1.

The role of radiation treatment

·         Review on radiation induction of damage to cells and tissues

Specific describe of radiation biophysical mechanism, radiation induced cell death,

and ability of cellular repair.
·         Review on radiosensitivity, radioresistance, and cellular response.

Radiresistance

Radioresistance is the level of ionizing radiation that organisms are able to withstand. Ionizing-
radiation-resistant organisms (IRRO) were defined as organisms for which the dose of acute ionizing
radiation (IR) required to achieve 90% reduction (D10) is greater than 1000 gray (Gy)

Cell response

radioresistance in the established radioresistant isogenic cells can be at least partially attributed to
the enhanced DNA double-strand break repair, altered expression of DNA damage signalling and
repair genes. On the other hand, in radiosensitive isogenic cells the reduced ability to repair a high
number of induced DNA double-strand breaks and no transcriptional response in DNA damage
signalling genes indicate on a lack of adaptive response to irradiation. Altogether, our results
confirmed that these isogenic cells with different radiosensitivity are an appropriate model to study
the mechanisms of radioresistance.
·         Review on Dosimetry.

Dosimetry is the study, measurement, method of measurement, or instrument of measurement of

radiation dose. Dosimetry often refers to the status of wearing a personnel badge that measures and
monitors dose. It may also refer to dose history and the records where dose history is maintained.

More specifically, radiation dosimetry is the calculation of the absorbed dose in tissue resulting from
exposure to ionizing radiation. Dose is reported in units of gray (Gy) for mass, and dose equivalent is
reported in units of sieverts (Sv) for biological tissue, where 1 Gy or 1 Sv is equal to 1 joule per
kilogram. Traditional units are still prevalent as well, where dose is often reported in rads and dose
equivalent in rems. By definition, 1 Gy = 100 rads and 1 Sv = 100 rems. Workers who may be exposed
to radiation carry personal dosimeters. These dosimeters measure dose, based on a variety of
measuring systems. The average background dose for a human being is about 350 milli-rems per
year, resulting mostly from cosmic radiation and natural isotopes in the earth. 

Radiation dose refers to the amount of energy deposited in matter and its biological effect on living
tissue, and should not be confused with activity, measured in units of curie or becquerel. Exposure
to a radioactive source will give a dose which is dependent on the activity, time of exposure, energy
of the radiation emitted, distance from the source and shielding. The dose equivalent is then
dependent upon the additional assignment of weighting factors describing biological effects for
different kinds of radiation on different organs. 
·         Review on clinical use, whether for curative intent or palliative intent. Also
review on conventional radiation, LINEC, gamma knife, cyberknife, etc.
radioterapi di gunakan untuk :

1. kuratif : improve local control dan meningkatkan kemungkinan sembuh

2. paliatif : bisa untuk memperbaiki simtom (pain, obstruction, bleeding)

·         Review on methods of delivery and penetration.

1. External beam radiation

most often uses photon beams. The radiation comes from a machine outside the body and is
focused on the cancer. It’s a lot like getting an x-ray. This type of radiation is most often given by
machines called linear accelerators (linacs).

External beam radiation can be used to treat large areas of the body. It also can treat more than one
area, such as the main tumor and nearby lymph nodes. External radiation is usually given daily over
several weeks. It’s given in an outpatient clinic or treatment center, so you don’t have to stay in the
hospital. The radiation is aimed at the cancer, but in most cases it affects the normal tissue it passes
through on its way into and out of the body. (Intensity modulated proton therapy (IMPT), described
below, works differently, but is not used very often.)

Special ways to deliver external beam radiation Three-dimensional conformal radiation therapy
(3D-CRT)

This technique uses imaging scan pictures and special computers to map the location of a tumor very
precisely in 3 dimensions. The patient is fitted with a plastic mold or cast to keep the body part still
during treatment. The radiation beams are matched to the shape of the tumor and delivered to the
tumor from several directions. Careful aiming of the radiation beam may help reduce radiation
damage to normal tissues and better fight the cancer by increasing the radiation dose to the tumor.
Photon beams or particles (like protons) can be used in this way. A drawback of 3D-CRT is that it can
be hard to see the full extent of some tumors on imaging tests, and any part not seen will not get
treated with this therapy.

