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FUN2: 10:00-11:00
Scribe: Brannon Heape
Wednesday, December 10, 2008
Proof: Ryan O’Neill
Dr. Johnson
Cancer Chemotherapy
Page 1 of 5
Oral cancer will be the main topic of discussion today.
I. Introduction [S1]: What is cancer? Uncontrolled cell growth.
a. Small Pox, TB, and other infections and viruses have been the paradigm of medical treatment.
b. We have no cures for genetic based diseases (Sickle Cell, etc.) and cancers fall into this realm. This is why
treating cancer has been so difficult.
c. The most effective treatment for cancer is the oldest also--surgery.
II. Objectives [S2]
III. Head and Neck Cancer [S3]
a. Carcinoma of the upper aerodigestive tract including the: nasal cavity, paranasal sinuses, nasopharynx, oral
cavity, hypopharynx, larynx, esophagus, and salivary gland.
b. Below the eye’s and above the collar bone.
IV. Worldwide Epidemiology [S4]:
a. Globally: 8th most common site of malignant tumors.
b. South/SE Asia: 1st or 2nd most common site for malignancy
i. 30-40% of all malignancy
c. US: 34,000 cases per year and 2-6% of all malignancy
i. This disparity is due to refrigeration and behavior. There are also genetic factors in cancer.
V. Risk Factors: [S5]
a. Cigarette smoking*, High alcohol consumption*, Chewing tobacco*, chewing of betal nuts (Asia)*, Industrial
chemical agents
i. (* means these are behavioral)
b. Human papilloma virus (particularly HPV16 and 18).
VI. Risk Factors [S6]: Smoking plus excess alcohol increases odds ratio 44-fold compared with non-smokers and
occasional drinkers.
VII. Alcohol as a Risk Factor [S7]:
a. Males: no more than 3 units per day
b. Females: no more than 2 units per day
c. Avoid binge drinking and have at least 2 alcohol free days per week
VIII. Alcohol as a Risk Factor [S8]: see chart in notes
a. One can of beer is 1.5 units. So only two beers is enough.
b. They are not sure what the mechanism is for alcohol-causing cancer.
i. Possibly due to the lifestyle of smoking and drinking.
IX. Head and Neck Cancer [S9]
a. Diagnosis: Can only be done by taking a tissue sample, staining it, and having a pathologist look at it.
i. There are many types of oral cancers.
b. Staging: to see how advanced the cancer is.
c. Treatment Options
i. Surgery: most effective treatment and oldest
ii. Radiation: 2nd most effective treatment
iii. Chemotherapy: least effective treatment; has been around since the Egyptians
d. The term chemotherapy was coined by Paul Ehrlich during the identification of agents that inhibited bacterial cell
growth and is now applied to use of cytoxic drugs used to treat cancer.
X. Head and Neck Cancer Symptoms [S10]
a. A lesion in the mouth that does not heal within two weeks
b. A lump or thickening in the cheek
c. A white (leukoplakia) or red patch (erythroplasia) on the gums, tongue, tonsil, or lining of the mouth
d. A sore throat or a feeling that something is caught in the throat
e. Difficulty chewing or swallowing
f.
Difficulty moving the jaw or tongue
g. Numbness of the tongue or other area of the mouth (*oral cancer is treated well because it can be diagnosed
in early stages; compared to pancreatic cancer where usually once you diagnose it it’s too late)
h. Swelling of the jaw that causes dentures to fit poorly or become uncomfortable
XI. Head and Neck Cancer Diagnosis – Histopathology [S11]: *Only pathologists can diagnose cancer!
a. Incisional or Punch biopsy: the area where the plug was removed will not bleed much, and heals normally
without the need for any stitches since it’s so small.
b. Oral CDx: in a recent study of 945 patients, Oral CDx detected all cases of oral cancer correctly, even when
dentists didn’t suspect the presence of cancer from the presence of the lesion.
i. No pain or bleeding and requires no anesthetic. Has 100% effectiveness.
