'Chemotherapy' is the use of chemical substances to treat disease. In its modern-day use, it refers primarily to
cytotoxic drugs used to treat
cancer.
In its non-
oncological use, the term may also refer to
antibiotics (''antibacterial chemotherapy''). In that sense, the first modern chemotherapeutic agent was
Paul Ehrlich's
arsphenamine, an arsenic compound discovered in
1909 and used to treat
syphilis. This was later followed by
sulfonamides discovered by
Domagk and
penicillin G discovered by
Alexander Fleming.
Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are the treatment of
autoimmune diseases such as
multiple sclerosis and
rheumatoid arthritis and the suppression of
transplant rejections (see
immunosuppression and
DMARDs).
History
Main articles: History of cancer chemotherapy
The first drug used for cancer chemotherapy was not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed to treat cancer, and drug development since then has exploded into a multi-billion dollar industry. The targeted-therapy revolution has arrived, but the principles and limitations of chemotherapy discovered by the early researchers still apply.
Principles
Cancer is the uncontrolled growth of
cells coupled with
malignant behavior: invasion and
metastasis. Cancer is thought to be caused by the interaction between
genetic susceptibility and environmental toxins.
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body - in other words, the body attacks its own cells. In contrast,
transplant rejection happens because a normal healthy human immune system can distinguish foreign tissues and attempts to destroy them. Also the reverse situation, called
graft-versus-host disease, may take place.
Broadly, most ''chemotherapeutic'' drugs work by impairing
mitosis (
cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed ''cytotoxic''. Some drugs cause cells to undergo
apoptosis (so-called "programmed cell death").
Unfortunately, scientists have yet to identify specific features of malignant and immune cells that would make them uniquely targetable (barring some recent examples, such as the
Philadelphia chromosome as targeted by
imatinib). This means that other fast dividing cells such as those responsible for
hair growth and for replacement of the
intestinal epithelium (lining) are also often affected. However, some drugs have a better
side-effect profile than others, enabling
doctors to adjust treatment regimens to the advantage of patients in certain situations.
As chemotherapy affects cell division, tumours with high ''growth fractions'' (such as
acute myelogenous leukemia and the aggressive
lymphomas, including
Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing
cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly.
Drugs affect "younger" tumors (i.e. more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumour cells, differentiation is typically lost, growth becomes less regulated, and tumours become less responsive to most chemotherapeutic agents. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include
radiation therapy (both
brachytherapy and
teletherapy) and
surgery.
Over time, cancer cells become more resistant to chemotherapy treatments. Recently, scientists have identified small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Research on
p-glycoprotein and other such chemotherapy efflux pumps, is currently ongoing. Medications to inhibit the function of
p-glycoprotein are undergoing testing as of June, 2007 to enhance the efficacy of chemotherapy.
Treatment schemes
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.
''Combined modality chemotherapy'' is the use of drugs with other
cancer treatments, such as
radiation therapy or
surgery. Most cancers are now treated in this way. ''Combination chemotherapy'' is a similar practice which involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.
In ''
neoadjuvant chemotherapy'' (''pre''operative treatment) initial chemotherapy is aimed for shrinking the primary tumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective.
''
Adjuvant chemotherapy'' (''post''operative treatment) can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of resistance developing if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fast-dividing, and therefore very susceptible.
''Palliative chemotherapy'' is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.
All chemotherapy regimens require that the patient be capable of undergoing the treatment.
Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required.
Types
The majority of chemotherapeutic drugs can be divided in to:
alkylating agents,
antimetabolites,
anthracyclines, plant
alkaloids,
topoisomerase inhibitors, monoclonal antibodies, and other antitumour agents. All of these drugs affect
cell division or
DNA synthesis and function in some way.
Some newer agents don't directly interfere with DNA. These include the new
tyrosine kinase inhibitor ''
imatinib mesylate'' (Gleevec® or Glivec®), which directly targets a molecular abnormality in certain types of cancer (
chronic myelogenous leukemia,
gastrointestinal stromal tumors).
