John R. Tkach, M.D.
300 North Willson, Suite 203B
Bozeman, MT 59715
(406) 587-5442

5- FU (5-fluorouracil, Carac, Efudex) Treatment of Actinic Keratoses

Patient Information Sheet

What's It All About?

The Skin Cancer Foundation estimates that there will be 3.5 million skin cancers in the USA in 2014. 5-FU is a cream that is applied to sun-damaged areas of skin (usually the face) once daily for 90 days to kill off hidden precancerous cells. The idea is to get rid of these bad cells while they are still precancerous, before they have had time to convert to actual cancer. It is 65-85% effective, but not perfect. Actinic keratoses are scaly flat flesh colored to red-brown colored areas that occur due to the sun. Sometimes they are white.

Actinic keratoses are the most common reason for going to a dermatologist making up 14% of all dermatologic visits.

Your choice to go through a course of topical 5-FU is a serious decision because it is a commitment to your having irritated skin for 90 days.

In my humble opinion (based on over 40 years of experience) the best way to prevent skin cancer is to combine the following:

  1. Use a good sunscreen daily such as Neutrogena Ultra Sheer Dry Touch Sunblock SPF 100+.
  2. Freeze actinic keratosis that you can see or feel by touch early while they are still mild.
  3. Apply Carac daily to at-risk-skin areas for 90 days to kill hidden precancerous cells.

By the way, 5-FU does not work for melanoma. It helps actinic keratoses, non-pigmented skin cancers like squamous cell cancer, and, to a limited extent basal cell cancer. 5-FU generally does not substitute for cutting out actual cancers. In most cases, cancer should be cut out. 5-FU absolutely does not work for melanoma.

How Cancer Develops

What I am going to tell you is true for all cancers not just skin. One day a woman feels fine. The next she detects a lump on a breast, sees a doctor and is told the biopsy showed cancer. It gives the illusion that this developed quickly. It comes as a surprise.

In actuality, most (but not all) cancers develop over a period of years, not just days. Cancer develops in four steps:

  1. Initiation - some event or exposure damages cells' chromosomes or DNA or inappropriately switches on the bad genes. For the skin, this is usually sunburn or years of accumulated sun exposure and sun damage. It is different from one cancer to another.
  2. Promotion - the sun-damaged cells do not turn into cancer right away. They sit around for 5 years, 10 years, 15years, as much as 60 years waiting to turn into cancer. This is what actinic keratoses are. If we can get rid of them at this step, we can prevent the need to excise, most of the time. This is the point where freezing with liquid nitrogen and treating with 5-FU can be effective.
    Freezing with liquid nitrogen at minus 320 degrees F. for about 2-3 seconds usually works great for the spots the doctor can see. But what about the insidious (hidden) precancerous cells? That's where 5-FU comes in. It seeks out and kills precancerous actinic keratosis cells even when they are still hidden. It is about 65%-85% effective in preventing those cells from turning into cancer.
    Not all actinic keratoses will turn into cancer. In my opinion, only about 4% will turn into cancer. Whereas, Dr. Kopf in New York City thinks it is 17%, and the Doctors Graham in North Carolina think it is 25% with people of Scottish ancestry who work on fishing boats.
  3. Conversion to Cancer - If we do not get rid of the bad cells while they are still precancerous, some may turn into cancer. At this point, you have to cut the cancer out or it will spread.
  4. Cancer Spreads and Invades - After the conversion to cancer, the cancer cells are good at invading locally and spreading to other parts of the body. The body makes scar-like tissue (collagen) and tries to seal them off. But, they make an enzyme that dissolves collagen and sets the cancer cells free. They develop ways to invade into blood vessels and adhere to the blood vessel walls long enough to invade.

Dr. Tkach's Theory of Cancer Treatment (January 2000) - "contained within each cancer cell is the mechanism for its own self-destruction." Our cells are supposed to make a self inventory with each cell division and ask, "Am I a cancer cell? If yes, destroy myself (apoptosis). If no, go about my business normally."

More About 5-FU

In 1954 Dr. Cantarow and Dr. Paschkiss observed that liver cancer cells absorbed more uracil than non-cancer cells. This quickly lead to development of 5-FU by Hoffman-La Roche labs. In 1957, Dr. Heidelberger published the first paper on using 5-FU on cancers in mice. You know, we can really do amazing things to help mice. One of my professors Henry Claman always said, "If you have to have cancer, be a mouse. We can probably cure you if you are a mouse."

During the 1960's, continued research lead to using 5-FU injected by vein to treat metastatic breast cancer. In the 1960's, 5-FU was being used commonly for breast cancer. I remember doing slow IV push injections at Denver General Hospital for a lady with metastatic breast cancer. Now we have other newer drugs for breast cancer.

Some doctors noticed that I.V. 5-FU helped warts and skin cancers. Between 1962 and 1971, Dr. Klein and his colleagues published 4 papers on the use of topical 5-FU for treatment of actinic keratoses, skin cancers, and keratoacanthoma. It caught on by 1967.

