CLASS: 10:00-11:00Scribe: Bo Bradford

DATE: December 9, 2010Proof: Ross Isbell

PROFESSOR: JohnsonCancer Chemotherapy IPage1 of 6

  1. CANCER CHEMOTHERAPY

II.OBJECTIVES

  1. How do you talk about cancer chemo in two hours?
  2. He could give us a list of drugs & tell us the mechanisms of action & so on and so forth but we’re not going to be prescribing these kind of drugs
  3. This lecture about chemotherapy will be about the concepts, how & why it’s delivered; this lecture will be more focused towards oral cancers which is a very rare type of cancer, which is extremely dependent about on the type of cancer you get; we can groups things together a little more in regard to oral cancer. What he’s going to tell us today is all true but there are many exceptions
  4. Cancer is over 100 diseases

III. HEAD & NECK CANCER

  1. In the head & neck area, we’re talking about everything b/t the eyes & collarbone & this is a tiny portion of the structures & tissues- for example, you can develop lip cancer via a squamous cell carcinoma on the lips
  2. Each structure is associated with a different treatment protocol
  3. To look up cancer treatment protocol go to nccn.org to find look up any type of cancer
  4. This website lists the most up to date guidelines which are completely accessible & written in flow charts; it also allows you to see all the other alternatives

IV.WORLD WIDE EPIDEMIOLOGY

a. in terms of head & neck cancers, globally it is a huge problem in southeast Asia

b. this is a classic example of how different demographics can effect specific types of cancer. What was

leading type of cancer 100 years ago in the US? Gastric cancer…which is now extremely rare due

due to refrigeration of meats in contrast to using nitrites & nitrates which are still common in Asia

c. these high levels of gastric cancer in Asia are environmental

d. In Asia, breast cancer numbers are much lower than in the US- current research suggests this is due to

the intake of Isoflavones. There are different components linked with cancer: environmental

components, behavioral components.

e. Oral cancers are much more prevalent in other countries of the world than it is in US

f. Of course the most common risk factor is chewing tobacco

V. RISK FACTORS

a. cigarette smoking, high alcohol consumption, chewing tobacco, & the chewing of betal nuts ( in Asia)

b. Also exposure to industrial agents & toxins

c. more recently there’s been a link b/t HPV (Human Pampilloma Virus) & oral cancers. There’s a link b/t

a lot of anti-cancer agents that were developed as anti-viral agents; strong link b/t cancers &

viruses

d. It’s only been in the last 25 years, That cancer has been recognized as a genetic disease. The bullets

listed with an * are mostly behavioral traits

e. but there are genetic components linked with oral cancer, but haven’t been well defined at all

VI. ALCOHOL AS A RISK FACTOR

  1. For males, no more than 3 drinks/ day (a beer is a unit)- females no more than 2
  2. If you drop below these levels, alcohol no longer becomes a risk factor

VII. RISK FACTORS

  1. Smoking & Drinking is an example of SYNERGY where alcohol & tobacco are both risk factors, but both alcohol & smoking combined with one another are greater than the sum of the parts
  2. Chemotherapy can work this way also, you can take two drugs- anti-cancer A & anti-cancer B- when you combine them they are more than additive. This is also called synergy, and smoking together with alcohol creates a significant increase in terms of your risk factor for developing oral cancer

VIII. HEAD & NECK CANCER

  1. symptoms of oral cancer depend upon the location, and there are a lot of locations
  2. symptoms can be attributed to many, many different things-almost all of us have had at least some of these symptoms listed at one time or another but this is one of the difficult things about diagnosing cancers.
  3. pancreatic cancer is one of the most lethal cancers (Arethra Franklin just diagnosed w/ disease) due to the fact that the symptoms, like head & neck cancers, mimic very common symptoms that people have: peptic stress, lower quadrant pain, can also be mistaken for indigestion. Pancreatic cancer also doesn’t image well, doesn’t show up well on a CT scan.
  4. when pancreatic cancer presents it’s always in the latter stages; if caught in time surgical procedures can be pursued. Arethra Franklin’s situation has been diagnosed early enough for surgical treatment, whereas 80% of others are not so lucky.
  5. The problem w/ head & neck cancers is that the symptoms mimic commonly occurring problems that a lot of people have.
  6. Do you diagnose cancer by just looking at it, can you tell by looking? NO YOU CAN’T-cannot tell by looking

