1.

1. Differentiation well differentiation poor differentiation 2. Proliferation ()3. Invasion 4. Metastasis 1. Initiation (DNA mutation) 2. Promotion reversible stage

3. Conversion step 4. Tumor progression

** oncogene, DNA repair gene suppressor gene (angiogenesis)

TNM

T tumor size

N lymph node involvement

M metastasis

Induction Consolidation induction Intensification Maintenance Adjuvant chemotherapy neoadjuvant , primary chemotherapy palliative salvage regimen induction

(BSA ) BSA =

lab

lab 1. Platelet > 100, 000 /mm32. Hct 30%

3. WBC > 3000 /mm34. ANC > 1500

2. (cell cycle) 2 1 cell cycle (cell cycle phase specific anticancer)phaseanticancer

1. (preparation phase interphase) cell cycle1.1 G0 phase

2. 1.2 G1 phase gap1 phase DNAAsparagenase

1.3 S phase synthesis phase Antimetabolites, MTX, 5FU, Ara-C, 6MP, gemcitabine

1.4 G2 phase gap2 phase Bleomycin, podophyllotoxin, mitomycin C, etoposide

2 mitotic phase M phase nucleus cytoplasm 2 M 2 Go G1Antimitotics: vinka alkaloid vincristine, taxol paclitaxel

1. cell cycle phase specific: 3 1

2. non cell cycle phase specific: phase alkylating agents cyclophosphamide, ifosfamide, cisplatin, carboplatin

2

Antimetabolites:

Methotrexate (Antifolate)

dihydrofolate reductase (DHFR) inhibitor DNA S phase () - dose limiting toxicity: (mucositis) - : acute hepatitis

- : pneumonitis

*continuous infusion * bolus infusion ** Leucovorin (reduce folate) antidote MTX continuous infusion cell cycle

5-fluorouracil (5-FU)

Prodrug, Pyrimidines analogue

thymidylate synthase (TS) inhibitor DNA

5-FU FUMP FUDP FUTP RNA

dose limiting toxicity: mucositis ()

leucovarin FdUMP TS enzyme

Capecitabine

Prodrug 5-FU

5-FU

- dose limiting toxicity: hand foot syndrome ( vitamin B6 150 mg/day) mucositis, **hand foot syndrome 2-12 (dysesthesia) 2 hand foot syndrome 4

Cytarabine (Ara-C)

Pirimidine analog

DNA/RNA polymerase inhibitor ( DNA)dose limiting toxicity: () : , hepatitis, IT necrotizing leukoencephalopathy

gemcitabine

DNA polymerase inhibitor

ribonucleotide reductase inhibitordose limiting toxicity: ( )

Cyclophosphamide

Prodrug

phosphamide mustard DNA DNA dose limiting toxicity: () hemorrhagic cystitis ( acrolein cyclophosphamide) mesna (mesna acrolein )

ifosfamide

Prodrug

isophosphamide mustard DNA DNA dose limiting toxicity: () hemorrhagic cystitis ( acrolein ifosfamide) mesna (mesna acrolein )

Mitomycin-C

DNA alkylation cross linking

dose limiting toxicity: ( )

Streptomyces caespitosus

Hydroxyurea

Reboneucleotide reductase inhibitor S phasedose limiting toxicity:

Antimetabolites: platinum compounds:

Cisplatin

Platinum DNA platinum-DNA adduct intrastrand crosslink DNA ** RNA dose limiting toxicity: nephrotoxicity ototoxicity ( irreversible) peripheral neuropathy sensory neuropathy** cisplatin 50 mg/m2 NaCl 1-2 mannitol 12.5-25 cisplatin

carboplatin

platinum-DNA adduct intrastrand crosslink DNA ** RNA

dose limiting toxicity: () ototoxicity

peripheral sensory neuropathy

nephrotoxicity** carboplatin target AUC Scr ** D5W

oxaliplatin

platinum-DNA adduct intrastrand crosslink DNA ** RNA ** dose limiting toxicity: sensory neuropathy ()

ototoxicity

Antimicrotubules: Vinca Alkaloids

Vincristin, Vinblastin

Vincristine : R1 = CHO, Vinblastine R1 = CH3 polymerization depolymerization microtubule mitotic spindle chromosome cell death- Vincristine: dose limiting toxicity: peripheral neuropathy- Vinblastine Vinorelbine: dose limiting toxicity: neutropenia-** potent vesicant agent ()-

Antimicrotubules: Taxol

Paclitaxel

. Subunit tubulin polymerization tubulin depolymerization

- dose limiting toxicity: neutropenia

- : Hypersensitivity reaction cremorphore EL premedication dexamethasone

- Peripheral Neuropathy

- Dermatologic hand-foot syndrome

- Vesicant drug

Docetaxel

. Subunit tubulin polymerization tubulin depolymerization

- Fluid retention syndrome: premedication corticosteroid 3 doses 2. Dermatologic toxicity hand-foot syndrome : vitamin B6

