Transcript phl_425_basis_of_cancer_chemotherapy

BASIS OF CANCER CHEMOTHERAPY
PHL 425
Dr. Mohamed M. Sayed-Ahmed
Clinical Strategies for Cancer Treatment
1- Surgery
2- Chemotherapy
3- Radiotherapy
4- Immunotherapy
5- Biological and targeted-therapy
6- Combined therapy
BASIS OF CANCER CHEMOTHERAPY
• CHEMOTHERAPY is the treatment of cancer using specific
chemical agents or drugs that are selectively destructive to
malignant cells and tissues.
• Chemotherapy is the systemic (whole body) treatment of
cancer with anticancer drugs. Broadly, most chemotherapeutic
drugs work by impairing mitosis (cell division), and effectively
targeting fast-dividing cell.
• This means that normal fast dividing cells such as those
responsible for hair growth and for replacement of the
intestinal epithelium lining are also affected.
• As chemotherapy affects cell division, tumours with high
GROWTH FRACTIONS (such as acute myelogenous leukemia
and the 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.
Cancer Chemotherapy and cell cycle
1- Cell-cycle non specific agents: are cytotoxic in any
phase of the cycle even on G0 phase and so are more
effective against large slowly growing tumors.
2- Cell-cycle specific agents: are cytotoxic on all phases
but not on cells out of the cycle (at G0 ) and so are
more effective against rapidly growing tumors. Work
better in combination than alone
3- cell-cycle Phase specific agents: act on specific phase
of the cycle
Cancer Chemotherapy and Cell Cycle
TYPES OF CLINICAL CHEMOTHERAPY
1- Adjuvant chemotherapy
Adjuvant chemotherapy (postoperative treatment)
refers to giving patients anti-cancer drugs after the
primary tumor has been removed by surgery or
Radiotherapy and there is no evidence that cancer
remains in the body.
The intent of adjuvant chemotherapy is to attack
microscopic cancer cells that remained after tumor
removal.
Types of cancer treatment used as adjuvant
therapy
1- Chemotherapy. Chemotherapy uses drugs to kill cancer
cells. Chemotherapy treats the entire body, killing cancer
cells, no matter where they may be located. Adjuvant
chemotherapy isn't helpful in all situations, so talk to your
doctor about whether this treatment is right for you and how
much of a benefit it may provide.
2-Hormone therapy. Some cancers are sensitive to
hormones. For these cancers, treatments to stop hormone
production in your body or block the effect of hormones on
your cancer may be helpful. Cancers that are commonly
hormone sensitive include breast, uterine and prostate
cancers. Your cancer will be analyzed to see if it's hormone
sensitive. If it is, you might benefit from hormone therapy.
Hormone therapy can be used in conjunction with surgery,
radiation or chemotherapy.
3- Radiation therapy.
Radiation therapy uses high-powered energy beams, such as X-rays,
to kill cancer cells. Radiation therapy can be given internally or
externally. Adjuvant radiation therapy focuses on the area around the
original cancer site to reduce the risk that cancer will recur in that area.
4- Immunotherapy.
Immunotherapy works with your body's own immune system to fight off
remaining cancer cells. Immunotherapy treatment can either stimulate
your body's own defenses or supplement them.
5- Targeted therapy.
Targeted therapy aims to alter specific abnormalities present within
cancer cells. For example, women with a type of breast cancer that
makes too much of a protein called human growth factor receptor 2
(HER2) may choose a targeted therapy drug that blocks the action of
that specific protein. These medications target the specific protein
within those cancer cells. More targeted therapies are under
development and may one day be available for use as adjuvant therapy
6- Stem cell transplant:
A stem cell transplant is the infusion of healthy stem cells
into your body. A stem cell transplant may be necessary if
your bone marrow stops working and doesn't produce
enough healthy stem cells. A stem cell transplant can help
your body make enough healthy white blood cells, red blood
cells or platelets, and reduce your risk of life-threatening
infections, anemia and bleeding.
Although the procedure to replenish your body's supply of
healthy blood-forming cells is generally called a stem cell
transplant, it's also known as a bone marrow transplant or an
umbilical cord blood transplant, depending on the source of
the stem cells. Stem cell transplants can use cells from your
own body (autologous stem cell transplant), or they can use
stem cells from donors (allogenic stem cell transplant).