Intensity modulated radiation therapy (IMRT)

This is an advanced form of external radiation therapy. As with 3D-CRT, computer programs are used
to precisely map the tumor in 3 dimensions. But along with aiming photon beams from several
directions, the intensity (strength) of the beams can be adjusted. This gives even more control over
the dose, decreasing the radiation reaching sensitive normal tissues while delivering higher doses to
the tumor.

A variation of IMRT is called volumetric modulated arc therapy. It uses a machine (called RapidArc®)
that delivers the radiation quickly as it rotates once around the body. This allows each treatment to
be given over just a few minutes. Although this can be more convenient for the patient, it’s not yet
clear if it’s more effective than regular IMRT.

Because of its precision, it’s even more important that a person remain in the right position and be
perfectly still during treatment. A special cast or mold may be made to keep the body in place during
treatment. Again, miscalculations in tumor size and exact location can mean missed areas will not
get treated.

Because IMRT uses a higher total dose of radiation, it may slightly increase the risk of

second cancers later on. This is something researchers are looking into.

Image-guided radiation therapy (IGRT) is an option on some newer radiation machines that have
imaging scanners built into them. This advance lets the doctor take pictures of the tumor and make
minor aiming adjustments just before giving the radiation. This may help deliver the radiation even
more precisely. It might result in fewer side effects, but more research is needed to prove this.

Intensity modulated proton therapy (IMPT) is IMRT using proton beams instead of photon beams.
Protons are parts of atoms that in theory can deliver radiation to the area that they are aimed at
(like the cancer), while doing less damage to nearby normal tissues. Still, there have been no studies
showing that proton beam radiation is better than the more common photon beam in terms of
cancer outcomes or side effects. In fact, a 2012 study of proton beam therapy used to treat localized
prostate cancer did not show fewer side effects compared to the more common photon beam
radiation. More study on this is needed. Meanwhile, IMPT is often used for tumors near critical body
structures such as the eye, the brain, and the spine.

Protons can only be sent out by a special machine called a cyclotron or synchrotron. This machine
costs millions of dollars and requires expert staff to use and maintain it. Because of this, proton
beam therapy is expensive, and very few treatment centers in the United States offer it. Many more
studies are needed to compare outcomes between proton and photon treatment so that each is
used for the cancer type for which it works best.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy

These use advanced image-guided techniques to deliver a large, precise dose of radiation to a small,
well-defined tumor. The term “surgery” may be confusing because no cutting is involved. This
technique is used to treat tumors that start in or spread to the brain or head and neck region. If the
radiation is given as a single dose, it’s called stereotactic radiosurgery. If the radiation is spread out
over several doses, it’s called fractionated stereotactic radiotherapy.

When the radiation is aimed at the head, a frame or shell is used to hold the head still and allow for
precise aiming of radiation beams.

A related term, stereotactic body radiation therapy (SBRT), is used to describe this technique when
it’s used for tumors in other parts of the body, for instance, the spine, liver, pancreas, kidney, lung,
and prostate.

Once the exact location of the tumor is mapped (using imaging scans), narrow radiation beams from
a machine called a Gamma Knife® are focused at the tumor from hundreds of different angles for a
short time. The process may be repeated if needed. Another approach that’s much like this uses a
movable linear accelerator controlled by a computer. Instead of delivering many beams at once, the
linear accelerator moves around to deliver radiation to the tumor from different angles. Several
machines, with names like X-Knife®, CyberKnife®, and Clinac® work in this way.

Intraoperative radiation therapy (IORT)

With this technique, radiation is given during surgery. The radiation may be given using
a machine for external beam radiation (a linear accelerator). Another option is to put a radioactive
substance into the treatment area for a short time (like brachytherapy). IORT is often used along
with a course of external radiation given before or after the operation.

IORT is useful for cancers that are deep inside the body, because normal tissues can be moved aside
during surgery, exposing the cancer. After as much tumor is removed as possible, one large dose of
radiation is directed straight at the cancer without going through normal tissues. Shielding can also
be used to further protect the nearby normal tissues. IORT is given in a special operating room lined
with radiation-shielding walls.

IORT is most often used for abdominal (belly area) or pelvic cancers that cannot be completely
removed (such as those that have grown close to vital body parts) and for cancers that tend to grow
back after treatment. This technique is not widely available.

