Clinical Chemotherapy

Pharmacology
 TREATMENT PRINCIPLES AND
APPROACHES
• Chemotherapy has a narrow therapeutic window. Potential
complications from chemotherapy range from drug reaction to death.
Consequently, administration of chemotherapy requires more
intensive preparation than other drug prescriptions.
• Before giving chemotherapy, we recommend going over a checklist:
• 1. The cancer diagnosis must be confirmed histologically;
• 2. The chemotherapy agents must be appropriate for the diagnosis
• 3. Patient must be healthy enough to stand up to the rigors of
chemotherapy
• (ECOG performance status of 0, 1, or 2 and an estimated survival of ≥3
months)
• Laboratory results should be adequate (WBC ≥ 3000 [ANC > 1500]),
• platelets ≥ 100,000. AST, ALT, GGT, LDH, and alkaline phosphatase ≤ 3
xnormal. Bilirubin must be ≤1.5 x normal. Creatinine ≤ 2 mg% or
creatinineclearance ³ 50 mL/min)
• The chemotherapy dosing usually calcuation follows a function of
body surface. If the patient’s body surface area is more than 2, the
chemotherapy dose is usually limited to BSA of 2.
 Timing of Chemotherapy
• Neoadjuvant: given prior to definitive treatment (surgery
or radiation) to reduce tumor burden
• Adjuvant: used after initial surgical or radiation therapy to
minimize recurrence
• Salvage: used after recurrence of refractory tumor after
previous chemotherapy, with “curative” intent
• Palliative: used for prolong survival time and improve
quality of life, not aim to cure cancer.
 Role of chemotherapy in cancer

Cure Palliation
As primary therapy • Prolong life

Synergistic with • Improve quality of

radiotherapy as primary life/relief symptoms
therapy

As induction chemotherapy

As adjuvant chemotherapy
 Chemotherapy before or after
primary therapy
Induction/neoadjuvant Adjuvant
Down-stage Prevent recurrence
Organ-preserved Delay relapse duration

• Breast cancer • Breast cancer

• Stage IIIb lung cancer • Colon cancer
• Laryngeal cancer • LN+ gastric cancer
• Lung cancer
• Osteosarcoma
 Melanoma
Renal cell carcinoma
Hepatoma
Chemosensitivity by tumor type

Cholangiocarcinoma
Pancreatic cancer
Soft tissue sarcoma
Esophageal cancer
Gastric cancer
Lung cancer
HN cancer
Colonrectal cancer
Breast cancer
Higher sensitivity Ovarian cancer
Small cell carcinoma
Germ cell tumor
Pediatric sarcoma
Hematologic malignancies
 Cytotoxic chemotherapy
Pros Cons

• Damage proliferating cells • Non-specificity of cell

by interfering with cell toxicity
cycles • The higher dosage and
• Rapid tumor response in combination agents, the
selected cancer type higher toxicity
• The higher dosage, the • Primary or secondary
better response drug resistance
• Slowing growth cancer
• Could combination used
• Multiple drug resistance
• Synergistic with gene
radiotherapy
 Hormone drug
Pros Cons

