Inflammation and cancer: one aspirin please!

Aspirin

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There have been some interesting studies recently that have suggested that taking an aspirin a day for five years reduced one’s risk of certain cancers (in this case it was colorectal and other solid cancers).  We have all heard the issue of older folks who take an aspirin a day to help prevent hear attacks or even a glass or red wine a night with similar properties, but cancer?  This seems rather odd.

Aspirin is known as a pain-killer but it is in the class of drugs known as non steroidal anti-inflammatory drugs or NSAIDs.  Thus, inherit in this drug are some anti-inflammatory properties.  In fact, it was when looking at people who were taking an aspirin a day to prevent heart disease, that researches started noticing that their cancer rates seemed lower.  Actually, it’s not that the rates of cancer are lower it’s that their incidence of death due to cancer was lower.  So, in a trial that looked at people who had taken aspirin for over 7 and 1/2 years that they had a 30 reduction in the 20-year risk of cancer for all solid cancers combined.  And they also had a 60% reduced risk for adenocarcinoma of the esophagus.   

Why is this?  How can an aspirin help prevent cancer.  Cancer and inflammation have been linked for many years.  However, as inflammation occurs regularly even in non cancer conditions (e.g. as normal responses to control infections) it has been a very difficult to study this in humans.  One of the more specific observation that was made by Dr. Dvork of Harvard University was that cancers share similar developmental processes or mechanisms and that tumors are indeed, “wounds that do not heal”.  In fact, it appears that chronic inflammation is part and parcel of almost all stages of cancer development from driving the initial genetic changes (mutations) to providing conditions that enable to cancer cell to migrate to another area (metastasize) and even preventing the anti-cancer immune response to take hold. 

There are a number of different genes and their protein products that regulate inflammation: too many to list here.  But, one of the hallmark set of proteins are the ones that belong to the NFKB pathways.  In fact, it might be accurate to say that NFKB is the master regulator of inflammation.  A number of cancers have hijacked this family of proteins for its own use.  And a number of cancers are also highly dependent on this pathway to be aberrantly expressed.  However, very few true inflammatory genes are oncogenes or tumor suppressors (the two types of genes that must be defective/mutated/changed) in all cancer cells.  So, the true/direct link between inflammation and cancer still needs further elucidation.

So the real question behind this issue is…;can we prevent cancer by reducing inflammation?  All NSAIDs class of drugs work mostly though blocking something known as Cox protein (or a set of proteins that work as signals inside the cell).  There are two major Cox proteins and one is regulated by pro-inflammatory proteins in the body and the other by stomach related factors (or gastrointestinal signals).  Aspirin blocks both of these but other NSAIDs work by blocking only one or the other.  However, to make a long story short, Cox2 inhibitors can have bad side effects including heart problems and many of these drugs were removed from the market after people started having heart troubles.  So, if drugs can be made that have less of this side effect but inhibit inflammation, perhaps they could be used by more people to help prevent cancer (ar at least reduce the chances of dying from certain cancers).  This will take time and there are no magic bullets.  We will see if the link between inflammation and cancer can really be used to save people’s lives in the future…but for now we have aspirin and that is one step in the right direction.

Dr. C

Thank you for reading: for more information on cancer see previous blog articles and visit Cancer Made Simple.

Melanoma: its only skin deep or is it?

Skin Cancer: Recognition and Management

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Skin cancer is actually quite nicely treatable despite the horror stories you might hear.  But, here is the catch….only when it is caught early.  Melanoma (the lethal form of skin cancer) before it spreads is fairly easy to treat…scary but treatable.  Unfortunately, as is the case with many cancers, once it has spread to different sites of your body, in a process called metastasis, it is very difficult to treat.  The most severe stage of the disease is known as stage IV metastatic melanoma, and this is a deadly incurable form of the disease.  Sadly, the only approved drug, a type of chemotherapy, only reduced the cancer in 10% of patients.  What’s even worse is that even in those 10% where the drug seems to work, the patients will still die of the disease.  This drug, like many, poison the cell as it undergoes cell division in a process known as proliferation.  To make a long story short, any dividing cell is potentially vulnerable to this drug so it is a very broad killer of cells.  The melanoma cells are slightly more sensitive to this drug, but so are hair follicles, cells lining the gut, and other rapidly dividing cells in your body. 

As is the case for many forms of cancer, researchers are looking for agents that might be a little bit (or a whole lot) more selective in targeting the cancer cell itself and sparing the normal cells (like the hair follicles, etc.).  Melanoma is one cancer that has been probably the most studied in this area.  One such area of investigation is the use of ‘immunotherapy’ to try to treat the disease.  In these types of therapies certain drugs or proteins are used to help the patients’ own immune system to defend against the cancer.  One of these developed drugs is an antibody known as ipilimumab or anti-CTLA4.  This antibody binds CTLA4 that is present on the T cell in hopes of increasing the anti-T cell function against the cancer.  It does seem to work in some patients who receive this in addition to another agent.  This other agent is a protein that is found highly expressed on the cancer cells itself known as gp100.  This protein is given as a vaccine to help boost the T cell response against the cancer.  These two together do show some promise in some patients who have stage IV melanoma.  However, at the moment the final clinical trials are being conducted, so it is not widely available and not proven yet. 