FUN2: 10:00-11:00
Scribe: Brannon Heape
Wednesday, December 10, 2008
Proof: Ryan O’Neill
Dr. Johnson
Cancer Chemotherapy
Page 2 of 5
XII. Diagnosis (pictures) [S12, 13, 14, and 15]: read directly off notes
a. Case 1
b. Case 2
c. 1 and 2 look very different but both are Squamous Cell Carcinoma: a carcinoma arising in flat epithelial cells.
They are puffy and red. Have to take to a pathologist to confirm that it is cancer.
d. Case 3: white plaque on the gum but it is a aspirin burn
e. Case 4, 5, 6, 7, and 8 are all cancer.
f. Metastasis means the cells break away and take root elsewhere in the body. Once this has happened surgery
isn’t possible and chance of survival decreases dramatically.
XIII. Principles of Cancer Treatment [S16]
a. Staging (Solid Tumors)
i. T – size of primary tumor (T1-T4)
ii. N – involvement of regional lymph nodes (N1-N3); an N of 0 is the best meaning it hasn’t spread yet.
iii. M – whether distant metastases are present (M0-M3)
b. TNM values are tumor-specific
c. Overall staging is based on TNM values, usually stage I – IV
d. Results of the staging determine:
i. Type of treatment (modalities)
ii. Goal of treatment (cure vs. palliation)
iii. They know now that certain types of drugs work best at certain times of cancer development.
e. Early detection results in 80-90% cure
XIV.
Staging [S17]
Stage:
Extent of Disease
Treatment Modalities
I
Localized
Surgery/radiation
II/III
Local or regional spread
Surgery/radiation/ chemotherapy
IV
Distant metastasis
Chemotherapy
XV. Brief History [S18]
a. 1950 – 1990 Tripod Treatment Regimens Developed
i. Surgery, Radiation, Chemotherapy: the first chemotherapy drugs were introduced in the early 50’s.
b. 1987 – Introduction of PCR; we realized in the 80’s that cancer was a genetic problem (due to tumor
suppressors and oncogenes) and that you couldn’t catch it from someone.
c. 1990 – Present: Human Genome Project, Molecular Basis of Cancer, Rational Design of Chemotherapy drugs
i. Then a whole new class of drugs came out that specifically target certain molecular structures in a tumor.
For example, Herseptin specifically targets a receptor that is over-expressed on many tumor cells.
XVI.
Graph [S19]: graph showing that when PCR came about in was about 10 years later that we saw a huge
expansion of new drugs.
a. Nitrogen Mustard: “nerve gas”; they gave this to patients because it is an alkylating agent that kills tumor cells
by alkylating DNA and inhibiting the rapid division of cancer cells.
b. The problem with alkylating agents is that they aren’t specific for cancer cells and also harm rapidly dividing
human cells like WBC’s, hair follicles, and others.
XVII. Principles of Chemotherapy [S20]
a. Skipper’s Law: found out that chemotherapy drugs were under 1st order kinetics; this means that the number of
cells killed is proportional to the amount of the chemotherapy drug given.
b. Gomptertizian: human tumors follow non-linear growth curves – most drugs are better against actively dividing
cells.
i. Gomptertizian was studying population growth in cities and found that when you looked at a city with
minimal infrastructure you saw little growth. But when you build roads and stuff you see exponential growth.
Then when you get a population that outgrows its resources it will move on. This mathematical formula also
explains how cancer growth occurs.
c. Goldie-Colman Hypothesis: said that tumors are not clonal.
d. You want to administer chemotherapy drugs when the cells are in exponential growth.
e. You can’t visualize a cell until it is at the 10^9 level. Removing it during surgery and then giving chemo after is to
prevent the tumor from growing back.
f. 3 types of Chemotherapy to treat Squamous Cell Carcinoma:
i. Alkylating agents,
ii. Antimetabolite drugs,
iii. Vinca alkaloids.
FUN2: 10:00-11:00
Scribe: Brannon Heape
Wednesday, December 10, 2008
Proof: Ryan O’Neill
Dr. Johnson
Cancer Chemotherapy
Page 3 of 5
g. We discovered that giving two chemo drugs together with each having a different mechanism of action is the
best way to treat because they have an additive effect and if you’re very lucky they may have a synergistic
effect.
h. Chemotherapy fails because of resistance to dose limiting toxicity (DLT). You can’t kill the patient.
