The Basic and Principles of Rational

Chemotherapy

Kartika Widayati Taroeno-Hariadi,

Ibnu Purwanto
Division of Hematology and Medical Oncology, Department of Internal Medicine
Faculty of Medicine Universitas Gadjah Mada - Dr Sardjito Hospital
YOGYAKARTA
 Clinical strategies for Cancer Treatment:
The Role of Drug
• Cancer treatment needs the cooperative
efforts of multiple medical specialties.
• Surgeon, radiotherapist, medical oncologist,
palliative doctors, and psychotherapist
• The array of alternatives for treatment of
cancer is constantly expanding. New drugs
and new biologics, multimodalities treatment,
initial treatment plan, input of specialists are
needed.
Bruce A Chabner 2011 Cancer Chemotherapy and Biotherapy
 TREATMENT PLANNING

Histology Staging
Treatment choice Surgery

Treatment Choice Treatment choice Monitor and

Chemotherapy radiotherapy ResponseEvaluation
HISTOLOGY AND MOLECULAR DIAGNOSIS
CLINICAL STAGING
 Systemic Treatment for Cancer

• Chemotherapy ( single or combination)

• Targeted treatment : hormonal, antibodies,
small molecules
• Other agents
biphosphonates
immunological agents
Aim of Systemic Treatment

Curative /
Adjuvant
Palliative

Neoadjuvant Metronomic
 Definition :
• Adjuvant chemotherapy :

• Adjuvant therapy, also known as adjunct therapy,

add-on therapy, and adjuvant care, is therapy
that is given in addition to the primary or initial
therapy to maximize its effectiveness.

• conventional regimens are used as maximum tolerated dose

(MTD), in which relatively high doses are given with 2-3-week
intervals ( N.Andr”e et al, e Lancet Oncology, vol. 14, no. 6, pp. e239–248, 2013.)
 Definition :

• Neoajuvant chemotherapy :
• Treatment given as a first step to shrink a tumor before the
main treatment, which is usually surgery.

• conventional regimens are used as maximum tolerated dose

(MTD), in which relatively high doses are given with 2-3-week
intervals ( N.Andr”e et al, e Lancet Oncology, vol. 14, no. 6, pp. e239–248, 2013.)
Metronomic Chemotherapy (MTC)
• The term “metronomic chemotherapy” (MTC)
is currently used for frequent and regular
administration of lower doses of
chemotherapeutic drugs with minimal drug
free time intervals, or simply “lower doses,
longer times”, in order to establish a
prolonged and lower albeit an active range of
plasma concentration enabling a favorable
side-effect profile
(G. Bocci and R. S. Kerbel, “Pharmacokinetics of metronomic chemotherapy: a
neglected but crucial aspect,” Nature ReviewsClinical Oncology, vol. 13, no. 11, pp. 659–
 Indication of MTC
• Starting in Palliative treatment
• Unfit elderly patients
• Patients who are ineligible for standard
treatment options
 Biologic and Pharmacologic Basis of
Cancer Chemotherapy and Biotherapy

Roland T Skeel adn Samir N. Khleif. Handbook of Cancer Chemotherapy. 7 ed

 General Mechanisms by Which
Chemotherapeutic Agents Control Cancer
• Purpose of treating cancer :
prevent cancer cell from multiplying,
invading, metastazing, and killing the host
• Most traditional chemotherapeutic agent appear to exert
their effect on cell proliferation.
• Cell multiplication is a characteristic of many normal cells 
most chemotherapeutic agents have toxic effect on normal
cells
• The most effective regimens: highest efficacy in eradicating
neoplastic cells while preserving normal marrow, other
organs, and improving function and quality of life
 Mechanisms of Metronomic Action
• The preliminary role of MTC is derived from its
antiangiogenic mode of action is shared by
two classes of therapies metronomic
chemotherapy and anti-VEGF monoclonal
antibodies.
 Mechanisms of MTC ..
• MTC selectively depletes Treg and thus restores the
natural killer (NK) and T cell functions
• MTC also induces anti angiogenic
proteinThrombospondin-1, inhibits angiogenic HIF-1𝛼
(Hipoxia-Indicible Factor –1 Alpha), and decreases
circulating VEGF levels
• There are plentiful data that demonstrate that MTC
particularly induces angiogenic dormancy by
upregulating and downregulating antiangiogenic
factors such as Trombospodin 1/TSP-1 ( protein
inhibitor of angiogenesis) and proangiogenic factors
such as VEGF,
The Empiric Methods of Discovering
New Effective Anti Cancer Agents
Ideal Development of Cancer Chemotherapeutic Agents
 Macromolecular synthesis
And Functions
Cytoplasmic Organization and
Signal transduction

