1.

SITOSTATIKA
= ONKOLITICA (Yun. kytos= sel, stasis= terhenti ongkos= benjolan, lysis=
melarutkan) adalah zat-zat yang dapat menghentikan pertumbuhan pesat dari
sel-sel ganas. Prinsipnya penggunaan obat-obatan untuk merusak langsung DNA
(dan RNA) sel. Senyawa ini mematikan sel-sel dengan menstimulir apoptosis.

2.
Chemotherapy
Treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by
stopping them from dividing. Chemotherapy may be given by mouth, injection, or infusion, or
on the skin, depending on the type and stage of the cancer being treated. It may be given
alone or with other treatments, such as surgery, radiation therapy, or biologic therapy.

3.
What is chemotherapy, and how does it work?
Chemotherapy is the use of medicines or drugs to treat a disease, such as cancer. Many
times this treatment is just called chemo. Surgery and radiation therapy remove, kill, or
damage cancer cells in a certain area, but chemo can work throughout the whole body.
Chemo can kill cancer cells that have metastasized (meh-TAS-tuh-SIZED) or spread to parts
of the body far away from the primary (original) tumor.
More than 100 chemo drugs are used in many combinations. A single chemo drug can be
used to treat cancer, but often multiple drugs are used in a certain order or in certain
combinations (called combination chemotherapy). Multiple drugs with different actions can
work together to kill more cancer cells. This can also reduce the chance that the cancer may
become resistant to any one chemo drug.
youll get treatment. All of these decisions will depend on the type of cancer, where it is, how
big it is, and how it affects your normal body functions and overall health.

What is the goal of chemo?

Depending on the type of cancer, its stage (how far it has spread), and where you are in the
treatment process, chemo can be used to:
Cure the cancer.
Keep the cancer from spreading.
Slow the cancers growth.
Kill cancer cells that may have spread to other parts of the body.
Relieve symptoms caused by cancer.

How will the chemo be given to me?

Into a vein
Most chemo drugs are put right into your bloodstream through a tiny, soft, plastic tube called
a catheter. A needle is used to put the catheter into a vein in your forearm or hand; then the
needle is taken out, leaving the catheter behind. This is called intravenous (INtruh-VEEN-us)
or IV treatment. Intravenous drugs are given in these ways:
The drugs can be given quickly through the catheter right from a syringe over a few
minutes. This is called an IV push.
An IV infusion can last from 30 minutes to a few hours. A mixed drug solution flows from a
plastic bag through tubing thats attached to the catheter. The flow is often controlled by a
machine called an IV pump.
Continuous infusions are sometimes needed and can last from 1 to 7 days. These are
always controlled by electronic IV pumps.
The needles and catheters can scar and damage veins with ongoing chemo. Another option
is the central venous catheter (CVC). The CVC is a bigger catheter thats put into a large
vein in the chest or upper arm. It stays in as long as youre getting treatment so you wont
need to be stuck with a needle each time. With a CVC, IV medicines can be given more
easily. Blood can also be drawn from CVCs.
Many different kinds of CVCs are available. Some are soft tubes that stick out of the skin
and require no needles. Another type is a port, which is like a small drum with a thin tube

going into the vein. Ports are permanently placed under the skin of the chest or arm during
surgery. Special needles are then stuck through the skin into the port to use it.

Other routes
Depending on the drugs and where the cancer is, chemo also may be given in one or more
of these ways:
Orally or PO This means by mouth. You swallow the chemo as a pill, capsule, or liquid
just as you do other medicines. This is usually more convenient because the chemo can
often be taken at home. If you take chemo drugs by mouth, its very important to take the
exact dosage, at the right time, for as long as youre supposed to do so. For more
information, please see Oral Chemotherapy: What You Need to Know.
Intrathecal or IT The chemo is put into the spinal canal and goes into the fluid that
surrounds your brain and spinal cord. This fluid is called the cerebrospinal fluid or CSF.
Chemo put into the CSF is carried throughout the brain and spinal cord. You may either have
a needle put right into your spine to quickly give the drug, or a longterm catheter and port
can be put under the skin on your head during surgery. This port is called an Ommaya
reservoir. The Ommaya is a small drum-like device that has a small tube attached to it. The
tube goes into the CSF in a cavity of your brain. The Ommaya stays in place under your
scalp until treatment is done.
Intra-arterial The chemo drug is put right into an artery to treat a single area (such as the
liver, an arm, or leg). This method helps limit the effect the drug has on other parts of the
body and is called regional chemo.
Intracavitary Chemo drugs may be given through a catheter into the abdominal cavity
(the space around the bowels and other organs in the belly; this is called intraperitoneal
chemo) or chest cavity (the space around the lungs and other organs in the chest).
Intramuscular or IM The drug is put in through a needle into a muscle (as an injection or
shot).
Intralesional A needle is used to put the drug right into a tumor in the skin, under the skin,
or in an internal organ.
Topical The drug is put right on an area of cancer on the skin as a cream, gel, or
ointment.