Other companies are developing drugs that interfere with signaling pathways that are highly activated in cancer cells and less so in on cancer cells.  50% of all patients with advanced melanoma are known to have mutations in a pathway that leads to activated growth.  The mutations map to a protein (enzyme) known as BRAF.  This mutation keeps the enzyme protein in the active state that leads to continued growth where in normal cells the protein is keep in an inactive state.  Chemical drugs have been found that bind to a certain region in the protein that blocks this mutated protein and thus helps to either kill the cell expressing the mutated protein BRAF or at least stop it from being active.  Again, this novel drug is still undergoing testing in clinical trials and if it passes muster it will be released for use in cancer centers. 

Limitations:  There are certainly going to be some limitation that make these and probably most future therapies less effective that we wish.  One has to do with cost.  Immunotherapies tend to be very expensive.  The antibodies or proteins cost a lot to make and the patient ends up paying tens of thousands of dollars per year (sometimes more).  The novel chemical drugs are usually more expensive than existing drugs as the drug company passes off the cost of development to the consumer (the cancer patient).  The other issue is that even with these new ‘cancer specific’ drugs, different patients will react differently.  It is VERY hard to predict which patients will respond well or not.  For the BRAF inhibitor discussed above, it is fairly easy to determine which patients to give the drug to (the 50% of the patients who have the mutation and not that ones that do not have mutated forms of BRAF).  But, it is another thing to know which patients will respond and which will not.  The same goes for the immunotherapies.  No one can predict which patients will response to immunotherapies…we just don’t know enough about the millions of different things that happen in human bodies that can interfere with a good anti-cancer immune response. 

So, lest you get too depressed and think that no one is doing anything about it…millions of dollars and some of the world’s brightest scientist and clinicians are working to solve this problem of the lethality of late stage skin cancer.  But, it takes time and it is complex.

Thankyou for reading and do let me know if you have any further questions/comments about advanced forms of skin cancer or cancer in general.  Be sure to visit my cancer information website at Cancer Made Simple!

Dr. C 

Cancer: Personalized Medicine

A schematic illustration showing how nanoparti...

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Regardless of whether you use the term Personalized or Individualized Medicine, or what the NCI director Harold Varmus likes to call, “genetically informed medicine”, the idea that we must start thinking about each person who has cancer as his/her own self and not as a group, has certainly caught on.

Most cancer drugs have been tested in multi million dollar clinical trials studies by large pharmaceutical companies (few other can afford them).  The limitation (and there are many) is that these studies look at testing new anti cancer drugs using a large and randomized mixed populations.  It is probably no surprise then when you realize that the effectiveness of novel anti cancer therapies are around 30%.  Or, another way to look at this is that high failure rates of on average of 70% are seen as these drugs can not account in any way for how individuals respond. 

So, cancer therapies rely on the traditional standard three forms of therapy and a very limited set of targeted anti-cancer drugs that are pretty weak in the overall population.  The second large problem is that in hospitals all over the country (US) as well as internationally, oncologists are mixing and matching their patients with these new drugs in their own ways.  In essence, creating their own mini clinical trials one patient at time.  These oncologists do look for improved clinical responses and do try to publish these findings.  However, due to limited resources and the nature of powerful drug trials, these ‘small’ publications and case reports are often ignored.  One must have thousands of small case reports that show the same thing across the world before anyone would listen or take note. 

So, there is a disconnect between the efforts that the pharmaceutical industry is doing and publishing and what is actually being done on the ground in hospitals.  Pharmaceutical companies are selling their drugs and designing their studies to treat everyone who has a particular cancer at a certain stage with certain designated prior failures to therapy (or newly diagnosed in some cases).  While, clinicians are treating their patients one at a time, as they should be.  It is the N of ‘1’ trail versus the four stage clinical trials involving thousands of dollars. 

The good news is that 1) pharmaceutical companies know this and are spending millions to acquire tools to look at individuals’ genetics and compare them to responsiveness of a particular drug, 2) the N of 1 experiments when done properly are gaining ground and acceptance, and 3) there are companies such as Cancer Commons (http://cancercommons.com/) that are encouraging oncologists to start reporting their ‘in-house’ results in order to get more and more data from ‘individualized’ treatments throughout the US and elsewhere.

So, things look promising, but it’s going to take some time before we can say we are treating the patient before us and not all patients before us.

Thanks,

Dr. C

For more information….please see Cancer Made Simple

Smoking and cancer: two steps behind

Unlit filtered cigarettes

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Smoking as I outlined in my last blog entry is now probably the most well-studied carcinogen known to man and one of the most dangerous.  The health care costs for decades and decades of smoking will be felt for years to come and only now are we being confronted with the peak in female lung cancers which corresponds to the peak in female smokers in the US 20 years ago.