Inhibition of Cell Multiplication and

Tumor Growth
Environment of Cancer
Cell Growth
Cell Membrane and Associated Cell Surface Receptor
synthesis, expression, and function
 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

 Anti Cancer Agent
• Chemotherapies
• Hormonal agents
• Kinase inhibitors
• Monoclonal antibody
• Antibody-drug conjugate
• immunotherapies
 1.Classic Chemotherapy Agents
• Chemotherapy agents are divided into
different categories according to their
mechanisms of action
• There are cell cycle speci
fic agents and cell cycle
non specific drugs
Sites of Action of Various Chemotherapeutic agents
CANCER GROWTH AND RESPONSE TO TREATMENT

NT

HM Hatcher 2011. Oncology

 Rationale for Combining chemotherapy agents

• Resistance to a single drug

• Giving treatment at an increased frequency
also increase toxicity
• Activity and scheduling: synergistic activity
• Mechanisms of action: different
complementary
• Toxicities: different
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
Responsiveness of tumors to chemotherapy

• Childhood cancers
Curable • Hodgkin lymphoma and other aggressive lymphoma
• Carcinoma of testis, chorioca, adult acute leukemia, ovarian ca

Improved • neuroblastoma
• NHL
survival • Small cell lunc ca, breast ca, osteogenic sarcoma

• NHL intermediate and low grade

Palliation • Chronic leukemia, multiple myeloma, endocrine gland tumor

Occasional • Soft tissues sarcoma

• Brain ca
response • NSCLC, malignant melanoma
 CONTRAINDICATION OF CHEMOTHERAPY

• When facility 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
 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
 MOLECULAR TARGETED THERAPY

Molecular Targeted Therapy is a new approach to cancer treatment

Characteristics:
The molecule is uniquely expressed in cancer cells
Therapetic agents will specifically target the cancer
The molecule is important for the maintenance of the malignant
phenotype

1. cell-signaling targeted therapy

2. Angiogenesis targeted therapy
3. Protein degradation targeted therapy
4. Immune modulation
5. Phenotype-directed targeted therapy
2. Hormonal Therapy
3. Monoclonal antibody
 Increase Proliferation

Decrease apoptosis

Enhanced cancer cell

motility

Angiogenesis

http://www.biooncology.com
4. Kinases Inhibitor
TARGETED TREATMENT OF HER FAMILY
RECEPTORS
5. Antibody-drug conjugate
6. immunotherapy
immunotherapy
IMMUNOTHERAPY
 KEYTRUDA/ Pembrolizumab
• KEYTRUDA is an anti-PD-1 therapy that works by
increasing the ability of the body’s immune system
to help detect and fight tumor cells.
• KEYTRUDA is a humanized monoclonal antibody
that blocks the interaction between PD-1 and its
ligands, PD-L1 and PD-L2, thereby activating T
lymphocytes which may affect both tumor cells and
healthy cells.
• KEYTRUDA is administered as an intravenous
infusion over 30 minutes every three weeks for the
approved indications. KEYTRUDA for injection is
supplied in a 100 mg single-dose vial.
 Assessment of Response to Treatment

• Response Criteria for

Solid Tumor (RECIST)
• Measurable lesions :
can be acurrately measured in
at least one dimensions with LD ≥
20 mm using conventional CT or LD
≥ 10 mm with spiral CT

• Non measurable lesion

all other lesion eg. Bone lesion,
leptomeningeal disease, ascites, pleu
ral / pericardial effusion
 RESPONSE CRITERIA
• TARGET LESION
Complete response (CR) Disapperance of all target lesion
Partial Response (PR) At least a 30% decrease in the sum of
the LD of target lesions taking as
reference th baseline sum LD
Progressive Disease (PD) At least a 20% increase in the sum of the
LD of target lesions, taking as reference
the smallest sum LD recorded since
treatment started or the appearance of
one or more new lesions
Stable Disease (SD) neither sufficient shrinkage to qualify
for PR nor sufficient increase to qualify
PD, taking as reference the smallest sum
LD since the treatment started
EVALUATION OF NON TARGET LESION
Complete Response (CR)
Incomplete Response / Stable Disease
Progressive Disease (PD)
Disappearance of all non target lesions
and normalization of tumor marker level
Persistence of one or more non-target
lesion(s) or/and maintenace of tumour
marker level above normal limits
Appearance of one or more new lesions
and/or unequivocal progression of existing
non-target lesion
ADVERSE EFFECT
 Extravasation of anthracyclin

Day-1 Grade 1 erythema, pain, Day-4 grade 2 more severe Day -8

edema, phlebitis

Day-10 grade 3 ulceration, tissue Day-14 Day-16

damage, necrosis