Electromagnetic-guided radiation therapy

This is another way of aiming the radiation beam that can be used with 3D and IMRT. It uses tiny
electromagnetic implants (called transponders) that are placed into the area being treated. These
implants send out radio waves to tell the radiation therapy machines where to aim. This lets the
machine compensate for movement (like during breathing) and may help keep some of the radiation
from going to normal tissues. It also helps to refocus radiation beams as organs shift or cancer
shrinks over time. It’s sometimes known as 4-D therapy, because it includes time in the radiation
planning formula. One such system is marketed under the brand name Calypso®. In theory, better
focusing radiation could lower side effects. So far, though, studies have not found this type of
radiation to be better for patients than other approaches.

Internal radiation therapy (brachytherapy)

Internal radiation therapy is also known as brachytherapy, which means short-distance therapy.
With this method, sources of radiation are put into or near the area that needs treatment. The
radiation only travels a short distance, so there’s less risk of damaging nearby normal tissues.
Brachytherapy can be used to deliver a high dose of radiation to a small area in a fairly short period
of time. It’s useful for tumors that need a high dose of radiation or are near normal tissues that are
easily hurt by radiation.

The main types of internal radiation are:

 ●  Interstitial radiation: the radiation source is placed directly into or next to the tumor
using small pellets, seeds, wires, tubes, or containers.
 ●  Intracavitary radiation: a container of radioactive material is placed in a cavity of the
body such as the chest, rectum, uterus, or vagina.
 Convenstional radiation
Radiasinya dipecah jadi beberapa kali treatment biar sel yang rusak bisa ada waktu
diperbaiki, jadi selnya lumayan bisa menghindari apoptosis atau sel injury.
Radiation therapy is used to shrink or destroy tumours using high-energy X-rays.
Conventional (also called fractionated) radiation therapy delivers a part (fraction) of the
complete radiation dose over several sessions. The treatment will take place everyday for
several weeks to deliver the complete radiation dose.
LINEC
Prinsip kerja linac yaitu mempercepat elektron sehingga energi kinetiknya bertambah dari 4
MeV menjadi 25 MeV. Di dalam linac elektron dipercepat mengikuti lintasan yang lurus pada
struktur khusus yang dinamakan Accelerating waveguide. Saat ini Linac dilengkapi dengan
beberapa pilihan berkas radiasi, yaitu berkas elektron dan foton. Sistem kontrolpada foton
maupun elekron yang dihasilkan oleh Linac menggunakan sistem kontrol dengan komputer,
sistem pemindai tubuh dengan menggunakan Electronic Portal Imaging Device (EPID),
pengaturan dosis radiasi dengan menggunkan Multi Leaf Collimator (MLC) dan pengaturan
dosis sepenuhnya menggunakan modulasi intensitas. Teknologi Treatment Planning System
(TPS) pada linac menggunakan kalkulasi 3D dengan sistem MLC yang dapat menghasilkan
bentuk yang presisi pada treatment radiasi volume target.
Gamma knife
 Gamma Knife stereotactic radiosurgery technology uses many small gamma rays to deliver a
precise dose of radiation to a target. Gamma Knife radiosurgery is a type
of radiation therapy used to treat tumors, vascular malformations and other abnormalities
in the brain. (spinal cervical)

Cyber Knife
 The CyberKnife System is a non-invasive treatment for cancerous and non-cancerous tumors
and other conditions where radiation therapy is indicated. It is used to treat conditions
throughout the body, including the prostate, lung, brain, spine, head and neck, liver,
pancreas and kidney, and can be an alternative to surgery or for patients who have
inoperable or surgically complex tumors. CyberKnife treatments are typically performed in 1
 to 5 sessions. The CyberKnife System has more than two decades of clinical proof and has
helped thousands of cancer patients.

·         Review on side effect of radiation treatment.

 Dry mouth.
 Mouth and gum sores.
 Difficulty swallowing.
 Stiffness in the jaw.
 Nausea.
 Hair loss.
 A type of swelling called lymphedema.
 Tooth decay.

2. Cancer chemotherapeutic agent

·         Review of basic categories of drugs related to cell cycle

Phase specific and phase nonspecific

·         Review on general pharmacology of alkylating agents

·         Review on general pharmacology of antimetabolites

Drugs that cause DNA strand breaks

Types (by chemical classification)

 Antibiotic: BLEOMYCIN
 Plant alkaloids:
 o Epipodophyllotoxin: ETOPOSIDE
o Camptothecins: IRINOTECAN/TOPOTECAN (there are other
camptothecins in use)
 Alkylating agent: PROCARBAZINE

DRUGS THAT PREVENT DNA SYNTHESIS

Antimetabolites are analogues of folate, pyrimidines or
purines that interfere with key enzymes used during
nucleotide synthesis.  ALL of these agents are CELL
CYCLE SPECIFIC (CCS), as their effects occur during S
phase.  A common mechanism for the development of
resistance to these agents is modification of the target
enzymes.  