XVIII. Skipper’s Law’s – 60’s Mouse Model’s [S21]: you give chemotherapy in cycles.
a. Doubling time of proliferating cancer cells is constant (L1220 cells leukemia cell line)
b. Death results when malignant cells reach a critical number or fraction of the mouse body weight
c. Survival is a function of the number of tumor cells injected
d. Cell kill by chemotherapy follows first-order kinetics (% of cells killed at a given dose is constant, regardless of
tumor size)
XIX.
Log-Kill Hypothesis [S22]:
a. The number of cells killed is proportional to dose.
b. Chemotherapy follows an exponential or log-kill model – a constant percentage of cells are killed regardless of
tumor size
c. Tumor cells will reaccumulate between chemotherapy doses
d. Chemotherapy can never completely reduce the tumor burden to zero. As soon as you stop chemo the tumor
cells will come back rapidly.
e. If you have a tumor that is 10^10 cells and you will 99% of them you still have 10^8 cells. This shows how
difficult it is to kill cancer cells and prevent them from coming back.
f. “Remission”: people going into remission means that the tumor is shrinking or the disease is lessening,
eventually tumors become resistant to chemo drugs though.
i. Cancer free is not the same as remission. Oncologists are very leery of the term “cancer free”.
XX.
Gompertzian Cell Growth [S23]:
a. Human tumors follow a non-linear growth curve
b. Growth fraction decreases as tumor size increases
c. Growth rate is initially rapid, then flattens out
d. Slowing of growth rate due to tumor outgrowing blood and nutrient supply
e. Implications for chemotherapy:
i. Most drugs are better against actively dividing cells or cells in S phase. Almost all work by interfering with
DNA replication or synthesis.
ii. Tumors are most sensitive when tumor is small and growth fraction is high.
iii. Give aggressive therapy as early as possible, when the tumors are growing rapidly.
XXI.
Goldie-Coldman Hypothesis – [S24]:
a. Based on the assumptions:
i. Tumors have an inherently higher mutation rate vs. normal cells. Tumors are not clonal, the bigger the
tumor is the more variation of cell type there will be in it. In each you will have cells that are susceptible to a
drug and cells that are resistant to the drug.
ii. With progression, there appears to be a continued increase in mutation rate
b. Probability of resistance cells depends on tumor size – Based on size of detectable tumors (109) and mutation
frequency (10-5) there may be as many as 104 resistant cells at time of diagnosis
c. 2 Types of Resistance:
i. Intrinsic: the cell won’t respond no matter what drug you put in.
ii. Acquired: cells will adapt to whatever environment you put them in. For example, if you grow cancer cells in
a low dose of drug they will become resistant to that drug within a few weeks.
XXII. Categories of Chemotherapy Drugs [S25]:
a. Alkylating Agents (oldest): drugs that work by directly reacting with the DNA of a cell. Most effective during DNA
synthesis. Administered orally or intravenously.
b. Nitrosoureas: similar to alkylating agents but inhibit DNA repair. Cross blood brain barrier. Administered either
orally or intravenously.
i. Primarily used for brain tumors since they can cross the blood brain barrier.
ii. Brain tumors are normally very resistant to chemotherapy drugs.
c. Antimetabolites: drugs that block DNA synthesis. Most effective during the S phase. Administered either orally
or intravenously.
i. These are derivatives of naturally occurring metabolites.
ii. 5-Fluro-uracil, a derivative of Uracil which is a building block for DNA replication, is an effective (3 rd most
used effective actually) cancer chemotherapy drug.
d. Antitumor Antibiotics: drugs that bind DNA to prevent replication or RNA synthesis. Administered intravenously.
e. Steroid Hormones: drugs that modify the growth of hormone dependent cancers. Common in treating breast and
ovarian cancers. Administered orally.
FUN2: 10:00-11:00
Scribe: Brannon Heape
Wednesday, December 10, 2008
Proof: Ryan O’Neill
Dr. Johnson
Cancer Chemotherapy
Page 4 of 5
f. Plant (Vinca) Alkaloids: prevent cell division by binding to tubulin. Prevent formation of mitotic spindles.
Administered intravenously.