• Indication: • Slowly response

• Used in hormonal sensitive
cancer: breast, endometrial
and prostate
• Paraneoplastic syndrome:
carcinoid syndrome,
cachexia
• Conveniences by oral or
IM/SC
• Lower toxicity
• No accumulation dose
 RESPONSE TO
CHEMOTHERAPY
• Complete response (CR): A complete disappearance of all clinical
evidence of tumor, including normalization of the CA-125 value,
determined by two observations at least 4 weeks apart. There
should be no evidence of disease by CT, PET scan or MRI if these
radiologic modalities are used.
• Partial response (PR): A >50% decrease in the sum of the product
of measured lesions, determined by two observations not less than4
weeks apart. No simultaneous increase in the size of any lesion
orthe appearance of new lesions may occur. Nonmeasurable lesions
must remain stable or regress to be included in this category.
• Stable disease (SD): A steady state of response less than PR, or
progression less than PD, lasting at least 4 weeks. No new lesions.
• Progressive disease (PD): An unequivocal increase of at least
50% in the product of the measured lesion. New lesions also
constitute PD.
 MEASURABLE DISEASE
• Measurable disease - the presence of at least one
measurable lesion. If the measurable disease is
restricted to a solitary lesion, its neoplastic nature should
be confirmed by cytology/histology.
• Measurable lesions - lesions that can be accurately
measured in at least one dimension with longest
diameter ≥20 mm using conventional techniques or ≥10
mm with spiral CT scan.
• Non-measurable lesions - all other lesions, including
small lesions (longest diameter <20 mm with
conventional techniques or <10 mm with spiral CT scan),
i.e., bone lesions, leptomeningeal disease, ascites,
pleural/pericardial effusion, inflammatory breast disease,
lymphangitis cutis/pulmonis, cystic lesions, and also
abdominal masses that are not confirmed and followed
by imaging techniques; and.
Administration of chemotherapy
• Oral: 5-FU, cyclophosphamide, ectoposide, mephalan, vinorelbine
• Convenient
• Usual maitain a steady drug level
• Poor compliance
• Intravenous: most common
• Not so complictaed
• Reliable drug pharmocodynamic
• Intra-artery:
• Complicated procedure
• Good local control ( partly ischemic effect)
• No difference in overall survival compared with intravenous
• cisplatin in osteogenic sarcoma
• Hepatic artery infusion: first pass effect
• Regional chemotherapy: limited depth of passive diffusion
• Intra-thecal: meningeal carcinomatosis: methotrexate, ara-c
• Intra-peritoneal: cisplatin for ovarian cancer
• Intra-pleural: Bleomycin as pleurodesis ( indirect effect)
• Intravesicel:mitomycin, doxorubicin
 Extravasation of vesicant
chemotherapy
• Actinomycin – D
• Amsacrine
• Daunorubicin
• Doxorubicin (Adriamycin)
• Epirubicin
• Idarubicin
• Mitomycin - C
• Nitrogen Mustard (Mustine)
• Vinblastine
• Vincristine
• Vindesine
• Vinorelbine
Port-a-cath
SITES OF ACTION OF CYTOTOXIC
AGENTS Cell cycle level
Antibiotics

Antimetabolites

S
(2-6h)
G2
(2-32h) Vinca alkaloids

M Mitotic inhibitors
(0.5-2h)

Taxoids

Alkylating agents

G1
(2-∞h)

G0
 CLASSIFICATION OF CYTOTOXIC
AGENTS
ALKYLATING ANTI- MITOTIC
ANTIBIOTICS OTHERS
AGENTS METABOLITES INHIBITORS

BUSULFAN CYTOSINE ETOPOSIDE BLEOMYCIN L-ASPARAGINASE

CARMUSTINE ARABINOSIDE TENIPOSIDE DACTINOMYCIN HYDROXYUREA

CHLORAMBUCIL FLOXURIDINE VINBLASTINE DAUNORUBICIN PROCARBAZINE

CISPLATIN FLUOROURACIL VINCRISTINE DOXORUBICIN

CYCLOPHOSPHAMIDE MERCAPTOPURINE VINDESINE MITOMYCIN-C

IFOSFAMIDE METHOTREXATE TAXOIDS MITOXANTRONE

MELPHALAN PLICAMYCIN
Chemotherapy Kinetcis
Tumor Log Kills
Higher dose higher Log kill
 Reason for chemotherapy
resistance
• Drugs toxicity
• Dose limiting toxicity ( esp. non-hematologic)
• Cumulative toxicity
• Doxorubicin cardiotoxicity
• Cisplatin neuropathy
• Multiple drug resiatnce
• Tumor growth and growth fraction
 Biology of tumor growth against
chemotherapy
• Models: L1210 rodent leukemia
• 100% proliferating cells
• Killing effect of cancer drug followed log-kill
kinetics
• While, human tumor growth in a Gompertzian and
exponential growth and regression
• Growth fraction peaks at 37% of its maxiaml
size
• Response to chemotherapy depends on whether the
tumor is in its phase of exponential growth
Tumor growth and detection

1012
cancer cells
Number of

109 Diagnostic
threshold
(1cm)

time
Undetectable Detectable
cancer cancer

Limit of Host
clinical death
detection
 Multiple drug resistance
• Transporter-mediated resistant
• MRD1 gene
• Natural product or semisynthetic analogue
• Vinca alkaloid, TopoI inhibitor, Taxanes, anthracyclines
• Detoxification by the cells
• Glutathione conjugation and expel by the GS-X pump
• Alkylating agent
• Enhance DNA repair
• Nitosurea (guanine alkylase, ot methyguanine methytransferase)
• Cisplatin (ERCC1)
• Alternating drug target
• Decrease Topoisomerase ( TopoI, TopoII)
• Antimetabolite
• Thymidylate synthetase
• Dihydrofolate reductase
 SIDE EFFECTS OF
CHEMOTHERAPY
Alopecia
Mucositis