In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.
Where available,
Anatomical Therapeutic Chemical Classification System codes are provided for the major categories.
Alkylating agents (L01A)
Main articles: Alkylating antineoplastic agent
Alkylating agents are so named because of their ability to add alkyl groups to many
electronegative groups under conditions present in cells.
Cisplatin and
carboplatin, as well as
oxaliplatin are alkylating agents.
Other agents are mechloethamine, cyclophosphamide, chlorambucil. They work by chemically modifying a cell's DNA.
Anti-metabolites (L01B)
Main articles: antimetabolite
Anti-metabolites masquerade as
purine ((azathioprine,
mercaptopurine)) or
pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the
cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.
Plant alkaloids and terpenoids (L01C)
These
alkaloids are derived from
plants and block cell division by preventing
microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are
vinca alkaloids and
taxanes.
Vinca alkaloids (L01CA)
Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (
M phase of the
cell cycle). They are derived from the
Madagascar periwinkle, ''Catharanthus roseus'' (formerly known as ''Vinca rosea''). The vinca alkaloids include:
★
Vincristine
★
Vinblastine
★
Vinorelbine
★
Vindesine
Podophyllotoxin (L01CB)
Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs,
etoposide and
teniposide. They prevent the cell from entering the
G1 phase (the start of DNA replication) and the replication of DNA (the
S phase). The exact mechanism of its action still has to be elucidated.
The substance has been primarily obtained from the
American Mayapple (''Podophyllum peltatum''). Recently it has been discovered that a rare
Himalayan Mayapple (''Podophyllum hexandrum'') contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained
recombinantively.
Taxanes (L01CD)
Taxanes are derived from the Yew Tree. Paclitaxel (Taxol®) is derived from the bark of the Pacific Yew Tree (''
Taxus brevifolia''). Researchers had found a much renewable source, where the precursors of Paclitaxel can be found in relatively high amounts in the leaves of the European Yew Tree (''
Taxus baccata''), and that Paclitaxel, and Docetaxel (a semi-synthetic analogue of Paclitaxel) could be obtained by semi-synthetic conversion. Taxanes enhance stability of microtubules, preventing the separation of
chromosomes during
anaphase. Taxanes include:
★
Paclitaxel
★
Docetaxel
Topoisomerase inhibitors (L01CB and L01XX)
Topoisomerases are essential
enzymes that maintain the
topology of DNA. Inhibition of type I or type II topoisomerases interferes with both
transcription and
replication of DNA by upsetting proper DNA
supercoiling.
★ Some type I topoisomerase inhibitors include ''camptothecins'':
irinotecan and
topotecan.
★ Examples of type II inhibitors include
amsacrine,
etoposide,
etoposide phosphate, and
teniposide. These are semisynthetic derivatives of
epipodophyllotoxins, alkaloids naturally occurring in the root of
American Mayapple (''Podophyllum peltatum'').
Antitumour antibiotics (L01D)
''See main article:
antineoplastic''
The most important immunosuppressant from this group is
dactinomycin, which is used in
kidney transplantations.
Monoclonal antibodies
Monoclonal antibodies work by targeting tumour specific antigens, thus enhancing the host's immune response to tumour cells to which the agent attaches itself. Examples are
trastuzumab (Herceptin),
cetuximab, and
rituximab (Rituxan or Mabthera).
Bevacizumab is a monoclonal antibody that does not directly attack tumor cells but instead blocks the formation fo new tumor vessels.
Hormonal therapy
Several malignancies respond to
hormonal therapy. Strictly speaking, this is not chemotherapy. Cancer arising from certain tissues, including the mammary and prostate glands, may be inhibited or stimulated by appropriate changes in hormone balance.
★
Steroids (often
dexamethasone) can inhibit tumour growth or the associated
edema (tissue swelling), and may cause regression of lymph node malignancies.