IX. DIAGNOSIS

a. squamous cell carcinomas

b both of the pics can be mistaken for the common cold sore

X. DIAGNOSIS

a. white plaque highlighted on the picture to the left is actually an aspirin burn. The red lesion on the

tongue to the right is the same type of cancer that was previously shown on the lips but just

at a different location.

b. All cancer diagnosis is made by a HISTOPATHOLOGIST- you can never actually look at something & diagnose it as cancer- lesion must be examined via microscope. They must look at the morphology of the cells & study a sample of a tissue.

c. Most of us wont be diagnosing cancer, however we’ll be referring patients to a histopathologist

(possible test question***)

XI. HEAD & NECK CANCER

  1. after diagnosis, we then begin staging the cancer, this will dictate what our treatment options will be.
  2. Today, we have three current treatment options. The oldest, most effective treatment is SURGERY
  3. Newest & most effective is RADIATION, and lastly CHEMOTHERAPY. Chemotherapy was introduced 3000 years ago by the Egyptians in their usages of alkaloids- we didn’t invent chemotherapy
  4. Of the three treatment modalities: chemotherapy is the least effective

XII. HEAD & NECK CANCER

  1. diagnosis is extremely important
  2. these are some of the ways to collect biopsy; the mouth & head area have accessible tissue, you don’t have that with pancreatic cancer or brain cancer- you must perform surgery. In pancreatic cancer, definitive diagnosis can’t be made without endoscopy, which is an ultrasound guided fine needle endoscopy. This requires anesthesia, the puncturing of the duodenum, placing a tube down ones throat & obtaining duodenum sections. Afterwards you must aspirate the tissue back out & examine the sections on a slide via a pathologist. Very invasive & unpleasant experience.
  3. The advantage & the success in the treatment of head & neck tissue is attributed to accessibility of the tissue-you can get to it easily. Originally, if you look at the literature-anything a few years ago will talk about incision or punch biopsies. You take a small punch of the tissue, fix it & make slides of the tissue. This causes discomfort, local anesthetics must be used, and there is also healing time & a little soreness.
  4. Today, Punch biopsies are being replaced by laser biopsies where CO2 lasers are used that lessen pain & bleeding, sometimes might require local anesthetic. Laser biopsies are often dependent upon the type of tissue that you are examining.
  5. Oral CDx- looks like a toothbrush. Completely non-invasive; you take a scrubbing of the section of tissue of interest. He’s seen a study of 900 patients using this method and all provided accurate diagnosis. CDx is mainly utilized within oral cavity.
  6. Veloscope- new, modern diagnosis method, shines blue light on the tissue & has a special filter on it that directs light back towards you; if the light shines back at you red then the tissue is considered to be abnormal. So we’ve gone from performing punch biopsies in the early days to now examining via the Veloscope. However, the veloscope is not a definitive form of diagnosis-only tells us something is wrong. Dr. Johnson recommends using this Veloscope to establish there is a problem then referring the patient to a pathologist for biopsy.
  7. The listed bullets are in order of the most invasive (at the top of the page) down to the least invasive ( Veloscope).

