Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Type
Nitrogen mustard
Alkyl sulfonate
Triazine DTIC
Metal salt
Obat
Chlorambucil, cyclophosphamide
Melphalan
Busulfan
Cisplatin
Actinomycin -D
Daunorubicin
Doxorubicin
ONCOLOGY
Drug development
Steps in cancer drug development
Pharmacology
Biochemistry
Drugs Development
Random Screening
Logical Design
Animal Data
Formulation
Phase 1 Trials (Toxicity maximum tolerated
dose)
ONCOLOGY
Drug development
Identification of candidate compounds: Natural products
Drug Type
Source
Streptomyces fungus
Taxane
Yew tree
Marine organisms
Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology. 1997;387-388.
Haskell CM. Cancer Treatment. 1995;35-36.
ONCOLOGY
Drug development
Identification of candidate compounds: Molecular-targeted screening
Computer-aided construction of
molecules
Mutant oncogenes (BCR-ABL)
Aberrant tumor suppressor genes (RB)
Protein kinases
Transcription activators
Grever MR, Chabner BA. Cancer: Principles & Practice of Oncology. 1997;385-394.
ONCOLOGY
Drug development
Screening for anticancer activity
Colon
Breast
CNS
Melanoma
Ovarian
Prostate
Preclinical development
followed by broad-based clinical trials
Specific disease-oriented
Phase I/II trials
ONCOLOGY
Drug development
Preclinical evaluation of cytotoxic agents
IN VITRO
IN VIVO
Mechanism of action
Stage I
Stage II
Target level
Cellular level
Dose-limiting toxicities
Schedule dependency
Efficacy
Route administration
Cross resistance
Combination therapies
ONCOLOGY
Drug development
Use of animal models in evaluation of cytotoxic agents
ONCOLOGY
Drug development
Clinical evaluation of cytotoxic agents
Study Phase
Objectives
Patient Population
Phase I
patients/treatment group)
More uniform disease characteristics
Phase II
Phase IV
standard
Support marketing approval
patients/treatment group)
Same tumor type
Broader patient pool
population
ONCOLOGY
Drug development
Clinical trials: Efficacy endpoints
Response rate
Survival
Disease-free survival
Time to disease progression
Duration of response
Quality of life
Pharmacoeconomics
ONCOLOGY
Drug development
Clinical endpoints: Complete remission
Primary
Tumor
Nodes
Treatment
Metastases
ONCOLOGY
Drug development
Clinical endpoints: Partial remission
Treatment
ONCOLOGY
Drug development
Clinical endpoints: Disease progression
Treatment
ABSOLUTE CONTRAINDICATIONS
- Terminal diseases (patients with very short life expectancy)
- Pregnancy (first trimester)
- Septicaemia
- Coma
B.
RELATIVE CONTRAINDICATION
- Infants under 3 months
- Old age (in particular elderly patients with slow-growing tumours with low
sensitivity to chemotherapy)
- Very low performance status (less than 40)
- Severe organ failure (for certain drugs) e.g. kidney, heart, liver, bone-marrow
- Brain metastases (if not treatable by radiotherapy)
- Dementia
- Inability of patient to attend clinic regularly
- Lack of co-operation on part of patient
- Tumour resistance to anticancer chemotharapy
Osteosarcoma
Incidence : 2,1 cases/ 1000.000
Peak : 10-14 yrs.
: = 1,6 : 1
Grade
I
II
III
IV
Effect
Grade
Effect
POOR RESPONSE
I
II
No effect identified
5% to 95% viable tumor remaining
GOOD RESPONSE
III
IV
- Class
Type
Alkylating
Nitrogen mustard
agent Nitrosurea Carmustine = BCNU
Obat
Mechlorethamine
Lomustine = CCNU
Semustine = methyl CCNU
ONCOLOGY
Cancer biology
Tumor growth and detection
Number of
cancer cells
1012
Diagnostic
threshold
(1cm)
109
time
Undetectable
cancer
Detectable
cancer
Limit of
clinical
detection
Host
death
1012
No response to therapy
early
1 kg
late
kecenderungan tumor
berkembang
clinically
dietectab
tumor
109
1g
long-term
remission
106
immune
resistance host
1 mg
humoral +
cellular
103
1ug
1
induction
consolidation
maintenance
cure
ONCOLOGY
Cancer biology
Dormancy of tumor cells
Malignant tumor cells can remain
dormant yet viable for years
Emergence from dormancy can lead
to disease recurrence
Possible mechanisms:
Cells may arrest in G0 phase
Rate of cell death counterbalances rate of
cell division
Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;141.