When a gene called p53 has a thymine substituted for uracil in a certain spot in its DNA, it fails to function properly. This defect, the mutated p53 gene, is found in 69% to 90% of actinic keratoses and squamous cell cancers. Obviously there is more to be learned.

5-FU is a thymine analog that falsely mimics cytosine. It binds to the enzyme thymidine synthetase. This stops cell division and causes the bad cells to self-destruct (apoptosis, ah-poh-tosis, the second p is silent).

As it turns out, precancerous cells and cancer cells grow differently than normal cells. They grow more rapidly. But they are not hardy. They are weaklings compared to healthy cells, but boy do they know how to divide. They grow so fast, they get out of control. And, that's why 5-FU works. The bad skin cells take up 5-FU faster. For every good cell killed by 5-FU, there are 16 bad cells killed. It is a wide safety margin.

In his article (8 ) Rogers Ceilley points out additional effects on messenger RNA synthesis and interleukin mediators of inflammation. Some authors favor the combined use of5-FU and freezing with liquid nitrogen.

The Doctor Takes a Dose of His Own Medicine: How He Does It

A patient undergoing 5-FU treatment

A patient (not Dr. Tkach) undergoing 5-FU treatment

Don't you wish more doctors would do that? January 15, 2014, I myself started my 5th course of 5-FU in 38 years. Here's how I use it, and you can too. I use it in the morning when I dress after showering. I apply it with my skin dry. I put green-pea-sized dabs on my index and middle fingers. I transfer one dab to the other hand and rub them in symmetrically starting with the upper face, working down and around the face, neck and ears. It takes me about 8-10 dabs total, but I have more exposed skin on the top of my head, if you know what I mean.

After you apply Carac, wash your hands so you don't rub it into your eyes. If you see a layer of white powder, you may be applying a little more than is necessary. Carac is expensive. With my AARP insurance, in January, I paid $250 for three tubes of 30 Gm each. Without insurance, it may cost $600 a tube. One tube will last 3-4 weeks. Ask your pharmacy or insurance plan what it will cost you for a 30 gram tube of Carac. The 90 day course will take 3 or 4 tubes.

Apply sunscreen about 30 minutes after applying Carac. I will give you a Medication Administration Record (MAR) to write down the date of applications and your reactions. If you get too irritated and need to stop for a few days, resume the MAR sequentially. What I want to know is how many days total you used Carac.

If you get too irritated, stop it for a week. Use the generic Westcort cream prescription I will give you. Wet the sore, irritated areas, and rub in Westcort 4 times a day. It will get better in 2-4 days, and then you can go back to Carac. Don't suffer. Call me if you have too much discomfort.

After you apply the daily dose of Carac, wash your hands. Otherwise, you will accidentally get Carac in your eyes. This is irritating. If you need relief, I suggest using eye drops such as Systane Ultra made by Alcon.

Out of a 90 day course of treatment, you might have 4 or 5 (or more) nights when the irritation wakes you up. Take a paper towel, wet it, and hold against the sore areas for 15-20 minutes. If that is not enough relief, put an ice cube in a baggie and hold it on the sore area 30-45 seconds.

Use old pillow cases since you might leave a couple of drops of blood on the pillow case on a few nights.

Why Use Carac 90 Days?

I am the only doctor I know prescribing a 90-day course of Carac. Most doctors prescribe 14 days. There is a trend to 30 days. I observed in myself that 5-FU attacks actinic keratosis rapidly and even though you continue applying it, the old spots fade. You will start seeing a reaction by 2 weeks. At one month, and two months, and three months, new spots show up that did not show up earlier. You get rid of a lot of bad cells if you use 5-FU for 90 days instead of 15-30 days. But I do not know if over 90 days is useful.

Why Use Carac and not a Cheaper Generic?

When Carac came out, I was very skeptical. I used to use 5% 5-FU cream (Efudex) twice a day for 90 days. Carac is just 0.5%. I was one of the last dermatologists in the state to switch. Normal skin cells go through a cell division cycle once every 457 hours (19 days). During the S-phase, synthesis, the cell doubles its DNA and chromosome content. 5-FU hits the bad cells during that phase. Wham!

Almost all topical medicines go into the skin and work for about 45 minutes to an hour. So, if you are applying the old standard 5-FU once a day, you are actually only getting treated less that one hour out of 24 hours. Carac packages 5-FU in millions of tiny particles that look like soccer balls with surface pores. I can show you under my microscope if you are interested. The medicine leaks out a few molecules at a time for about 8 hours. With Carac, you get 10 times more treatment. This allows the medicine to catch a greater proportion of the bad cells in their vulnerable part of cell division. It is great.

Who Should Use Carac?

If you have had a handful of actinic keratoses and no skin cancers, I don' t think you probably need Carac. If you have had hundreds of actinic keratoses and multiple skin cancers, Carac might save you from have some surgeries.

What are the Bad Things About Carac?