 Classification by Mechanism (labels):

 I. Nucleotide synthesis inhibitors
 II. Drugs that block DNA synthesizing enzymes
 III. Supporting agents
 Classification by Chemical Class (cards):
 I. Antimetabolites (structural analogues):
 5-FLUOROURACIL (5-FU) [CAPECITABINE],
6-MERCAPTOPURINE [AZOTHIOPRINE], 6-
THIOGUANINE, ALLOPURINOL, CLADRIBINE,
CYTARABINE, FLUDARABINE, GEMCITABINE,
LEUCOVORIN, METHOTREXATE,
PEMETREXED, PRALATREXATE
 II. Miscellaneous: HYDROXYUREA

I. Crosslinking agents
Mechanism (alkylating agents)

1. Must be (or become) strong electrophiles (as charged molecules

generally do not cross the blood/brain barrier very well)

2. Attack on cell nucleophiles: -SH of protein, -N- of protein or DNA

base (esp. N7 position of guanine), =O of DNA base or
phosphate
 3. DNA damage includes:
a. crosslinking (esp. if bifunctional agent)
b. miscoding of DNA bases (esp. G-T pairing)
c. DNA strand breakage (depurination)

Types (by chemical classification)

 Alkylating agents:
o Nitrogen
mustards: CHLORAMBUCIL,
CYCLOPHOSPHAMIDE,
IFOSFAMIDE, MECHLORETHAMINE,
MELPHALAN
o Nitrosoureas: CARMUSTINE (BCNU
), LOMUSTINE (CCNU)
o Others: BUSULFAN, DACARBAZINE, PROCARBAZINE,
TEMOZOLAMIDE

 Platinum analogues: CARBOPLATIN, CISPLATIN, OXALOPLATIN

 Antibiotic: MITOMYCIN

MECHLORETHAMINE was the 1st alkylating agent to be used clinically. It is a derivative

of mustard gas, a chemical warfare agent developed during World War I. Physicians treating
soldiers realized that bone marrow suppression was a problem in people who managed to survive
the initial vesicant effects.

There are many more alkylating agents than are included on your
list of "drugs that you need to know".

Many alkylating agents have specific therapeutic uses e.g.,

 thiotepa for breast and ovarian cancer

 TEMOZOLAMIDE for brain cancers remember your last Neuro PBL case!

Review on general pharmacology of antitumor antibiotics

Antibiotics: CYCLOSPORINE, EVEROLIMUS, TACROLIMUS,

TEMSIROLIMUS
Immunosuppressive antibiotics are used to prevent rejection following
bone marrow transplants (CYCLOSPORINE, TACROLIMUS) and as
angiogenesis inhibitors (EVEROLIMUS, TEMSIROLIMUS).  These drugs
are involved in 2 pathways that are involved in cell proliferation: 
1) NFAT-mediated regulation of interleukin synthesis and 2) mTOR
regulation of cell growth and angiogenesis. 

Mechanisms of action

 immunosuppressive antibiotics interfere with intracellular processes that

are key for cell proliferation and cytokine production and release

 the 1st step in the process that leads to IL-2 mediated cell proliferation is
activation of receptor tyrosine kinases (RTKs) - see also the
discussion under tyrosine kinase inhibitors
o immunosuppressive antibiotics do not interfere with this process;

they interfere with one of two intracellular signaling cascades

Antirejection

Pathway 1

 bind to cytoplasmic proteins and inhibit calcineurin

o CYCLOSPORINE binds to cyclophilin
 o TACROLIMUS binds to FK-binding protein

 calcineurin is necessary for activation of NFAT, a T cell-specific

transcription factor that is involved in the synthesis of interleukins by
activated T cells → decreased release of IL-2 → decreased activation of
IL-2 receptor → decreased cell proliferation