- dose limiting toxicity: neutropenia

- Hypersensitivity reaction paclitaxel tween 80 Fluid retention syndrome SE docetaxel

Topoisomerase inhibitors: phase specific (G2 phase, S phase)

Irinothecan

Topoisomerase I break single strand DNA cell - dose limiting toxicity: Neutropenia

**diarrhea acute 24 hr cholinergic activity atropine late diarrhea 5-11 loperamide 4 mg stat then 2 mg q 2-4 hr 12 hrs

Etoposide

Topoisomerase II

DNA double strand DNA DNA

- dose-limiting toxicity : mucositis

- hypotension ()

Anthracycline:

Doxorubicin, Epirubicin, Idarubicin

Topoisomerase II

DNA double strand DNA DNA

- acute dose limiting toxicity: - chronic dose limiting toxicity: Cardiotoxicity (cumulative dose limiting cardiomyopathy; doxorubicin 550 mg/m2, epirubicin 900 mg/m2) **Dexrazoxane free radical scavenger free radical 3. Vesicant drugs: ** doxorubicin baseline EKG LVEF CHF ** cardiomyopathy LVEF 10 LVEF < 50% cumulative dose doxorubicin ~ 450 mg/m2 baseline LVEF < 50% **doxorubicin Streptomyces species **liposomal doxorubicin

Miscellaneous agents:

Bleomycin

DNA DNA free radical dose limiting toxicity: pnuemocititis ()

Hydroxyurea

Reboneucleotide reductase inhibitor S phasedose limiting toxicity:

Selective estrogen receptor modulators (SERMs):

Tamoxifen

receptor estrogen antiestrogenic estrogen

SE: hot flush (menopause symptom), hypercalcemia, endometrial cancer uterine sarcoma** pre-menopause

Selective estrogen receptor downregulators (SERDs):

Fulvestrant

estrogen receptor drug-ER complex

Aromatase inhibitors:

Nonsteroidal compound: anastrozol, letrozol Steroidal compound: exemestane

aromatase testoseterone estradiol Reversible inhibitionSE: arthritis, arthralgia, cardiovascular events, decrease bone density ( bisphosphonate )**** post-menopause

Side Effects 1. Nausea/Vomiting

3

Emetic Risk

I.VOral

High risk- AC combination (doxo/epirubicin cyclophosphamide )

- Cyclophosphamide > 1500 mg/m2- Cisplatin > 50 mg/m2Day 1 : 5-HT3 RA + Dexamethasone + Apprepitant (Ondansetron 8 mg)

Day 2-3 : Dexamethasone + Apprepitant (Dexa 20 mg Aprepitant 12 mg)

Moderate risk (30-90%)- Cytarabine > 1 g/m2- Cyclophosphamide < 1500 mg/m2- Idarubucin, Ifosfamide

- Methotrexate 250 1000 mg/m2- Cisplatin < 50 mg/m2

- Carboplatin, Doxorubicin

- Epirubicin, Oxaliplatin > 75 mg/m2, Irinothecan

Cyclophosphamide

Etoposide

VinorelbineDay 1 : 5-HT3 RA + Dexamethasone (Dexa 12 mg Aprepitant)

Day 2-3 : 5-HT3 RA Dexamethasone Aprepitant AC combine cisplatin,irinothecan,MTX

Low risk (10-30%)- Docetaxel, Paclitaxel, 5-FU, Etoposide

- Gemcitabine, Methotrexate 50 250 mg/m2CapecitabineDay 1: Dexamethasone Prochlorperazine Metoclopamide Diphenhydramine

Minimal risk ( Docetaxel,

b. Secondary prophylaxis Primary prophylaxis

- G-CSF supportive therapy dose-dense regimen

3.Anemia

erythropoietin 4 NCI

Scales

None : 14 18 g/dL : 12 16 g/dL

Mild10 g/dL normal range

Moderate8-10 g/dL

Severe6.5 7.9 g/dL

Life-threatening< 6.5 g/dL

1. Asymptomatic

2. Symptomatic - oral parenteral

- parenteral premed diphenhydramine para test dose hypersensitivity reaction

Erythropoietic agent

Epoetin-alfa 150 U/kg sc TIW 300 U/kg sc TIW

Darbepoetin 3 mcgkg q 2 wk 5 mcg/kg sc 2 wk - 4 (Epoetin-alfa) 6 (Darbepoetin)hemoglobin 1 g/dL

4.Hypercalcemia

(Bone matastasis)

: GFR calcium excretion

: NSS Loop diuretic Bisphosphonate cancer pamidronate(1st line) i.v drip, zoledronic acid (1st line )