ONCOLOGY
Principles of chemotherapy
Classification of cytotoxic agents
Alkylating
Agents
AntiMetabolites
Mitotic
Inhibitors
Antibiotics
Others
L-asparaginase
Busulfan
Cytosine
Etoposide
Bleomycin
Carmustine
Arabinoside
Teniposide
Dactinomycin Hydroxyurea
Chlorambucil
Floxuridine
Vinblastine
Daunorubicin Procarbazine
Cisplatin
Fluorouracil
Vincristine
Doxorubicin
Mitomycin-c
Ifosfamide
Mitoxantrone
Melphalan
Methotrexate
Taxoids
Plicamycin
ONCOLOGY
Principles of chemotherapy
Action sites of cytotoxic agents
DNA synthesis
Antimetabolites
DNA
DNA transcription
Alkylating agents
DNA duplication
Mitosis
Cellular level
Intercalating agents
Spindle poisons
ONCOLOGY
Principles of chemotherapy
Action sites
of cytotoxic agents
PURINE SYNTHESIS
PYRIMIDINE SYNTHESIS
6-MERCAPTOPURINE
6-THIOGUANINE
RIBONUCLEOTIDES
METHOTREXATE
5-FLUOROURACIL
HYDROXYUREA
DEOXYRIBONUCLEOTIDES
CYTARABINE
ALKYLATING AGENTS
ANTIBIOTICS
DNA
ETOPOSIDE
RNA
PROTEINS
L-ASPARAGINASE
VINCA ALKALOIDS
ENZYMES
MICROTUBULES
TAXOIDS
ONCOLOGY
Principles of chemotherapy
Cyclophosphamide
HEPATIC
CYTOCHROMES
P 450
ACTIVATION
INACTIVATION
4-KETOCYCLOPHOSPHAMIDE
CARBOXYPHOSPHAMIDE
ALDEHYDE
4-OH CYCLOPHOSPHAMIDE
DEHYDROGENASE
ALDOPHOSPHAMIDE
ACROLEIN
PHOSPHORAMIDE
MUSTARD
TOXICITY
CYTOTOXICITY
ONCOLOGY
Principles of chemotherapy
Side effects of chemotherapy
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Sterility
Myalgia
Neuropathy
Renal failure
Myelosuppression
Phlebitis
ONCOLOGY
Patient management
Cancer patient management: Solid tumors
Clinical findings
Biopsy
Cancer diagnosis
Staging/Grading
Therapeutic intention
Therapeutic decision
CT scans
ONCOLOGY
Patient management
Tumor markers:
Examples
Prostate
cancer
PSA
EAP
Pancreatic
cancer
CA 19-9
Breast
cancer
CA 15-3
Ovarian
cancer
CA 125
Testicular
cancer
AFP, hCG
ONCOLOGY
Patient management
TNM classification
Tumor
Nodes
Metastasis
ONCOLOGY
Patient management
Tumor extent/staging
Tumor extent/staging
Metastatic disease
Extent
Chemotherapy
Radiotherapy
Surgery
Immunotherapy
Hormonal therapy
Palliative care
Localized disease
= limited stage
Resectable
tumor
Operable
patient
Surgery
+ Radiation therapy
+ Chemotherapy
+ Hormonal-immunotherapy
Nonresectable
tumor
Inoperable
patient
Radiation therapy
Chemotherapy
and/or
Hormonal therapy
Immunotherapy
ONCOLOGY
Patient management
Classification: Leukemias (NON SOLID CANCER)
Morphology and
cytochemistry (ie, lineage)
Maturational stage
Genotype
Scheinberg DA, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;2293-2321.
Deisseroth AB, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;2321-2343.
ONCOLOGY
Patient management
Staging: Lymphomas
Shipp AA, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997:2165-2220.
ONCOLOGY
Patient management
Surgery in cancer
Rosenberg SA. Cancer: Principles & Practice of Oncology, 5th ed. 1997;295-306.
ONCOLOGY
Patient management
Radiation therapy
ONCOLOGY
Patient management
Systemic therapies
Chemotherapy
Cytotoxic agent
Hormonal therapy
Biologic therapy
Kelompok III :
ONCOLOGY
Principles of chemotherapy
Aim of combination therapy
INCREASED EFFICACY
ACTIVITY
Different mechanisms of action
Different mechanisms of resistance
SAFETY
Compatible side effects
Drugs with differing toxicities to host tissues and different mechanism of action
may, when used in combinations :
(a) increase tumour-cell kill without a corresponding increase in host
toxicity :
improved preferential killing
(b) allow fore more rapid host recovery and better selectivity :
more rapid preferential killing
(c) kill various segment of neoplastic cells in different phases of the cycle :
more complete remissions, delay of resistant cell
populations
2.
B.
C.
A.