4.
Introduction In the early 1900s, the famous German chemist Paul Ehrlich set about
developing drugs to treat infectious diseases. He was the one who coined the term
chemotherapy and defined it as the use of chemicals to treat disease. He was also the first
person to document the effectiveness of animal models to screen a series of chemicals for
their potential activity against diseases, an accomplishment that had major ramifications for
cancer drug development. In 1908, his use of the rabbit model for syphilis led to the
development of arsenicals to treat this disease. Ehrlich was also interested in drugs to treat
cancer, including aniline dyes and the first primitive alkylating agents, but apparently was not
optimistic about the chance for success. The laboratory where this work was done had a
sign over the door that read,Give up all hope oh ye who enter.
Surgery and radiotherapy dominated the field of cancer therapy into the 1960s until it
became clear that cure rates after ever more radical local treatments had plateaued at about
33% due to the presence of heretofore-unappreciated micrometastases and new data
showed that combination chemotherapy could cure patients with various advanced cancers.
The latter observation opened up the opportunity to apply drugs in conjunction with surgery
and/or radiation treatments to deal with the issue of micrometastases, initially in breast
cancer patients, and the field of adjuvant chemotherapy was born. Combined modality
treatment, the tailoring of each of the three modalities so their antitumor effect could be
maximized with minimal toxicity to normal tissues, then became standard clinical practice (1
4).

5.
INTRODUCTION
The advent of modern-day cancer chemotherapy dates back to the mid-1900s when a
chemical warfare agent known as nitrogen mustard was seen to destroy the bone marrow
and lymph tissue of exposed individuals [1].In the following years, nitrogen mustard, along
with numerous other alkylating agents [2] took centre stage in the treatment of various
haematological malignancies including leukaemia, lymphoma, Hodgkins disease and
multiple myeloma. Several other serendipitous observations [3] lead to the development of
the rst primitive classes of cytotoxins (Figure 1).

6.

German chemist Paul Ehrlich- Coined

the term chemotherapy

Originally chemotherapy referred to treatment of disease with drugs or chemical

but by mid 1950s the term was only being used primarily in reference to drugs which
were used to treat cancer.

1943 - During World War II , soldiers were exposed to nitrogen mustard gas and
shows marked depletion in marrow and lymphoid cells.

Based on this finding, Alfred Gilman and Louis Goodman from Yale university
used Nitrogen Mustard to induced remission of Lymphoma in mice.

1948 - Sidney Farber showed that aminopterin, a folic acid analogue, developed
by Y. Subbarao can induced remission in acute lymphoblastic leukemia. Latter more
safer amethopterin (Methotrexate) was developed.

1950- Actinomycin D was developed as antibiotics, but found to be very toxic but have
significant antitumour activity.
1951 - Hitchings and Elion isolated 6-thioquanine and 6-mercaptopurine that inhibited
purine metabolism, which are widely used for various cancer and as immunosuppressant.

1970s

Golden

Age

of

medical

oncology.

Development of effective combination chemotherapy regimens.

New classes of drug developed - anthracyclines, platinum compounds .

Cures achieved in some forms of cancer (lymphomas, leukemias, testis cancer).

Significant responses in some common types of cancer (breast, stomach, small cell
lung cancer).

Effective use of chemotherapy to prevent recurrence in high risk breast cancer

patients.

Scientist continue to look for the magic bullet to eliminate cancer.

Nowdays research is being focused on specific agents that interfere with cell
division, as well as monoclonal antibodies, biologic modifiers, gene therapies, etc.