XIII. PRINCIPLES OF CANCER TREATMENT

  1. 25 different types of head & neck cancers
  2. each cancer has a specific treatment regiment. If the tumor has been staged as this or that- this is your specific treatment regiment. He can’t go through all treatment scenarios so he just lumps them all together for us.
  3. there are only three drugs we need to worry about in the treatment of these cancers. Whether or not you receive the treatment/drugs or not depends solely upon the TMN score
  4. TMN- Tumor Nodal involvement
  5. No chemotherapy needed unless there is metastasis. The most effective treatment is when you can keep it locally- Use Surgery to cut it out & requires no medications, you can cure cancer. When you start getting nodal involvement & distant metastasis you have to treat systemically.
  6. Obviously if your in Stage one on the TMN level you have a very small tumor & in the early stages of cancer, no metastasis has taken place & you can have surgery to remove cancer- this is 80 to 90% curable. Cancer is rapidly found in the mouth area & rapidly cut out; this allows for low death incidence
  7. In Advanced or Recurrent disease, the treatment turns palative- no survival, fatal condition. Only trying to make patient more comfortable (Elizabeth Edwards case)

XIV. BRIEF HISTORY

  1. Discusses the evolution of chemotherapy
  2. at the turn of the century when we invented antibiotics, surgery was the only treatment option. For years, we looked for something to treat it in an antibiotical approach; we’re going to find a drug that we can use for treatment and it will kill only cancer cells. Needless to say this never happened after screening thousands of drugs. Scientists found they could only slow growth progression or be toxic to rapidly dividing cells.
  3. Cancer cells come from our own progenitor cells, genetically they are identical it’s just that different genes are turned on or off; ONCOGENES-turned on, TUMOR SUPPRESSOR GENES- turned off.
  4. depends on the type of cancer on what kind of mutations your dealing with, but they are targeting genes that are in different cells but the drugs are not specific for cancer cells.
  5. Why treat cancer with radiation-doesn’t this cause cancer? Alkylating agents are almost to a fault-carcinogenic. Radiation causes single & double stranded DNA breaks during the cell cycle & forces cells to freeze. Depending on the damage done the cells can undergo apoptosis or cause damage- thus this process is most toxic to rapidly dividing cells. Exposure to radiation causes hair loss, GI problems- both of these contain rapidly dividing cells which die first
  6. if you image the cancer well, & focus the beam tightly you can use radiation like surgery, you can focus an intense beam of radiation specifically on the tumor but you must have something that you image well.
  7. The last & least effective treatment for cancer was chemotherapy. The beginning of chemotherapy came along during WWI via nitrogen mustard gas. The Soldiers that survived had low white blood counts, and this mechanism of action wasn’t known but in 1940’s this was tested on Leukemia patients, for a brief period of time scientists received a tremendous response. This was the first time that drug caused improvements of cancer treatments. This is what led to the thinking that cancer was curable. Nitrogen mustard gas=ALKYLATING AGENT
  8. From the 1950’s 80’s this tripod of therapy came out: if it’s early and we can detect it before it’s spread-surgery is curative. Depending on the tumor type, if surgery is not possible we can use radiation. If metastasis is shown then chemotherapy should be utilized as a more systemic treatment option.
  9. In the 1980’s, we started recognizing cancer as a genetic disease. Then a technique called PCR was introduced & allowed scientists to distinguish the genetic differences b/t normal cells & cancer cells-this began a revolution in target therapy. So there was the concept that cancer cells are different than the normal surrounding cells & if we can find genes that are expressed & necessary for cancer survival and if those genes are targeted we can have more specific types of treatments (anti-cancer treatments).
  10. Next came the sequencing of the human genome and now we have over 33,000 genes that are regulated in many ways & we don’t know what a fraction of them actually do.
  11. Very small fraction of the genes are involved in cancer
  12. You can take genetic information and try to design a new drug, you can have un-anticipated toxicity that has a molecular basis, and you can try to stage patients to more effective treatments.
  13. There was a guy in the 80’s that would culture tumors & test them against a series of drugs to see which ones responded to the tumor & treated the patients with that specific drug. Sounds good, but the results within the culture don’t always match the results of in vivo; this was the problem he faced & why this technique isn’t really used.