Anti-angiogenesis and anti-proliferation

Pathway 2

 receptor tyrosine kinases can also increase expression of mTOR, an

intracellular signaling molecule that increases cell division, increases
bioenergetics, and facilitates angiogenesis in many cell types
(see angiogenesis inhibitors)

 therefore, EVEROLIMUS and TEMSIROLIMUS also function as mTOR

inhibitors

N.B. A 3rd pathway for regulation of growth

factor/cytokine expression is shown on the diagram

o the Ras/Raf/Mek pathway is the target of one of the signal

transduction inhibitors that blocks angiogenesis (SORAFENIB)

Review on general pharmacology of topoisomerase inhibitors

II. Intercalating agents: ANTHRACYCLINE

ANTIBIOTICS
Mechanism

 primary mechanism: intercalation in major groove of DNA causing

several cytotoxic actions:
o inhibition of topoisomerase II
o single- and double-strand breaks (mutagenic) or sister chromatid
exchange (carcinogenic)

 secondary mechanisms:
 ointeract with cell membranes to alter fluidity and ion transport
oin the presence of NADPH, they react with cytochrome P450
reductase to form superoxide anion radicals à may also
cause unique cardiotoxicity
 CELL CYCLE NON-SPECIFIC (CCNS), but maximal toxicity in S
phase (at low concentrations will pass through S and die in G2)

Types (by chemical classification)

 all of the intercalating agents are anthracycline

antibiotics ("RUBICIN"s)
 the most clinically important
is DOXORUBICIN (one of the most widely used
antineoplastic drugs)
o others
include DAUNORUBICIN, EPIRUBICIN, EPIRUBICIN and MITO
XANTONE
 the other anthracyclines have identical properties but specific therapeutic
uses

Cell-Cycle Nonspecific Chemotherapy Facts

 Kill cancer cells at all phases of the cell cycle, including the resting phase.
 These medicines work best when given in a “bolus dose.” A bolus dose is a large dose, given
over a short period of time. For example, the dose may be given once over 20 minutes.
 The cells don’t always die right away. A cell may have to go through several cycles of
chemotherapy before it dies.
 Repeat doses of chemotherapy may be given to continue to kill cancer cells.

Cell-Cycle Specific Chemotherapy Facts

 These medicines are often given more than one time. This gives the chemotherapy the best
chance to kill as many cells as possible.
 They may be given in “divided doses” or given multiple times. For example, once a day for 5
days, or every 3 hours for 4 doses.
 They can also be given as a nonstop infusion. This is an infusion that runs for several hours or
more. Some chemotherapy infusions are given over several days.  

·         Review on general pharmacology of mitotic spindle agents

DRUGS THAT INTERRUPT MITOSIS

(antimitotics, spindle poisons)
Chemical Types

Plant alkaloids

I. Vinca alkaloids: VINBLASTINE, VINCRISTINE,
VINORELBINE (there are others)

II. Taxanes: CAPAZITAXEL, DOCATAXEL, PACLITAXEL (there are others)

Antibiotic

III. Epilone: IXABEPILONE

The vinca alkaloids (VINCRISTINE and VINBLASTINE), the taxanes

(PACLITAXEL) and the epilones (IXABELPILONE) are CCS drugs (M
phase) that act as mitotic spindle poisons.  Despite their structural
similarity, VINCRISTINE and VINBLASTINE have significantly different uses
and toxicities.

I. Vinca alkaloids: VINBLASTINE, VINCRISTINE,

VINORELBINE

Mechanism

 bind to tubulin at the forming end of

microtubules and TERMINATE (disrupt)
spindle assembly
o compared to normal cells (A,B), cells treated
with vinca alkaloids show significant
malformations in the mitotic spindle, including
misalignment of chromosomes due to
shortening of the spindle (C,D) and
misorganization of the centrosome (E,F)
o figure shows results
of VINBLASTINE treatment

 among all vinca alkaloids (there are others in addition

to VINBLASTINE and VINCRISTINE), minor changes in structure can
result in significant changes in toxicity and anti-tumour activity

II. Taxanes: CAPAZITAXEL, DOCATAXEL, PACLITAXEL

Mechanism
historical view of PACLITAXEL development

 bind to tubulin and ENHANCE AND STABILIZE spindle assembly

o compared to normal cells (left), cells treated with PACLITAXEL (right) show
significant malformations in the mitotic spindle, and in cytoskeleton formation

III. Epilone: IXABEPILONE
 antibiotic that binds to tubulin and ENHANCES AND
STABILIZES spindle assembly (similar to PACLITAXEL)