Goals of Chemotherapy
1. To cure : Wilms tumor, ALL, Testicular cancer, Burkitts lymphoma, NHL.
2. To control : Prolong remission, decreases rate of relapse.
3. Palliation : Relieve symptomps and improved quality of life.

Types of chemotherapy
1. Primary Chemotherapy

Chemotherapy is main modality of treatment

Can be single drug or combination chemotherapy

e.g. Hematological malignancy-

ABVD regimen for hodgkins lymphoma.

2. Adjuvant Chemotherapy

Combined with radiation or surgery.

For advanced cancer

e.g. Ca breast After surgery to remove microscopic foci.

3. Neoadjuvant chemotherapy

Chemotherapy is given before surgery.

Shrink a large cancerous tumour to make surgery easy.

e.g. laryngeal carcinoma before surgery.

4. Concurrent chemotherapy

Simultaneously with Radiation.

mainly act

as

radiation sensitizer, encourages the cancer cells to take

radiotherapy.

e.g.Head and neck CA, rectal CA, lung CA

Basic concepts of cancer cell growth

Cell life cycle and drug

Log kill hypothesis

Growth fraction

Tumour burden

PRINCIPLES OF COMBINATION THERAPY

Combination therapy involves the use of two or more drugs proven effective against a
tumor type.
Major advances in cancer treatment in the past 20 years.

Rationale of Combination Chemotherapy

Prevention of resistant clones.

Cytotoxicity to resting and dividing cells

Biochemical enhancement or effect Synergistic effect

Combination therapy is superior to single-drug therapy in terms of:

Higher tumor response rates.

Increased duration of remissions.

Minimal chances of resistance.

Principles for selecting drugs for combination regimens

Active as single agents
Different mechanism of action
Different dose limiting toxicity
Used at optimal dose and schedule
Given at consistent interval
Different resistance mechanism
Drugs with known synergistic biochemical interaction
Cell kinetics scheduling: on basis of cell cycle specificity / non specificity of drugs
and phase of cycle at which drug exert toxicity.

7.
History of Chemotherapy

Era of modern chemotherapy began in early 1940s

Goodman and Gilman first administered nitrogen mustard to patients with

lymphoma

nitrogen mustard was developed as a war gas rather than as a medicine

toxic effects on the lymphatic system led to clinical trials

Chemotherapy

Chemotherapy attacks tumors at the cellular level by interrupting processes or

inhibiting substances necessary for cellular replication and life

During the cell cycle, there is replication of the entire genome and division of the cell
into genetically identical daughter cells

Goals of Cancer Chemotherapy

Cure

Prolong survival

Palliation

Radiosensitive

G1 phase: cell prepares for DNA synthesis

S phase: cell generates complete copy of genetic material

G2 phase: cell prepares for mitosis

M phase: replicated DNA is condensed and segregated into chromosomes

G0 phase: resting state

Cell cycle phase specific

agents with major activity in a particular phase of cell cycle

schedule dependent

Cell cycle phase nonspecific

agents with significant activity in multiple phases

dose dependent

8.
Q: What is chemotherapy? A: Chemotherapy is the use of drugs to kill or slow the growth of
cancer cells.
Chemotherapy drugs are also called cytotoxics, which means poisonous (toxic) to cells
(cyto).
Many of these drugs are obtained from natural sources such as plants, while others are
completely developed in the laboratory. There are many types of chemotherapy drugs, which
are often used in different combinations and at different strengths.
Q: How does it work? A: Most chemotherapy drugs enter the bloodstream and travel
throughout the body to reach cancer cells in different organs and tissues.

Chemotherapy drugs target and injure rapidly dividing cells, but because it is not cancer
specific, both cancer cells and some normal cells are affected. When normal cells are
damaged, this can cause side effects (see pages 2745).
Cancer cells dont repair easily, so they recover more slowly than normal cells. By the time
your next treatment starts, your bodys normal cells have recovered but the cancer cells
have not. This means that more cancer cells are destroyed with every treatment.

