Basic Oncology

Heri Fadjari
Hematology-Medical Oncology Div.
Dept. of Internal Meicine
Hasan Sadikin General Hospital
What is basic oncology?

Learn to describe the

pathophysiology of
carcinogenesis, discuss
prevention, screening and
detection guidelines, review the
process for diagnosing and
staging, discussing current
treatment modalities
Multistep carcinogenesis
Initiation Promotion ConversionProgression

Genetic
change

Clonal
Heredity expansion
Chemica
ls Genetic
Radiatio
n change
Inflamation
Viruses
Endocrine factors
Nutrition

Preneoplastic lesion

Tumor suppressor genes

Malignant lesion
Mitoses
Multistep carcinogenesis (cont’d)

Progression Clinical lump

Malignant lesion Metastases

Tumor growth

Number of cancer cells

10
12

diagnostic
threshold
(1cm)
10
9
time
undetectabl detectable
e cancer
cancer
limit of clinicalHost death
detection
The unique characteristics of
cancer cells

• Immortality
• Genetic instability
• Increase in growth factor
secretion
• Increase in oncogene expression
• Loss of tumor suppressor genes
• Loss of contact inhibition
• Progressive independence of
proliferation from growth
factors and nutrients
• Metastasis
The limit of cytoreduction
• Once that critical number of cells is
achieved,
chemotherapy can not further reduce
the cancer cell population

• Kinetic models have suggested that

one limitation to cytotoxic treatment
is the rapid regrowth of the
residual malignant cells.

• This problem may not be overcome by

the simple expedient of dose
escalation. This might be explain why
the results of HDCT in breast cancer
have been so consistent, even though
many different drugs combinations
Some Major Types of Cancer

Cancer is categorized according to the tissue in

which
it arises:

1. Sarcomas – connective tissues

2. Carcinomas – epithelium
3. Adenocarcinomas – glands or its ducts
4. Lymphomas – lymphoid tissue
5. Leukemia – blood
Cancer treatment modalities

• Goal(s): Cure, Control,

Palliation
• Treatment:
> Chemotherapy
> Radiation
> Biologic Response Modifiers
> Surgery
Classification of Chemotherapeutic Agents

ALKYLATING ANTI- MITOTIC

ANTIBIOTI OTHERS
AGENTS METABOLITEINHIBITORS CS
S
busulfan cytosine etoposide bleomycin l-sparaginase
carmustine arabinoside teniposide dactinomycin hydroxyurea
chlorambucil floxuridine vinblastine daunorubicin procarbazine
cisplatin fluorouracil vincristine doxorubicin
cyclophos- mercaptopurine vindesine mitomycin-c
phamide methotrexate taxoids mitoxantrone
ifosfamide melphalan
The cell cycle
Antibiotics

Antimetabolites

S Taxoids
(2-6h) G2
(2-32h) Vinca
alkaloid
M s
(0.5- Mitotic
2h) inhibitors

Alkylating
agents

G1
(2-∞ h)
G0 G0 Check point
Growth factors and oncogenes

Paracrine
e (Adjacent cells)
rin tion
t oc ula
Au tim
Growth s Growth
Factor Factor
Growth and
Factor Receptor
Receptor Synthesis
Post
receptor
Gene
signal
Activation
transduction
pathways Oncogenes
 Viral oncogenesis

RETROVIR
US
Oncogene
Oncogene protein
Oncoge Viral
ne RNA REVERSE
TRANSCRIPTAS
Viral E RNA TRANS
DNA INS messen CRIPTI
NUCLEUS E ger ON
R
T
I
O
TRANSCRIPT
N
DNA ION
Viral
Viral Oncogene genome
RNA

CELL CYTOPLAS
MEMBRANE M
Principles of Combination Chemotherapy

Rationale for combination

chemotherapy is to:
- Overcome drug resistance
to individual agents
- Improved remission rates
and duration compared
with single agent therapy
- Additive or synergistic
mechanisms of action
- Non-overlapping toxicity
profiles
Adjuvant Chemotherapy

• Given for patients after local control of

tumor (surgery or radiation) to prevent
metastatic or recurrence
• Eliminating residual tumor and
micrometastatic tumor deposits that
are present at time of diagnosis
• Should begin as soon as possible after
local therapy
• Delays to allow for recovery may
compromise chance of cure
Neoadjuvant
Chemotherapy

• Administration of chemotherapy
before definitive local therapy
• Avoids delays from surgery/radiation
• May improve local control by
shrinking the primary tumor and
making it more amenable to surgical
resection