★
Prostate cancer is often sensitive to
finasteride, an agent that blocks the peripheral conversion of
testosterone to
dihydrotestosterone.
★
Breast cancer cells often highly express the
estrogen and/or
progesterone receptor. Inhibiting the production (with
aromatase inhibitors) or action (with
tamoxifen) of these hormones can often be used as an adjunct to therapy.
★ Gonadotropin-releasing hormone agonists (GnRH), such as
goserelin possess a paradoxic negative feedback effect followed by inhibition of the release of FSH (
follicle-stimulating hormone) and LH (
luteinizing hormone), when given continuously.
Some other tumours are also
hormone dependent, although the specific mechanism is still unclear.
Dosage
''Dosage'' of chemotherapy can be difficult: if the dose is too low, it will be ineffective against the tumor, while at excessive doses the toxicity (side-effects,
neutropenia) will be intolerable to the patient. This has led to the formation of detailed "dosing schemes" in most hospitals, which give guidance on the correct dose and adjustment in case of toxicity. In immunotherapy, they are in principle used in smaller dosages than in the treatment of malignant diseases.
In most cases, the dose is adjusted for the patient's ''
body surface area'', a measure that correlates with blood volume. The BSA is usually calculated with a mathematical formula or a
nomogram, using a patient's weight and height, rather than by direct measurement.
Delivery
Most chemotherapy is
delivered intravenously, although there are a number of agents that can be administered orally (e.g.
melphalan,
busulfan,
capecitabine). In some cases,
isolated limb perfusion (often
used in
melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used. The main purpose of these approaches is to deliver a very high dose
of chemotherapy to tumour sites without causing overwhelming systemic damage.
Depending on the patient, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an
inpatient or
outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the
Hickman line, the
Port-a-Cath or the
PICC line. These have a lower infection risk, are much less prone to
phlebitis or
extravasation, and abolish the need for repeated insertion of peripheral cannulae.
Harmful and lethal toxicity from chemotherapy limits the dosage of chemotherapy that can be given. Some tumours can be destroyed by sufficiently high doses of chemotheraputic agents. Unfortunately, these high doses cannot be given because they would be fatal to the patient.
Newer and experimental approaches
===
Hematopoietic stem cell transplant approaches===
Stem cell harvesting and autologous or allogeneic
stem cell transplant has been used
to allow for higher doses of chemotheraputic agents where dosages are primarily
limited by hematopoietic damage. Years of research in treating solid tumors, particularly breast cancer, with hematopoeitic stem cell transplants, has yielded little proof of efficacy.
Hematological malignancies such as
myeloma,
lymphoma, and
leukemia remain the main indications for stem cell transplants.
Isolated infusion approaches
Isolated limb perfusion (often used in
melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours.
The main purpose of these approaches is to deliver a very high dose
of chemotherapy to tumour sites without causing overwhelming 'systemic' damage.
(Unfortunately, while these approaches can be useful against solitary or limited
metastases, they are - by definition - 'not' systemic and therefore do not
treat distributed metastases or
micrometastases).
Specially targeted delivery mechanisms toward higher effective doses and reduced toxicity
Specially targeted delivery vehicles aim to increase effective levels of chemotherapy
for tumour cells while reducing effective levels for other cells. This should
result in an increased tumour kill and/or reduced toxicity.
Specially targeted delivery vehicles have a differentially higher affinity for
tumour cells by interacting with tumour specific or tumour associated antigens.
In addition to their targeting component, they also carry a payload - whether this
is a traditional chemotheraputic agent, or a radioisotope or an immune stimulating factor.
Specially targeted delivery vehicles vary in their stability, selectivity and choice of
target, but in essence they all aim to increase the maximum effective dose that
can be delivered to the tumour cells. Reduced systemic toxicity means that they
can also be used in sicker patients, and that they can carry new chemotheraputic
agents that would have been far too toxic to deliver via traditional systemic
approaches.