9.
Origin of the word cancer
The origin of the word cancer is credited to the Greek physician Hippocrates (460-370 BC),
who is considered the Father of Medicine. Hippocrates used the terms carcinos and
carcinoma to describe non-ulcer forming and ulcer-forming tumors. In Greek, these words
refer to a crab, most likely applied to the disease because the finger-like spreading
projections from a cancer called to mind the shape of a crab. The Roman physician, Celsus
(28-50 BC), later translated the Greek term into cancer, the Latin word for crab. Galen (130200 AD), another Greek physician, used the word oncos (Greek for swelling) to describe
tumors. Although the crab analogy of Hippocrates and Celsus is still used to describe
malignant tumors, Galens term is now used as a part of the name for cancer specialists
oncologists.

Evolution of cancer treatments: Surgery

Ancient physicians and surgeons knew that cancer would usually come back after it was
surgically removed. The Roman physician Celsus wrote, After excision, even when a scar
has formed, none the less the disease has returned.
Galen was a 2nd-century Greek doctor whose books were preserved for centuries. He was
thought to be the highest medical authority for over a thousand years. Galen viewed cancer
much as Hippocrates had, and considered the patient incurable after a diagnosis of cancer
had been made. His views set the pattern for cancer management for centuries.
Even though medicine progressed and flourished in some ancient civilizations, there was
little progress in cancer treatment. The approach to cancer was Hippocratic (or Galenic) for
the most part. To some extent the belief that cancer cannot be cured has persisted even into
the 21st century. This has served to fuel the fear people have of the disease. Some people,

even today, consider all cancer incurable and put off seeing a doctor until its too late for
optimal treatment.
Cancer treatment has gone through a slow process of development. The ancients
recognized that there was no curative treatment once a cancer had spread, and that
intervention might be more harmful than no treatment at all. Galen did write about surgical
cures for breast cancer if the tumor could be completely removed at an early stage. Surgery
then was very primitive with many complications, including blood loss. It wasnt until the 19th
and early 20th centuries that major advances were made in general surgery and cancer
surgery.
There were great surgeons before the discovery of anesthesia. John Hunter, Astley Cooper,
and John Warren achieved lasting acclaim for their swift and precise surgery. But when
anesthesia became available in 1846, the work advanced so rapidly that the next hundred
years became known as the century of the surgeon.
Three surgeons stand out because of their contributions to the art and science of cancer
surgery: Bilroth in Germany, Handley in London, and Halsted in Baltimore. Their work led to
cancer operations designed to remove the entire tumor along with the lymph nodes in the
region where the tumor was located.
William Stewart Halsted, professor of surgery at Johns Hopkins University, developed the
radical mastectomy during the last decade of the 19th century. His work was based in part
on that of W. Sampson Handley, the London surgeon who believed that cancer spread
outward by invasion from the original growth. (The general concept of the radical
mastectomy can be traced all the way back to Lorenz Heister, a German who wrote about
his ideas for mastectomy and lumpectomy in his book, Chirurgie, published in 1719).
Halsted did not believe that cancers usually spread through the bloodstream: Although it
undoubtedly occurs, I am not sure that I have observed from breast cancer, metastasis
which seemed definitely to have been conveyed by way of the blood vessels. He believed
that adequate local removal of the cancer would cure it if the cancer later appeared
elsewhere, it was a new process. That belief led him to develop the radical mastectomy for
breast cancer. This became the basis of cancer surgery for almost a century. Then, in the
1970s, modern clinical trials demonstrated that less extensive surgery is equally effective for
most women with breast cancer. Today, a radical mastectomy is almost never done and the
modified radical mastectomy is performed less frequently than before. Most women with
breast cancer now have the primary tumor removed (lumpectomy), and then have radiation
therapy.