AC 4x Paxus 4x

surgery
Chemotherapy toxicities

Immediate: hours to days

1. Extravasation, phlebitis
2. Rash, anaphylaxis
3. Neurologic
4. Tumor Lysis
5. Renal Failure
6. Fever
7. Nausea and Vomiting
8. Hemorrhagic Cystitis
Chemotherapy toxicities

Early: days to weeks

1. Myelosuppression 
infection, anemia,
bleeding
2. Alopecia
3. Stomatitis, Mucositis
4. Diarrhea
5. Paralytic ileus
Chemotherapy toxicities

Delayed: weeks to months

1. Anemia
2. Constipation, Peripheral neuropathy
3. Aspermia
4. Nephrotoxicity
5. Ototoxicity
6. Hepatocellular damage
7. Hyperpigmentation
8. Pulmonary fibrosis
Adjuvant therapy for
women with early stage
ovarian cancer.
EORTC, 2003 Did not specify which patients
should receive adjuvant therapy

ESMO, 2001 • Poorly differentiated stage Ia, Ib

(consider chemotherapy)
• Stage Ic (chemotherapy regimen
not specified)

SOR, 2001 • Stage Ia, grade 2,3, Ib, Ic, IIa (no
standard treatment, options
include platinum-based
chemotherapy, external beam radiation, or
no adjuvant therapy

SOGC, 2000 Did not specify which patients should

receive adjuvant therapy
Adjuvant chemotherapy versus no chemotherapy

There is no benefit from adjuvant chemotherapy

in women with stage I epithelial ovarian cancer
who have undergone optimal surgical staging as
EORTC

Women with surgically staged stage I ovarian

cancer and good prognostic factors (grade 1,
non-clear cell histology) could be managed with
or without adjuvant chemotherapy

Women who have not undergone optimal

surgical staging can be offered two options:
- undergo re-operation and then be offered
adjuvant therapy.
- platinum-based chemotherapy to decrease the
risk of recurrence
and improve survival.
Adjuvant chemotherapy option

Intravenous carboplatin with or without

paclitaxel or docetaxel is the recommended
postoperative chemotherapy regimen for newly
diagnosed stage II-IV epithelial ovarian cancer.

Because the addition of doxorubicin to

chemotherapy increases toxicity, and the
magnitude of the survival benefit is unclear,
the incorporation of anthracyclines as part of
first-line therapy is not recommended at the
present time.
Summary of available trials

Study Patients Regimen Median

survival
(months)
GOG-111 Stage III & -paclitaxel 135 + cisplatin 75 vs 38 vs 24
1996 IV - cyclophosphamide + cisplatin p<0.001
suboptimal
N=386

Intergroup Stages IIb-IV - paclitaxel 175 + cisplatin 75 vs 36 vs 26

, N=680 - cyclophosphamide + cisplatin p=0016
2000
GOG-132, Stage III-IV - paclitaxel 135 + cisplatin 75 vs 26 vs 26 vs
2000 suboptimal - cyclophosphamide + cisplatin 30
N=614 vs p=0.31
- cisplatin 100

ICON3, Stages I-IV - paclitaxel 175 + carboplatin 36.1 vs 35.4

2000 N=2074 AUC=6 p=0.74
vs
- carboplatin alone OR
- cyclophosphamide 500 +
doxorubicin 50 + cisplatin 50
Summary of available trials (cont’d)

Study Patients Regimen Median

survival
(months)
SCOTROC, Stage IC-IV - paclitaxel 175 + carboplatin 15.4 vs 15.1
2003 N=1077 AUC=5 p>0.05
- docetaxel 75 + carboplatin
AUC=5

Kristensen, Stage IIb-IV - paclitaxel 175 + carboplatin 16.3 vs 17.2

2004 N=887 AUC= p>0.05
- paclitaxel 175 + carboplatin
AUC=5 + epirubicin 75

Du Bois, Stage IIb-IV -paclitaxel 175 + carboplatin 41 vs 45.8

2004 N=1282 AUC= p=0.71
- paclitaxel 175 + carboplatin
AUC=5 + epirubicin 60

Dutch/Danis Stage IIb-IV - paclitaxel 175 + cisplatin 75 35 vs 37

h2000 N=208 - paclitaxel 175 + carboplatin p>0.05
AUC=5
Risk assessment

Low risk High risk

Size <2cm >2cm

ER/PR positive negative

Grading 1 2-3

Age >35 <35

Comment All factors must be At least 1 factor

present present
Treatment plan

Multidisciplinary treatment
planning should be used to
integrate local and systemic
therapies as well as their
sequence.
 Node negative (N0) patient