Nanoparticles
Nanoparticles have emerged as a useful vehicle for poorly-soluble agents such as
paclitaxel.
Abraxane, also known as nab-paclitaxel, was approved by the US
FDA in January 2005 for the treatment of refractory
breast cancer, and allows reduced use of the
Cremophor vehicle usually found in paclitaxel.
Minicells
Bacterially-derived minicells (MacDiarmid J.A. et al. (2007). "Bacterially Derived 400 nm Particles for Encapsulation and Cancer Cell Targeting of Chemotherapeutics" Cancer Cell 11, 431–445, May 2007) are a new approach to selectively delivering chemotherapy to target tumour cells, awaiting research trials in human subjects.
Minicells (aka. EDVs) are surrounded by a rigid and stable biological membrane. Therefore, unlike liposomes, the EDVs do not fall apart or leak and release the payload to non-target cells. This results in minimal to no toxicity from it's chemotheraputic payload.
Minicells can be readily packaged with a wide range of different anti-cancer drugs including :
Doxorubicin,
Paclitaxel,
Vinblastine,
5-Fluorouracil,
Irinotecan,
Cisplatin, recently developed drugs like mitotic inhibitors etc.
Minicells are 'specifically targeted' to the desired cancer cells in-vivo by virtue of a
bispecific antibody where one arm carries anti-minicell specificity and the other arm has specificity to a relevant tumor cell-surface receptor (e.g. EGFR, HER2/neu etc).
The minicells are then selectively absorbed into the cancer cells by
endocytosis.
Targeted minicells (aka. EDVs) have been shown to be very stable and
therapeutically effective in-vivo (tumor xenograft models and endogenous tumor dog model).
Most recently, studies in 60 rhesus monkeys have demonstrated the safety of high
dose minicells.
'Most importantly', minicells offer the potential to safely deliver extremely
high effective dosages of chemotherapy selectively to cancer cells. Even highly
chemotherapy-resistant tumor cells like
melanoma can be destroyed by sufficiently
high dose chemotherapy (as studies in isolated limb perfusion have demonstrated).
The problem is that such high doses of traditional chemotherapy cannot be given
systemically because the overwhelming side effects would cause serious harm or death
to the patient. Minicells offer a potential way to circumvent this important limitation
and allow for far higher effective doses of chemotherapy to be delivered to
tumor cells.
For recent publications on minicells :
Cell Cycle : Sept 1st, 2007
[
[1]]
Cancer Cell : May 14th, 2007
[
[2]]
For more general information on minicells :
New Scientist :
[
]
BBC :
[
[3]]
Washington Post :
[
[4]]
Australian Story :
[
[5]]
[
[6]]
Side-effects
The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):
★
Nausea and
vomiting
★
Diarrhea or
constipation
★
Anemia
★
Malnutrition
★
Memory loss
★ Depression of the
immune system, hence (potentially lethal)
infections and
sepsis
★
Hemorrhage
★
Secondary neoplasms
★
Cardiotoxicity
★
Hepatotoxicity
★
Nephrotoxicity
★
Ototoxicity
★
Death
Immunosuppression and myelosuppression
Virtually all chemotherapeutic regimens can cause depression of the
immune system, often by paralysing the
bone marrow and leading to a decrease of
white blood cells,
red blood cells and
platelets. The latter two, when they occur, are improved with
blood transfusion.
Neutropenia (a decrease of the
neutrophil granulocyte count below 0.5 x 10
9/
litre) can be improved with synthetic
G-CSF (
granulocyte-colony stimulating factor, e.g.
filgrastim, lenograstim, Neupogen, Neulasta).
In very severe ''myelosuppression'', which occurs in some regimens, almost all the bone marrow
stem cells (cells which produce
white and
red blood cells) are destroyed, meaning ''allogenic'' or ''
autologous''
bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the patient before the treatment, multiplied and then re-injected afterwards; in ''allogenic'' BMTs the source is a donor.) However, some patients still develop diseases because of this interference with bone marrow.
