

� Larynx cancer� Esophageal cancer

� Locally advanced breast cancer



Chemotherapy of Advanced or

Metastatic Disease(palliative)� Symptom palliation, improve life of

quality

� Clinical study of new agents

� Improve survival at responders

� Endpoints

: response rate, remission duration,

overall survival, life of quality



Chemotherapeutic Agents� Antimetabolite

� Vinca alkaloid

� Topoisomerase inhibitor

� Alkylating agent

� Antitumor antibiotics



Antimetabolites� Pyrimidine analogue

� 5-FU, cytarabine, gemcitabine

� Purine analogue

� fludarabine, cladribine, 6-MP, 6-TG



Vinca alkaloids� Vincristine

� Vinblastine

� Paclitaxel, docetaxel



Topoisomerase inhibitors� Anthracycline

� doxorubicine, daunorubicine, epirubicine,

idarubicine

� Epipodophyllotoxin

� Irinotecan



Alkylating agents� Cyclophosphamide

� Ifosfamide

� Melphalan

� Busulphan

� Platinum compound



Antitumor antibiotics� Bleomycin

� Mitomycin-c



Side effects of chemotherapy� Bone marrow depression

� Oral mucositis, diarrhea

� Alopecia

� Nausea/vomiting

� Various organ dysfunction

Principle of Chemotherapy

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