Pulmonary fibrosis
Nausea/vomiting
Cardiotoxicity
Diarrhea
Local reaction
Cystitis
Sterility Renal failure

Myalgia Myelosuppression
Neuropathy
Phlebitis
Complication of chemotherapy by time point
• Acute (<2weeks)
•Emesis, diarrhea, hiccup
•mucositis
•neutropenia
• Subacute (2weeks – 6months)
•alopecia
•anemia
•neuropathy
• Chronic (>6 months)
•2nd leukemia
•Congestive heart failure
•infertility
 Grading of chemotherapy adverse
effect
• NCICTC V.4
• 0 = No Adverse Event or
within normal limits
• 1 = Mild Adverse Event
• 2 = Moderate Adverse
Event
• 3 = Severe and undesirable
Adverse Event
• 4 = Life-threatening or
disabling adverse event
• 5 = Death related to
Adverse Event
 Specific chemotherapy toxicities
Doxorubicin Cardiotoxicity
Dilated myopathy, cumulative dose: 550 mg/m2
Bleomycin Pulmonary fibrosis( > 400 total unit)

Cyclophosphamide Hemorrhagic cystitis

Tubulin inhibitor neuropathy

Cisplatin Nausea/vomiting, nephropathy, neuropathy

5-FU Hand foot Syndrome

Mitomycin-C Cumulative and prolonged

myelosuppression:platelet
L-asparaginase Allergic reaction
 Combination chemotherapy
• Single drug in standard dose does not cure cancer
• Combination chemotherapy
• Maximal cell kill within the range of toxocity
• Broader range of coverage of resistant cell lines
• Goldie Coldman mathematical model
• 103 to 106 number of cells of a tumor would develop resistant
lines
• Treat at small tumor and with combination
• Principle of drug combination
• Drugs known to be partial effect against the tumor
• Not overlap toxicity
• Use in their optimal dose and schedule
• Given at constant level
 Example of combination
• 5-FU+cisplatin
• Few overlapping toxicity
• Different mechanism
• Cisplatin increase Tetrahydrofolate pool
• docetaxel and capecitabine
• Different mechanism
• Doctaxel up-regulate thymidylate
phosporylase
• But share with common toxicity
 AIM OF COMBINATION
THERAPY
INCREASED EFFICACY

ACTIVITY SAFETY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance
How chemotherapy regimen be
choice by clinician
• Not like antibiotics, cancer did not have “sensitivity” test
• Antitumor mechanism for chemotherapeutic agent usually
targeted common pathway: the cell growth (proliferation)
machinery. Therefore, one chemotherapeutic agent may
effective against a variety of cancer types.
• The choice of appropriate regimen for a certain stage of
cancer is empirical, and by EBM.
• EBM: clinical trial.
• Phase I: decision for dose (maximal tolerable dose), toxic
profiling.
• Phase II: test the antitumor activity for a certain type of cancer
• Phase III: compare with the standard care, usually is a
randomized controlled trial.
• Drug (regimen) shown superior to the current standard of care
will be consider the new priority to be used.
Estrogen Production in Pre- and
Post-menopausal Women
Hypothalamus
Premenopausal Postmenopausal and
Premenopausal
Gonadotropins Adrenocorticotropic
(FSH + LH) hormone (ACTH)
Pituitary gland

Ovary
Prolactin
Adrenal gland
Growth Hormone

Corticosteroids
Estrogens Progesterone
Progesterone Androgens
Estrogens

34
 Inhibition of
Estrogen-Dependent Growth
Antiestrogens

Estrogen
biosynthesis
Nucleus

Estrogen
biosynthesis

Aromatase Inhibition of
cell
inhibitors proliferation
Tumor cell

35
 Other anticancer therapies
• Targeted therapies are a relatively new
class of anticancer agents.
• Targeted cancer therapies are drugs that
block the growth and spread of cancer by
acting on specific factors important in
carcinogenesis and tumour growth.
 Examples of targeted therapies
Categories Target Therapeutic agent
Tyrosine Kinase Inhibitors EGFR Gefitinib (Iressa; AstraZeneca)
Erlotinib (Tarceva; Roche)
Cetuximab (Erbitux; BMS)
Lapatinib (Tykerb; GSK)
HER2/neu Trastuzumab (Herceptin; Roche)
Lapatinib (Tykerb; GSK)
Angiogenesis inhibitors VEGF Bevacizumab (Avastin; Roche)
Pazopanib (GSK)