Corticosteroids prednisolone

2. Neurologic complication

Peripheral neuropathy tingling paresthesia,loss of angle jerk reflex - Platinum compound Cisplatin,Oxaliplatin ()- Methotrexate

- Taxanes

- 5-FU

- Vinca alkaloid

- Cytarabine

:

- Calcium gluconate 1 g + MgCl2 1 g - Gabapentin 200 300 mg

:

- Calcium gluconate 1 g + MgCl2 1 g 3. Cardiotoxicity

cardiomyopathy Anthracycline- Dexarazone cardioprotectant - Doxorubicin liposomal -5-FU cardiomyopathy continuous bolus

- Taxanes 4. Extravasation

Vesicant tissue necrosis Anthracyclines

Antibiotics antitumors

Vinca alkaloids

Taxanes

Cisplatin > 0.5 mg/ml

Irritant necrosis

Alkylating Ifosfamide,Carmustine

Platinum

Topoisomerase II inhibitor

:

scar, vein NSS flush 2-3 Doxorubicin, Taxanes

Vinca alkaloid , Etoposide

antidotes

5 antidote extravasation

DrugsAntidote

AnthracyclineDMSO

Dexarazone ( DMSO)

MitomycinDMSO

Vinca alkaloidsHyaluronidase

Taxanes, EtoposideHyaluronidase

5. Dermatologic complication Taxanes

5-FU

Capecitabine

Hand-foot syndrome,onychomadesis ( Capecitabine 5-FU )

: , , - Pyridoxine

6. Diarrhea and Mucositis

Mucositis - Antimetabolites (5-FU , Methotrexate )

- Vinca alkaloids

- Anthracyclines

:

- Cryotherapy : 30

- Ranitidine Omeprazole Cyclophosphamide, Methotrexate,5-FU

- palifermin

:

Diarrhea Vincristine, Irinothecan : Loperamide

7. Nephrotoxicity

- Platinum compounds: cisplatin : , mannitol furosemide, KCl MgSO4- Cyclophosphamid Methotrexate

: 49

4 50 Non-Small Cell Lung Cancer (NSCLC) Satge IV

Cisplatin 100 mg/m2 IV drop over 1 hour on day 1

Etoposide 100 mg/m2 IV drip over 1 hour on day 1,2

60 kg. 180 cm Surface area= 1.73 m2 1. Cisplatin a. 150

b. 175

c. 200

d. 225

e. 250

2. Acute Emetic

a. Ondansetron

b. Dexamethasone

c. Metoclopramide

d. Ondansetron + Dexamethasone

e. Metoclopramide + Dexamethasone

3. Cisplatin a. Akylating agent

b. Topoisomerase II inhibitor

c. Antimetabolite

d. Intercalating agent

e. Inhibitor of mitosis

4. Cisplatin (Nephrotoxicity) a. b. Magnesium

c. Osmotic diuretic Mannitol

d. Cisplatin Sodium chloride

5. etoposide stability

: At temperature in D5W or NS in polyvinyl

0.2 mg/ml : 96 hours

0.4 - 0.21 mg/ml : 48 hours

0.6 - 0.41 mg/ml : 8 hours

1.0 - 0.61 mg/ml : 2 hours

manufacturer does not recommended administration at conc. more than 0.4 mg/ml due to highly unpredictable time to precipitation

etoposide (100 mg/m2) D5W 500 ml a. 96 .b. 48 .c. 8 .d. 2 . 50

Case Cancer

Pt. CHOP regimen , . pt. s/e 49

9

+ Lab + +BSA 1. BSA

2. BSA

1. cisplatin

1. coordinate platinum anticancer drug

2. oral parenteral

3. Cis trans isomer 4. 5. 2. 1. alkylating agents DNA 2. folic acid antagonist nucleic acid

3. purine antagonist nucleic acid

4. pyrimidine antagonist nucleic acid

5. DNA 3. drug interaction 1. Tamoxifen-warfarin

2. Mercaptopurine-allopurinal

3. Cisplatin-cimetidine

4. Methotrexate-phenobarbital

5. Doxorubicin-tetracycline4. ondansetron 1. 30 2. 4 3. antiemetic potent 72 4. 5.

5. 1. antiproliferative agent

2. 3. 4. 5.

6. cyclophosphamide 1. Nausea/vomiting

2. Dermatitis

3. Hemorrhagic cystitis

4. Alopecia

5. agranulocytosis7. Vincristin1. Alkylating agents

2. Vitamin D derivative

3. Antimetabolites

4. Alkaloid 5. hormone8. leucovarin methotrexate 1. uptake MTX 2. MTX 3. MTX 4. MTX

9. 1. Carmustine2. Darcarbazine

3. Doxorubicin

4. 5-fluorouracil

5. vincristine