Treatment with vinca alkaloids and taxanes commonly leads to the

development of multi-drug resistance, due to increased expression of
P-glycoprotein.  IXABEPILONE does not produce MDR, and is
therefore approved for use in breast cancer patients who have failed
anthracycline antibiotic and taxane treatments.

 used in combination with CAPECITABINE for the treatment of

metastatic breast cancer following treatment failure with
an anthracycline antibiotic and PACLITAXEL (i.e., it is a 3rd line
treatment)

 metabolized in the liver

 causes bone marrow suppression (esp. neutropenia), peripheral

neuropathy and cardiac arrhythmias

 can also produce hypersensitivity reactions

·         Review on general pharmacology of adrenocorticosteroid and antiestrogen

Principles of anti-hormone chemotherapy

 some tumours are dependent on steroid hormones for their growth

 most steroid-sensitive cancers have specific receptors:
o prednisone-sensitive lymphomas
 o androgen-sensitive prostate cancers
o estrogen-sensitive breast cancers

 reducing steroid hormone concentrations can be effective treatment

o in the case of prostate cancer, this approach is called androgen
deprivation therapy --- or ADT
 all drugs that work by decreasing testosterone concentrations
cause impotence, decreased libido, hot flushes, muscle
wasting and decreases in bone density
o don't forget about corticosteroids in this context --- these drugs are
useful in the treatment of acute leukemia, lymphoma, multiple
myeloma and other hematologic malignancies, as well as advanced
breast cancer

 can biopsy for steroid receptor content and predict the benefits of a
particular therapy

I. Decrease steroid concentrations:

a. Inhibit LH and FSH secretion

i. GnRH analogues: GOSERELIN,, LEUPROLIDE

ii. GnRH antagonists: DEGARELIX

b. Androgen biosynthesis inhibitors:

i. 5α reductase inhibitors: DUTASTERIDE, FINASTERIDE

ii. 17α hydroxylase inhibitor: ABIRATERONE ACETATE

c. Aromatase inhibitors: AMINOGLUTETHIMIDE, ANASTROZOLE,

LETROZOLE, EXEMESTANE

II. Antagonize receptors:

a. Anti-androgens: BICALUTAMIDE, FLUTAMIDE

b. Anti-estrogens: FULVESTRANT, RALOXIFENE, TAMOXIFEN,

TOREMIFENE

 Review on the biologic effects of monoclonal antibodies.

Mode of action of monoclonal antibodies. (A) Ligand blockade with antibodies will prevent
ligands from activating their cognate receptors. (B) Signal transduction by ligands may also
be blocked by antibodies that target the cognate receptors and inhibit their activation and
function. (C) Ab binding can also result in receptor internalization and downregulation. (D)
In contrast, antibodies may act as agonists for specific receptors and induce activation
signals. (E) Antibody-drug conjugate (ADCs) use the Ab's specificity to precisely deliver the
payload drug (a radio/chemotherapeutic, antibiotic or cytokine) to the target cell. (F)
Binding of antibodies to surface antigens can result in cell depletion via Ab-dependent cell
cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and opsonophagocytosis.
ADC, antibody-drug conjugate; FcγR, Fcγ receptor; MAC, membrane attack complex. 

Drug development trials (phase I, Phase II, Phase III, meta-analysis)

 Phase 1 : check safety obat, mencari dosis yang pas untuk manusia, di check
ke orang sehat. Maksimal 50 sample

Phase 2 : check efektifitas obat pada orang sakit , kriteria inklusi ketat dan
terbatas smaple 50-100

Phase 3: harus ada kontrol dan blind (single blind (pasien ga tau clinical trial),
double blind (dokterdan pasien ga tau) , triple blind (dokter , pasien dan ahli
statistik ga tau)

3a. klinis kontrol : inklusi harus lebih luas dari fase 2, dilakukan oleh 1 specialis
ex kalau kanker di check oleh dr oncologi,

3b. inklusi sama ekslusi lebih besar lagi dan di lakukan oleh lebih banyak
spesialis

phase 4: obat sudah di keluarkan dan baru di sruvey hasilnya , tujuan untuk
mencari efek samping dan menyakinkan efektifitas

metaanalysis : sudah pasti dan terbukti

3. Response to treatment (complete remission, partial remission, minimal

remission, progression, stable disease)
4. Palliative care and end of life