Proteasome inhibitors NF-kappa-B Bortezomib (Velcade; J&J)

Immunotherapy Rituximab (MabThera; Roche)

 Current targeted therapy fro
common cancers
Cancer type Molecular pathway Represent drugs
Breast HER2 MoAb: Herceptin,
pertuzumab, T-DM1
TKI: Lapatinib
Lung Mutated EGFR TKI: geftinib, erlotinib,
Afatinib
Colon VEGF Bevacizumab,

EGFR MoAB: Cetuximab,

panituzumab
ras Regofenib
Renal cell carcinoma VEGF MoAB: bevacizumab
TKI: sunitinib, sorafenib,
axininib, pazopanib
mTor everolimus
GIST C-Kit Imatinib, sunitinib, nilotinib
CML Abl-bcr Imatinib, nilotinib, dasatinib
Common chemotherapy
regimen

FOR YOUR REFERENCE

 Lung cancer
• Small cell carcinoma
• EP: etoposide and cisplatin

• Non-small cell lung cancer

• Cisplatin based regimen, in combination of the
following
• Paclitaxel
• Docetaxel
• Vinorelbine
• Gemcitabine
 Breast cancer
• Anthracycline based
• FAC: 5-FU, doxorubicin, cyclophosphamide
• AC
• Taxane based
• Paclitaxel + gemcitabine
• Docetaxel + capecitabine
• Vinorelbine
• Capecitabine
• Trastsuzumab ( anti-HER2)
 Colon cancer
• 5-FU+leucovorin (bio-modulation)
• 5-FU based in combination with
• Oxaliplatin
• Irinotecan
• Target therapy
• Bevacizumab
• Cetuximab
 Gastric cancer
• 5-FU based
• 5-FU+ cisplatin
• 5-FU+epirubicin+cisplatin
• Docetaxel + cisplatin+ 5-FU
 Pancreas cancer
• Gemcitabine and cisplatin
 Urotheial carcinoma
• Cisplatin based
• mVAC
• Methotrexate
• Vinblastin
• Doxorubicin
• Cisplatin
• Gemcitabine + cisplatin
 Renal cell carcinoma
• Immunotherapy with cytokine
• Interfreon-a
• Interleukin 2
• Target therapy
• VEGF: bevacizumab, sunitinib
• VEGF, raf: sorafenib
• mTor: temsirolimus
 Ovarian cancer
• Taxanes
• Paclitaxel + carboplatin
• Docetaxel
• Anthracycline
• Doxorubine, cyclophosphamide and cisplatin
• Liposomal doxorubicin
 Prostate cancer
• Docetaxel
• Mitoxantrone+ prednisolone
• estrameustine
 Sarcoma
• CYVADIC
• Cyclophophamide
• Vincristine
• Doxorubicin
• Dacarbazine
• High dose Methotrexate
• With leucovorin rescue
• Doxorubicin+ Ifosphamide+/- cisplatin
 Head and neck cancer ( SCC)
• 5-FU + cisplatin
• Cisplatin + 5-FU+ docetaxel
 Testicular cancer
• Cisplatin based
• Viblastine, cisplatin and belomycin
• Etoposide, cisplatin
 Acute leukemia
• AML
• Induction:
• anthracycline or anthracycline-like drug
(daunorubicin, idarubicin, mitozantrone) for 3 days
+ cytarabine (Ara-C) for 7 days
• Post-remission:
• Ara-C (intermediate or high dose) based regimen
• ATRA( all-tran retnoic acid) for APL
• Anti-CD33 antibody for AML
 Chronic leukemia
• CML
• Target therapy (tyrosine kinase inhibitor
against abl-bcr or c-kit)
• Imatinib, Nilotinib, Dasatinib
• Conventional therapy:
• Interferon + Ara-C, hydroxyurea
• CLL
• chlorambucil, cyclophosphamide, Fludarabine,
Anti-CD20 antibody (Rituximab)
 Indolent lymphoma
• COP:
• cyclophosphamide, vincristine, Prednisolone
• R-COP
• Rituximab + COP
• Fludarabine base regimen
• FND: Fludarabine, Mitoxantrone, dexan
• Anti-HP therapy for gastric MALT
lymphoma
 Aggressive lymphoma
• Intensive chemotherapy according to
pathological subtypes
• R-CHOP: Rituximab + Doxorubicin,
cyclophosphamide, vincristine, Prednisolone
• ESHAP: Etoposide, fSolumedrol, Cisplatin,
High dose Ara-C