At the same time Halsted and Handley were developing their radical operations, another
surgeon was asking, What is it that decides which organs shall suffer in a case of
disseminated cancer? Stephen Paget, an English surgeon, concluded that cancer cells
spread by way of the bloodstream to all organs in the body but were able to grow only in a
few organs. In a brilliant leap of logic he drew an analogy between cancer metastasis and
seeds that are carried in all directions, but they can only live and grow if they fall on
congenial soil.
Pagets conclusion that cells from a primary tumor spread through the bloodstream but could
grow only in certain, and not all, organs was an accurate and highly sophisticated hypothesis
that was confirmed by the techniques of modern cellular and molecular biology almost a
hundred years later. This understanding of metastasis became a key element in recognizing
the limitations of cancer surgery. It eventually allowed doctors to develop systemic
treatments used after surgery to destroy cells that had spread throughout the body so that
they could use less mutilating operations in treating many types of cancer. Today these
systemic treatments may also be used before surgery.
During the final decades of the 20th century, surgeons developed greater technical expertise
in minimizing the amounts of normal tissue removed during cancer operations. Like the trend
from radical mastectomy to lumpectomy, progress was also made in removing bone and soft
tissue tumors of the arms and legs without the need for amputation in most cases, and in
avoiding a colostomy for most patients with rectal cancer. This progress depended not only
on understanding cancer better as a disease and on better surgical instruments, but also on
combining surgery with chemotherapy and/or radiation.
Until near the end of the 20th century, diagnosing cancer often required exploratory surgery
to open the abdomen (belly) or chest so the surgeon could take tissue samples to be tested
for cancer. Starting in the 1970s, progress in imaging tests such as ultrasound (sonography),
computed tomography (CT scans), magnetic resonance imaging (MRI scans), and positron
emission tomography (PET scans) have replaced many exploratory operations. CT scans
and ultrasound can also be used to guide biopsy needles into tumors.
Today, doctors use instruments with fiberoptic technology and miniature video cameras to
look inside the body. Surgeons can operate using special surgical instruments through
narrow tubes put into small cuts in the skin. These instruments can be used to look and work
inside the abdomen (laparoscopic surgery) or chest (thorascopic surgery). A similar
instrument, the endoscope, can be used to remove some tumors in the colon, esophagus, or
bladder by entering through natural body openings such as the mouth or anus.

Less invasive ways of destroying tumors without removing them are being studied and/or
used. Cryosurgery (also called cryotherapy or cryoablation) uses liquid nitrogen spray or a
very cold probe to freeze and kill abnormal cells. Lasers can be used to cut through tissue
(instead of using a scalpel) or to vaporize (burn and destroy) cancers of the cervix, larynx
(voice box), liver, rectum, skin, and other organs. Radiofrequency ablation transmits radio
waves to a small antenna placed in the tumor to kill cancer cells by heating them.

Evolution of cancer treatments: Chemotherapy

During World War II, naval personnel who were exposed to mustard gas during military
action were found to have toxic changes in the bone marrow cells that develop into blood
cells. During that same period, the US Army was studying a number of chemicals related to
mustard gas to develop more effective agents for war and also develop protective measures.
In the course of that work, a compound called nitrogen mustard was studied and found to
work against a cancer of the lymph nodes called lymphoma. This agent served as the model
for a long series of similar but more effective agents (called alkylating agents) that killed
rapidly growing cancer cells by damaging their DNA.
Not long after the discovery of nitrogen mustard, Sidney Farber of Boston demonstrated that
aminopterin, a compound related to the vitamin folic acid, produced remissions in children
with acute leukemia. Aminopterin blocked a critical chemical reaction needed for DNA
replication. That drug was the predecessor of methotrexate, a cancer treatment drug used
commonly today. Since then, other researchers discovered drugs that block different
functions in cell growth and replication. The era of chemotherapy had begun.
Metastatic cancer was first cured in 1956 when methotrexate was used to treat a rare tumor
called choriocarcinoma. Over the years, chemotherapy drugs (chemo) have successfully
treated many people with cancer. Long-term remissions and even cures of many patients
with Hodgkin disease and childhood ALL (acute lymphoblastic leukemia) treated with chemo
were first reported during the 1960s. Cures of testicular cancer were seen during the next
decade. Many other cancers can be controlled with chemo for long periods of time, even if
they are not cured. Today, several approaches are available to improve the activity and
reduce the side effects of chemo. These include:
New drugs, new combinations of drugs, and new delivery techniques
Novel approaches that target drugs more specifically at the cancer cells (such as liposomal
therapy and monoclonal antibody therapy) to produce fewer side effects