Nausea and vomiting
Nausea and
vomiting caused by chemotherapy; stomach upset may trigger a strong urge to vomit, or forcefully eliminate what is in the stomach.
Stimulation of the vomiting center results in the coordination of responses from the diaphragm, salivary glands, cranial nerves, and gastrointestinal muscles to produce the interruption of respiration and forced expulsion of stomach contents known as retching and vomiting. The vomiting center is stimulated directly by afferent input from the vagal and splanchnic nerves, the pharynx, the cerebral cortex, cholinergic and histamine stimulation from the vestibular system, and efferent input from the
chemoreceptor trigger zone (CTZ). The CTZ is in the area postrema, outside the blood-brain barrier, and is thus susceptible to stimulation by substances present in the blood or cerebral spinal fluid. The neurotransmitters dopamine and serotonin stimulate the vomiting center indirectly via stimulation of the CTZ.
The 5-HT
3 inhibitors are the most effective
antiemetics and constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. These drugs are designed to block one or more of the signals that cause nausea and vomiting. The most sensitive signal during the first 24 hours after chemotherapy appears to be 5-HT
3. Blocking the 5-HT
3 signal is one approach to preventing acute emesis (vomiting), or emesis that is severe, but relatively short-lived. Approved 5-HT
3 inhibitors include:
Dolasetron (Anzemet
®),
Granisetron (Kytril
®), and
Ondansetron (Zofran
®). The newest 5-HT
3 inhibitor,
palonosetron (Aloxi
®), also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment.
Another drug to control nausea in cancer patients became available in 2005. The
substance P inhibitor
aprepitant (marketed as Emend®) has been shown to be effective in controlling the nausea of cancer chemotherapy. The results of two large controlled trials were published in 2005, describing the efficacy of this medication in over 1,000 patients.
[1]
Some studies
[2] and patient groups claim that the use of
cannabinoids derived from
marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (
Tetrahydrocannabinol or THC) such as
Marinol may be practical for this application. Natural marijuana, known as
medical cannabis is also used and recommended by some oncologists, though its use is regulated and not everywhere legal
[7] and there is still lack of sufficient studies to prove its efficacy.
Other side effects
In particularly large tumors, such as large
lymphomas, some patients develop
tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect which can lead to death if left untreated.
A proportion of patients reports fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called
post-chemotherapy cognitive impairment, colloquially referred to as "
chemo brain" by patients' groups
[3]
Specific chemotherapeutic agents are associated with organ-specific toxicities, including
cardiovascular disease (e.g., doxorubicin),
interstitial lung disease (e.g., bleomycin) and occasionally
secondary cancer (e.g. MOPP therapy for Hodgkin's disease).
See also
★
Cancer
★
Gene therapy
★
Experimental cancer treatments
★
Chemotherapy regimens
★
Cancer Treatment Options
★
Safe Handling of Hazardous Drugs
References
1. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials, Gralla R, de Wit R, Herrstedt J, Carides A, Ianus J, Guoguang-Ma J, Evans J, Horgan K, , , Cancer, 2005
2. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. ''Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review.'' BMJ 2001;323:16-21. PMID 11440936.
3. Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. ''J Clin Oncol'' 2004;22:2233-9. PMID 15169812.
External links
★
American Cancer Society - Chemotherapy
★
Cancerbackup - Understanding Chemotherapy
★
Johns Hopkins Breast Cancer Center
★
The leukemia and lymphoma society
★
Video: What is Chemotherapy?
★
Chemocare.com chemotherapy drug information
★
Chemotherapy.com Educational and support information about chemotherapy and associated side effects
★
Starlight Starbright Children's Foundation "Coping with Chemo" developed by
Animax Entertainment
★ [http://www.chemobuddies.org - Online community that connects patients, caregivers and healthcare professionals to give and receive support from those who understand.
العربية
中国
Français
Deutsch
Ελληνική
हिन्दी
Italiano
日本語
Português
Русский
Español