- Choice of drug
- Dose
- Route
- Schedule
- Single or combination
- Sequence
ONCOLOGY
Patient management
Performance status scales
Correspondence between ECOG and Karnofsky scales
ECOG
Grade
0
Criteria (simplified)
Normal activity
KARNOFSKY
%
100
90
60
50
40
30
100% bedridden
Dead
80
70
Functional status
20
10
0
Dead
Clinical Trials
in Head & Neck Cancer
TAX 323/EORTC
TAX 323/Q of L
TAX 324/Dana Farber
TAX GORTEC 200001
TAX 323/EORTC
Neck dissection
Inoperable
SCCHN
Stage 3/4
Stratification:
1 tumour site
Institution
TCF arm:
Taxotere (75 mg/m)
Cisplatin (75 mg/m)
5-FU (750 mg/m/dx5)
Q 3 weeks x 4 cycles
R
CF arm:
Cisplatin (100 mg/m)
5-FU (1000 mg/m/dx5)
Q 3 weeks x 4 cycles
Radiotherapy
(~70 Gy over
7 weeks)
Follow-up
Secondary objectives
Performance status
(EGOC)
0
1
Median age (years,
range)
Gender
Male
Female
PF (n=181)
N (%)
TPF (n=177)
N (%)
91 (50.3)
90 (49.7)
90 (50.8)
86 (48.6)
53 (3071)
162 (89.5)
19 (10.5)
53 (3170)
159 (89.8)
18 (10.2)
PF (n=181)
N (%)
TPF (n=177)
N (%)
32 (17.7)
84 (46.4)
52 (28.7)
13 (7.2)
31 (17.5)
81 (45.8)
53 (29.9)
12 (6.8)
Tumour grading
Grade 1 + 2
Grade 3 = 4
U+X
122 (64.7)
31 (17.1)
28 (15.4)
111 (62.7)
40 (22.5)
26 (14.7)
100
80
60
40
Randomised
arm
CF
20
TCF
Years
Probability (%)
Phase III
100
90
80
70
60
50
40
30
20
10
0
Mean survival
Hazard ratio
p-value
TCF
CF
0
1
2
1
8
2
4
3
0
3
6
4
2
48
Months
5
4
6
0
6
6
7
2
CF
TCF
14.2 m
18.6 m
0.73 [0.560.90]
0.0052
Pattern of recurrence
OS = Overall survival
Survival
Overall survival :
5-years: 56% (95% CI 53-59%)
10-years: 52% (95% CI 49-55%)
Osteosarcoma Chemotherapy
Protocols
Salvage therapy
Ifosfamide 3000 mg/m2 (d1-4) with mesna
uroprotection
Etoposide 75 mg/m2 (d1-4)
Salvage regimens
Neoadjuvant
chemotherapy
Patients < 40 yo, with newly diagnosed HGOE with metastases at
presentation
New protocol therapy higher dose in Ifosfamide and MTX
Site of metastases :
Lung 43 pts
Bone 3 pts
Lung and bone 9 pts
Lymph node 2 pts
Treatment protocol
Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients
treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003
Results
Primary tumor
Clinical and radiological response to
chemotherapy 79%
Histological response of the primary tumor:
Good (54%) , Poor (46%)
Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients
treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003
Results
Metastases response to chemotherapy
Type of response
Metastases
Response
Radiological
response
Complete : 5 pts
Partial : 10 pts
Stable : 26 pts
Mixed : 2 pts
Radiological
response
- Stable : 8 pts
- Progressive : 4 pts
Surgical treatment
and histological
reponse
Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients
treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003
Outcomes
Bacci G, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients
treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 14:1126-34, 2003
Terapi Suportif
- Pembedahan
- Radiasi
- Terapi sistemik kanker
Untuk mendukung
keberhasilan modalitas
utama pengobatan:
- yg bertujuan kuratif
- yg bertujuan paliatif
- yg bertujuan end of life /
hospice care
(kemoterapi, terapi
target, terapi hormon,
terapi biologik)
Terapi
SUPORTIF
Tujuan pengobatan
kanker tercapai:
kuratif: sembuh /
disease free survival >
paliatif: keluhan
komplikasi kanker (-)/
<<<<
end of life or
hospice management
(prediksi bertahan
hidup < 6 months)
Solid tumors
1. Early stage:
Adjuvant
2. Locally advance/ Bulky tumors:
Neoadjuvant
3. Metastatic / Recurrence:
First line
Maintenance
Second line
Third line
Adjuvant Therapy of
Musculoskeletal Tumors:
-Early / locally stage
Surgery
Adjuvant
Chemotherapy
Radiation +
Chemotherapy as
Radiosensitizer
Sequential Therapy of
Neoadjuvant
chemotherapy
Locally advanced
stage
Bulky tumors
Surgery
Chemotherapy
post surgery
TERIMA KASIH
TERIMA KASIH
TERIMA KASIH
TERIMA KASIH
TERIMA KASIH