 Drugs to reduce side effects, like colony-stimulating factors, chemoprotective agents (such
as dexrazoxane and amifostine), and anti-emetics (to reduce nausea and vomiting)
Agents that overcome multi-drug resistance (when the cancer doesnt respond to the usual
treatment drugs)
Early in the 20th century, only cancers small and localized enough to be completely removed
by surgery were curable. Later, radiation was used after surgery to control small tumor
growths that were not surgically removed. Finally, chemotherapy was added to destroy small
tumor growths that had spread beyond the reach of the surgeon and radiotherapist. Chemo
used after surgery to destroy any remaining cancer cells in the body is called adjuvant
therapy. Adjuvant therapy was tested first in breast cancer and found to be effective. It was
later used in colon cancer, testicular cancer, and others.
A major discovery was the advantage of using multiple chemotherapy drugs (known as
combination chemotherapy) over single agents. Some types of very fast-growing leukemia
and lymphoma (tumors involving the cells of the bone marrow and lymph nodes,
respectively) responded very well to combination chemo, and clinical trials led to gradual
improvement of the drug combinations used. Many of these tumors can be cured today by
appropriate combination chemotherapy.
The approach to patient treatment has become more scientific with the introduction of clinical
trials on a wide basis throughout the world. Clinical trials compare new treatments to
standard treatments and contribute to a better understanding of treatment benefits and risks.
They are used to test theories about cancer learned in the basic science laboratory and also
test ideas drawn from the clinical observations on cancer patients. They are necessary for
continued progress.

10.
Halstedian concepts of

cancer biology (1894)

Tumors spread in an orderly defined
manner

based

on

The Fisher (alternative) hypothesis of

tumor biology (1968)

There is no orderly pattern of tumor

cell dissemination.
Tumor cells traverse lymphatics by

mechanical

considerations.
Tumor cells traverse lymphatics to

embolization, challenging the merit

lymph nodes by direct extension,

supporting en bloc dissection.

The positive lymph node is an

of en bloc dissection.
The positive lymph nodes are an
indicator of a host-tumor relationship

indicator of tumor spread and is the

that

instigator of distant disease.

Regional lymph nodes are barriers

metastases,

to the passage of tumor cells.

Regional lymph nodes are

anatomic importance.
The blood stream

is

of

of
little

regional disease.
The extent and

nuances

rather

of

than

the

instigator of distant disease.

Regional
lymph
nodes

are

spread.
Regional

biological importance.
The blood stream is of considerable

importance in tumor dissemination.

Complex
host-tumor

lymph

nodes

are

of

interrelationships affect every facet

of

operation are the dominant factors

development

ineffective as barriers to tumor cell

significance as a route of tumor

dissemination.
A tumor is autonomous of its host.
Operable breast cancer is a local-

permits

of the disease.
Operable breast

systemic disease.
Variations in local-regional therapy

influencing patient outcome.

cancer

is

are unlikely to substantially affect

survival.

11.
Phases of the cell cycle
The cell cycle has 5 phases. Since cell reproduction happens over and over, the cell cycle is
shown as a circle. All the phases lead back to the resting phase (G0), which is the starting
point.
When a cell goes through the cell cycle, it reproduces 2 new identical cells. Each of the 2
cells made from the first cell can go through this cell cycle again when new cells are needed.
G0 phase (resting stage): The cell has not yet started to divide. Cells spend much of their
lives in this phase. Depending on the type of cell, G0 can last from a few hours to a few
years. When the cell gets a signal to reproduce, it moves into the G1 phase.
G1 phase: The cell starts making more proteins and growing larger, so the new cells will be
of normal size. This phase lasts about 18 to 30 hours.
S phase: The chromosomes containing the genetic code (DNA) are copied so that both of
the new cells formed will have matching strands of DNA. This phase lasts about 18 to 20
hours.

 G2 phase: The cell checks the DNA and gets ready to start splitting into 2 cells. This phase
lasts from 2 to 10 hours.
M phase (mitosis): The cell actually splits into 2 new cells. This phase lasts only 30 to 60
minutes.

Why the cell cycle matters

The cell cycle is important because many chemotherapy drugs work only on cells that are
actively reproducing (not cells that are in the resting phase, G0). Some drugs specifically
attack cells in a particular phase of the cell cycle (the M or S phases, for example).
Understanding how these drugs work helps oncologists predict which drugs are likely to
work well together. Doctors can also plan how often doses of each drug should be given
based on the timing of the cell phases.
Chemotherapy drugs cant tell the difference between reproducing cells of normal tissues
(like those that are replacing worn-out normal cells) and cancer cells. This means normal
cells are damaged along with the cancer cells, and this causes side effects. Each time
chemotherapy is given, it involves trying to find a balance between destroying the cancer
cells (in order to cure or control the disease) and sparing the normal cells (to lessen
unwanted side effects).

12.