XV. GRAPH

  1. development of anti-cancer drugs over the last 45 years
  2. first compound discovered= nitrogen mustard gas
  3. afterwards Cyclophosphamide, then Vincristine, Pacltaxel (introduced in the 1980’s). 5,4 Uracil was introduced in late 1940-early 1950’s.
  4. After PCR was discovered in 1980, around 1990 scientists started looking into targeted therapy & there was an explosion of new drugs that were introduced. The graph is only up to date through 2005. If he would’ve graphed it out to the present day, we would see that the curve plateaus off. This was the attempt of industries to introduce target therapies. The Grandfather of targeted therapy was Glevac (associated w/ the Philadelphia chromosome, you have two genes a PCR able gene & a chromosomal aberration-both genes come together & one is the PCR gene & the other is the able gene) which functions by constitutively turning on of only one tyrosine kinase which causes cell proliferation in a certain type of leukemia-chronic myelogenous leukemia. If you target this one gene product you actually cause regression in this one type of cancer; however this is the exception and not the rule. This is the one example were one gene defect can be attributed to a single type of cancer-usually this is NOT THE CASE* this is a very rare type of cancer. It was the poster child for specific/targeted therapies; since then we’ve had things like perceptin come out.
  5. Perceptin-identified in breast cancer & involved with gene amplification so it’s mechanism of action is completely different. In breast cancer cells you have more copies of Perceptin genes than you do inn normal cells surrounding it- so you can look for it via FISH. You can also look for increase numbers of DNA copies (this is the gold standard). In breasts you always look for estrogen, progesterone & perceptin; you look for receptors & this targets our therapies towards certain drugs or not. Most difficult breast cancer to treat is called Triple Negative where all the tests come out negative. As a result, treatment options in regard to chemotherapy are very limited.
  6. Right now for oral cancer, there are no molecular testing that is done or any specific biomarker that is looked at to guide therapy. Basically therapy is strictly guided based upon the TMN scoring of the biopsy obtained.

XVI. CHEMOTHERAPY

  1. The goal of chemotherapy is to kill tumor cells
  2. Again, there is no specificity with any chemotherapy agents. The medical oncologist balances how much chemotherapy agents he can give
  3. Must balance how much drug to give patient with host toxicity
  4. Almost no chemotherapy is given as only a single agent-this is not affective; chemotherapy is usually given with multiple drugs
  5. He again mentions the website URL cancer treatment guidelines

XVII. PRINCIPLES OF CHEMOTHERAPY

  1. summary of how every chemotherapy drug works
  2. Drugs are going to either interrupt DNA synthesis or function, disrupt pyriminidine/purine synthesis, or disrupts DNA assembly (mentions this process w/ microtubules)
  3. Also have areas of target therapy that works by different mechanisms, depending upon what type of therapy your talking about.
  4. first three bullets & vast majority of chemotherapy drugs target rapidly dividing cells that need to replicate their genome; targets some point of DNA synthesis or stability
  5. Right now there are about 400 FDA approved chemotherapy drugs on the market in the US today

XVIII. SKIPPER’S LAWS/ LOG-KILL HYPOTHESIS

  1. back in the 60’s at SRI there were a few drugs but there was much confusion on how to administer these drugs
  2. when given to patients-cancer drugs caused death
  3. As a result of patient deaths, scientists used Xenoograph models to study mice. Each mouse was given different chemotherapy agents and established skipper’s law. BE FAMILIAR W/ THE POINTS OF SKIPPERS LAW.
  4. Skipper’s Law- Chemotherapy drugs follow first order kinetics. Tumor cells will re-grow as you treat. (if you continue to treat with chemotherapy you could kill patient-thus is important to have breaks in b/t treatments). Importantly, chemotherapy will never reduce a tumor burden to zero. If doctor told patient that a drug could kill 99% of the tumor cells in your body you can only do so many rounds of treatment on the patient. You’ll NEVER reduce the burden number to ZERO
  5. Tumor cells regrow in cycles of chemotherapy

XIX. COMPARSION CELL GROWTH