2- Neoadjuvant (Primary) chemotherapy
•
Neoadjuvant chemotherapy (preoperative treatment), is the use of
anticancer drugs as the main form of treatment or as a treatment prior
to Surgery or Radiotherapy.
•
In some cases, the tumor may be so large that surgery to remove it
would destroy major organs or would be quite disfiguring. Primary
neoadjuvant chemotherapy may reduce the tumor size, making it
possible for a surgeon to perform a less traumatic operation.
•
Examples of cancers in which primary chemotherapy may be followedup with less extensive surgeries include: anal cancer, bladder cancer,
breast cancer, esophageal cancer, laryngeal cancer, osteogenic
sarcoma, and soft tissue sarcoma.
3- Induction Chemotherapy
• High-dose, usually combination, chemotherapy given with the
intent of inducing complete remission when initiating a curative
regimen. This term is usually applied to Hematologic
malignancies but is equally applicable to solid tumors.
4- Consolidation Chemotherapy
Repetition of the induction regimen in a patient who has
achieved a complete remission after induction, with the intent
of increasing cure rate or prolonging remission.
5- Intensification Chemotherapy
• Chemotherapy after complete remission with higher doses of
the same agents used for induction or with different agents at
high doses with the intent of increasing cure rate or remission
duration.
6- Maintenance Chemotherapy
•
Long-term, low-dose, single or combination chemotherapy in a patient
who had achieved a complete remission, with the intent of delaying
the re-growth of residual tumor cells.
7- Palliative Chemotherapy
• Is given without curative intent, but simply to control
symptoms, decrease tumor load and increase life expectancy in
a patient in whom cure is unlikely. For these regimens, a better
toxicity profile is generally expected.
8- Combination chemotherapy
• In most cases, single anticancer drugs cannot cure cancer
alone. The use of two or more drugs together is often a more
effective alternative. This approach is called combination
chemotherapy. Scientific studies of different drug
combinations help doctors learn which combinations work best
for various types of cancers.
Drug Schedule in combination chemotherapy
•
Initiate therapy with cycle-nonspecific drugs followed by cycle-specific drugs.
e.g. start with alkylating agents to reduce tumour bulk and recruit slowly dividing tumours
into DNA synthetic phase in which antimetabolites as Methotrexate and 5-Fluorouracil are
most active.
CAMF Protocol for Breast Cancer
Drug
Cyclophosphamide
Doxorubicin
Methotrexate
5-Fluorouracil
Dose
Day
Mg/m2
1
750
30
40
500
+
+
Repeated every 21 days
•
Comments:
- Cytoreduction with cell cycle phase-nonspecific agents on day 1.
- S-phase specific agents on day 8
- Methotrexate given before 5-Fluorouracil on day 8.
8
+
+
Kinetic Basis of Chemotherapy
The objective of cancer treatment is to reduce the tumor cell
population to zero cells. Chemotherapy experiments using
rapidly growing transplanted tumors in mice have established
the validity of the fractional cell kill hypothesis, which states
that a given drug concentration applied for a defined time
period will kill a constant fraction of the cell population,
independent of the absolute number of cells.
Regrowth of tumor occurs during the drug-free interval
between cycles. Thus, each treatment cycle kills a specific
fraction of the remaining cells. The results of treatment are
a direct function of (a) the dose of drug administered and (b)
the number and frequency of repetitions of treatment
Kinetic Basis of Chemotherapy
Most current chemotherapy regimens are based on
cytokinetic considerations and use cycles of intensive
therapy repeated as frequently as allowed by the tolerance
of dose-limiting tissues, such as bone marrow or
gastrointestinal tract.
The object of these cycles is to reduce the absolute number
of remaining tumor cells to zero (or less than one) through
the multiplicative effect of successive fractional cell kills. (For
example, given 99% cell kill per cycle, a tumor burden of
1011 cells will be reduced to less than one cell with six
cycles of treatment: [1011 cells] × [0.01]6 <1.)
Rationale for Combination Chemotherapy
•
Drugs effective as single agent against the particular tumor being
targeted should be selected.
•
Drugs with different mechanism of action should combined.
•
Drugs with different mechanism of resistance should be combined.
•
Drugs with different dose-limiting toxicities should be combined.
Rational for the use of combination chemotherapy
1-Synergistic cytotoxcicity
2-Independent cell kill
3-Decrease resistance