A patient undergoing 5-FU treatment

A patient (not Dr. Tkach) undergoing 5-FU treatment

  1. t is an ordeal. Your face will be red for several months.
  2. It is somewhat expensive.
  3. It can be life-threatening in one very rare condition called "dihydropyrimidine dehydrogenase" deficiency. This enzyme breaks down 5-FU. If you do not have it, the amount of 5-FU entering the body goes unchecked, it builds up and, and it quickly becomes toxic.

If you apply the Carac one or two times more and get the following symptoms, stop it call me. They are signs of dihydropyrimidine dehydrogenase deficiency:

  1. Diarrhea
  2. Mouth sores
  3. Bloody diarrhea
  4. Abdominal pain
  5. Chills
  6. Red skin rash
  7. Fever

In preparing this information sheet for you, I did multiple extensive literature searches. There are some questions I had but could not find answers to. I think this is an okay treatment. There are a few reports of light skin colored scars. In 40 years, I have not seen that.

What Are Some Good Things About a Course of Topical 5-FU?

It cuts down the risk of getting skin cancer.

Many people who have gone through this treatment and had the most severe reactions have told me that people have told them they look 10 or 15 years younger. I don't think cosmesis is a good reason for using 5-F.U. This beneficial effect sometimes wears off in 7 years. It is not an FDA approved treatment for wrinkles.

In general, if you use sunscreen, avoid sunburns, have periodic dermatology visits to check and treat actinic keratosis, and do a 90 day course of Carac, you will have done everything you can to prevent getting skin cancer.

References:

  1. Klein, Ed, Tumors of the skin V. Local administration of antitumor agents to superficial multicentric basal cell carcinomas, J Invest Dermatol 1965; 45: 489-495.
  2. Stoll, H et al, Tumors of the Skin VII, Effects of varying the concentration of locally administered 5-fluorouracil on basal cell carcinoma, J Invest. Dermatol, 1967; 49 (3): 219-224.
  3. Padilla, RS, Epidemiology, natural history, and diagnosis of actinic keratoses, UpToDate, July 23,2013
  4. Jorizzo, Joseph, Treatment of actinic keratoses, UpToDate, June 21, 2013.
  5. Klein, E. et al, Tumors of the skin XII. Topical 5-fluorouracil for epidermal neoplasms, J. Surg. Oncol., 1971, 3 (3) 331-349.
  6. Thai, KE, A prospective study of the use of cryosurgery for the treatment of asctinic keratoses, International Journal of Dermatology 2004, 43, 687-692.
  7. Wikipedia, Fluorouracil, Jan, 26, 2014
  8. Ceiley, R., Mechanism of action of topical 5-fluorouracil: Review and implications for the treatment of dermatological disorders.
  9. Fluorouracil (topical): Drug Information , UpToDate, January 16, 2014.
  10. Goldsmith et al, Case-based considerations in the treatment of actinic keratoses: utilizing combination or sequential therapy with f-fluorouracil cream and destructive treatments, J. Drugs in Dermatol July 2010, 9.7: p. 864-72.
  11. Hagele, TJ, Practice trends in the treatment of actinic keratoses in the United States: 0.5% fluorouracil and combination cryotherapy plus fluorouracil are underused despite evidence of benefit, J. Cutan Med. and Surg Mar-Apr 2012, 16(2): 107-14.
  12. Kaur et al, Comparison of topoical 5-fluorouracil formulations in actinic keratoses treatment, J. Derm. Treat, 2010, 21:267-271.
  13. Han et al, Case-based considerations in the treatment of actinic keratoses: utilizing combination or sequential therapy with 5-fluorouracil cream and destructive treatments.
  14. Stockflith and Keri, Guideline for the management of actinic keratoses, European Dermatology Forum, 2006: 16(6): 599-606.
  15. Johnson, MR et al, Life-threatening toxicity in a dihydropyrimidine deficient patient after treatment with topical 5-fluorouracil.
  16. F. Al-Niaimi and C.Lyon, Resolving actinic keratoses: an unexpected side-effect of capecitabine therapy, Clin and Experiment Dermatol, 2011, 37, 68-80.
  17. MJ Ostro and RP Cullis, Use of liposomes as injectable-drug delivery systems, Am J. Health-system pharmacy 1989; 46(8): 1576-1587.
  18. Alvi, I et al, comparative study of transfersomes, liposomes,and niosomes for topical delivery of 5-fluorouracinl to skin cancer cells: preparation, characterization, in-vitro release, ad cytotoxicity analysis, Anti-cancer drugs, Sept 2011, 22(8): 774-82.
  19. Ceve, G & G. Blume, New, highly efficient formulation of diclofenac for the topical transdermal administration in ultradeformable drug carriers, transfersomes.
  20. Diclofenac (topical): Drug Information, UpToDate, Jan. 26, 2014.
  21. Jirakulaporn, T et al, Capecitabine for skin cancer prevention in sold organ transplant recipients. Clin Transplant 2011: 25: 541-548.

The information provided in these patient information sheets is offered for general informational and educational purposes only; it is not offered as and does not constitute medical advice. In no way are any of the materials presented meant to be a substitute for professional medical care or attention by a qualified practitioner, nor should they be construed as such.

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