XXIII. Current (2007) NCCN Guidelines [S26]:
a. This slide has a good website that tells you the current standard of care for any type of cancer. It has a flow
chart that is easy to follow.
b. What you can see here is that the primary treatment for oral cancer are the alkylating agents
XXIV. Alkylating Drugs [S27]: oldest type
a. Nitrogen Mustards:
b. Nitrosureas: Temodar is a new one used for brain tumors and has less toxicity. It increased survival by 2 months
and this was considered very significant.
c. Etheylenimines
d. Alkyl Sulfonates
e. Triazines and others
XXV. Alkylating Drugs [S28]: are used for solid tumors. Bone marrow suppression is the dose limiting toxicity.
a. Peoples white blood cell counts drop when given chemotherapy because they too are rapidly dividing cells. This
makes them more susceptible to infections.
b. DNA repair enzymes are how people become resistant to these.
XXVI. Platinums [S29]: notice the shape of them. These are not metabolized but instead attach to the DNA themselves
and transfer alkyl groups to guanine residues and causes crosslinking.
a. Mechanism of resistance for these is again DNA repair mechanisms.
XXVII. Antimetabolites [S30 and S31]: purine and pyrimidine analogues and folic acid antagonists.
a. They tested many different antimetabolites and found these are the most successful ones.
XXVIII. MTX and 5-FU Inhibit DNA Synthesis [S32]: the left has uracil and the right with 5-fluoro-uracil. The body
doesn’t know fluorine has been put in and it will follow the same pathway through the body.
a. He said he wouldn’t ask a detailed question from this but realize that here we gave two antimetabolites together.
Both, in one way or another, inhibited DNA synthesis.
XXIX. (Fluoro)pyrimidine Metabolic Pathway [S33]: this is just detail of how one drug, 5-FU, inhibits DNA synthesis.
a. Dihydropryimidine Dehydrogenase (DPD): 5-FU is broken down and eliminated by this enzyme. 85% of 5-FU is
rapidly broken down as soon as you administer it.
i. 5-FU can be incorporated into RNA, DNA, or it can form 4-deoxyuridinemonophosphate. When this 4deoxyuridinemonophosphate binds to thymidylate synthase (TS) it acts as a suicide inhibitor on the TS. It
shuts down TS and your rapidly dividing cells will die.
XXX. Plant (Vinca) Alkaloids [S34]: Taxanes are the ones used for Squamous cell carcinoma, particularly Paclitaxel
and Docetacel. These stimulate microtubule polymerization and inhibit mitosis. They are very effective when
given with antimetabolites because they work in M phase and antimetabolites work in S phase. So you want to
give drugs that have a different mechanism of action.
XXXI. Taxanes [S35]: these are examples of additive chemo drug combinations.
a. Remember that synergism is hard to attain.
XXXII. Combined Modality Approaches: [S36] combines chemotherapy with surgery, radiation in order to achieve the
best response.
XXXIII. Combination Chemotherapy [S37]:
a. Most drug combinations work in an “additive” way.
i. Cisplatin/fluorouracil
ii. Cisplatin/taxanes
b. Some drug combinations do demonstrate synergy (hard to attain however)
i. Cisplatin/topotecan
ii. Gemcitabine/platinum
1. Gemcitabine (antimetabolite) was originally very toxic but when given with platinum it was found to
be very efficient.
XXXIV. Why does Chemo fail? [S38]
a. Intrinsic vs. Acquired Resistance
b. MDR: multi drug resistance; if someone was given a particular chemo drug and they entered remission but then
got cancer again you would think you would give them the same drug again. However when you do this you see
no effect. If you give them a different drug you still see no response. It appears that tumors were pumping the
drugs out of the cells so it didn’t matter what class of drug you tried they wouldn’t give a response.
c. Increased deactivation can also cause resistance.
i. 5-FU example where it is broken down by DPD. Cancer cells will actually up-regulate DPD to increase
breaking down the 5-FU chemo drug.
FUN2: 10:00-11:00
Scribe: Brannon Heape
Wednesday, December 10, 2008
Proof: Ryan O’Neill
Dr. Johnson
Cancer Chemotherapy
Page 5 of 5
ii. Some patients also have a DPD defieciency. 5% of you in this class have this and will die if given 5-FU
because you cannot clear the drug.