Low risk (=endocrine responsive) Tamoxifen OR nil

Higher risk, endocrine responsive

– premenopausal Chemotherapy, Ovarian ablation
→ tamoxifen, OR
Chemotherapy → tamoxifen, OR
Ovarian ablation
– postmenopausal Tamoxifen, OR
Chemotherapy → tamoxifen

Higher risk, endocrine non-responsive

– premenopausal Chemotherapy
– postmenopausal Chemotherapy
Node positive (N+) patient

Endocrine responsive
– premenopausal Chemotherapy →
tamoxifen ±ovarian ablation
– postmenopausal Chemotherapy → tamoxifen,
OR
Tamoxifen

Endocrine non-responsive
– premenopausal Chemotherapy
– postmenopausal Chemotherapy
Adjuvant systemic therapy

Tamoxifen Patients with ER and/or PR

positive tumors should receive
tamoxifen 20mg/d for 5 years
Tamoxifen should be started when
chemotherapy is completed.

Aromatase For postmenopausal patients with

intolerance or inhibitor
contraindications to tamoxifen, adjuvant AI is
an option

Ovarian ablation Ablation of ovarian function

is effective adjuvant treatment for
premenopausal patients with
endocrine responsive tumors [I, A]

Chemotherapy
Adjuvant systemic therapy

Chemotherapy Adjuvant chemotherapy

should use a combination regimen.
In node positive and node-negative
disease anthracycline-
containing therapy has superior in
efficacy to CMF.
4 cycles of AC equal to 6 cycles of
CMF.
Adding 4 cycles of paclitaxel to 4
cycles
of AC improves outcome in node-
positive patients
At the St. Gallen consensus conference 2003, 4 cycles of AC
or 6 cycles of CMF were considered adequate treatment for
ER and/or PR positive patients, while ER and PR negative
tumors were considered candidates for more prolonged
chemotherapy.
Factors associated with
favourable prognosis in
metastatic breast cancer

ER/PR positive tumor

Long disease free interval (>1–2
year)
No visceral involvement
Limited metastatic sites, no bulky
disease
HER2 negative tumor
Treatment plan

Isolated local-regional recurrence should be

treated like a new primary with a curative
intent including adjuvant treatment
modalities.

Treatment for systemic disease is palliative.

Goals of treatment include improving quality
of life and prolongation of survival [I, A].

Treatment of metastatic breast cancer

usually involves
hormone therapy and/or chemotherapy with
or without trastuzumab.

Radiation therapy is an integral part of

palliative treatment.
Bisphosphonates are effective in
Patients with hormone-receptor positive tumor

Premenopausal patients
If no prior adjuvant tamoxifen or
discontinued for more than 12 months:
Tamoxifen with ovarian ablation (LHRH
analogs or surgery) [I, B].
Otherwise:
Third generation aromatase inhibitors
can be considered after or concomitantly
with ovarian ablation.

Postmenopausal patients
Tamoxifen or aromatase inhibitors. Third
generation aromatase inhibitors are
marginally
superior to tamoxifen in first line therapy
regarding response and time to
Patients with hormone-receptor negative tumo

Hormone-receptor negative and/or have progressed

on hormone
therapy are candidates for cytotoxic chemotherapy
(II,B)

The selection of the regimen should be based on

tumor and patients characteristics (e.g., rate of
disease progression, presence or absence of
comorbid medical conditions, previous adjuvant
systemic therapy) and patient/physician preferences.
At this time, there are no data supporting the
superiority of any particular regimen.

It is not clear whether single agent chemotherapy or

combination
chemotherapy is preferable for first-line treatment.

The optimal treatment duration for patients with

responsive or stable disease is unknown.
Selection of commonly used chemotherapy regimen

Non-anthracycline containing
Cyclophosphamide / methotrexate /
fluorouracil (CMF)

Antracycline containing
Adriamycin / cyclophosphamide (AC)
Fluorouracil / adriamycin /
cyclophosphamide (FAC)
Fluoroucil / epirubicin / cyclophoshamide
(FEC)

Taxane containing
Adriamycin / taxane (AT) (paclitaxel or
docetaxel)
Epirubicin / taxane (ET) (paclitaxel or
docetaxel)
Conventional chemotherapy

regrowth
Dose escalation
HDCT + BMT/PBSCT
Weekly scheduling
Xie … xie …
 Choice of adjuvant
chemotherapy: impact on
Estimated percentage still alive 100
survival
90

80

70 70.0%
65.6%
60

50
Combination regimen
Single agent
40

0 1 2 3 4 5+
Time (years)

Early Breast Cancer Trialists’ Collaborative Group (unpublished data)