If someone wants to smoke they can smoke.  It is not illegal to light up.  However, as the tobacco companies have settled (and world record comprehensive settlement have been made) with many individuals and states, it is very difficult for smokers today to sue and blame cigarette manufactures for their own negligence.  We all know in this country how dangerous smoking is and very few people deny it these days.  However, today I read in the on-line news media an article that suggests this is not the case all over the world.

In fact, health care professionals in Indonesia seem to be turning back the clock by recommending smoking to their patients.  Smoking is in fact on the rise in Indonesia, which has seen an explosion in smoking rates.  Not only is smoking amongst adults on the rise, it is quite common to see parents giving their children cigarettes to smoke.  And to go even further, some doctors (i should carefully use this word) are advising that their patients smoke to calm their nerves.  A well known pharmacologist (academic I believe) in Indonesia has reported to the government and the media that smoking is indeed not harmful to health at all but actually quite beneficial.  In some centers, smoke from cigarettes are introduced into the lungs of  patients with lung ailments.  The claim is that this filtered or cleaned smoke from cigarettes (they are removed of some inorganic compounds ) are actually healthy for you.

The world was shocked about six months ago when we saw children on the streets of Indonesia (I believe it was Jakarta) chain-smoking.  In some areas, children can readily buy cigarettes.  It is also reported by some health care professions who know the truth that it is big business now in Indonesia.  The government earns billions in tax revenues from cigarette consumption.  Now tobacco company money is flowing into many sectors of the economy and politics in that large Asian country.  Unfortunately, the tobacco companies who have seen their profits dwindle in many Western countries are turning to countries like Indonesia where cash registers are ringing.  Health care advocates are fewer and less effective in countries that have lax legislation or non-existent.  It seems quite sad that companies that were accused of HUGE cover ups here in the US and Europe have now seen opportunities in vulnerable countries that will have its citizens paying with their lives 10-30 years down the road.  Advertisements that target the youth are on the rise in many asian and Eastern European countries.  They will likely be unopposed and prolific.  Very little incentive is needed to make safer cigarettes in these countries…as no legislation stands in their way.

So, we have not won the war on Cigarette smoking and cancer…new profits are waiting to be made with vulnerable citizens and pocket are to be lined with politicians.  Lessons will be learned, but not after thousands if not millions of lives are lost and billions of dollars are needed.

Thanks for reading and let me know if you have any questions or comments.

Dr C

www.cancermadesimple.com

 

 

smoking and lung cancer: inseparable bedfellows

Common adverse effects of tobacco smoking (See...

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It is now absolutely and incontrovertibly certain that smoking is strongly linked to lung cancer.  And despite that so much evidence has been around for so long, lung cancer rates are still rising in women who smoke and cancer risks are rising in countries outside of the US (where legislation is weak and where smoking is gaining in popularity).  The denial between the link between lung cancer and smoking was so strong (and in some circles still here) that it took a very long time for the medical community and the legal community to agree that cigarettes needed to be regulated in some way or another to help minimize the impact of lung cancer is Americans.  Below is a kind of time-table to show the various stages of the smoking lung cancer sordid tale.

1.  About ten years after a link between scrotal/testicular cancer and the environmental exposure of chimney sweeps to soot was published John Hill claimed that snuff (oral tobacco) caused lip, mouth and throat cancer. (1761)

2. Tobacco import from the American south increases from 38 million pounds to more than 100 million pounds from 1700 to 1770.

3.  Tobacco rolled and put in paper was introduced, making it easier to smoke and simpler to mass produce. @1855

4. Cigarette smoking goes from a per capita of one cigarette per year to about 3,500 per person from 1870 to 1953.

5. The first case-controlled study of its kind was performed by a little known medical student to ask about the association between smoking and cancer.  He was told by the ‘Surgeon General’ at that time that it was a complete waste of time and like linking milk to cancer development.  His own supervisor, a famous lung pulmonary surgeon, did not think it a wise study but let him do it for the practice of performing a clinical trial.  His preliminary data was largely ignored when he presented it in around 1948-49.

6.  Doll and Hill publish their seminal findings from a clinical trial that found a strong association between smoking and development of lung cancer. Smoking and Carcinoma of the Lung was published by the British medical journal in 1948.

7. A more realistic (Prospective trial one that allows the researcher to capture a change as it’s happening as opposed to a prospective trial that only allows you to go back and time as was done in 1948) trial was performed in the UK with medical doctors asking them about their smoking habits.  During Oct. 1951 and March 1954, from about 41,024 total doctors who answered the surveys, 789 deaths were reported.  Death from lung cancer and death from other caused were separated and easily showed that all the lung cancer deaths were linked to smoking.

8.  Philipp Morris introduced the Marlboro Man and smoking is at an all time high.  1955

9.  Gross annual sales of cigarettes in American peaks (around 5 billion dollars) in 1960’s.

10.  The average American was smoking about 11 cigarettes per day, nearly one for every hour they were awake.

11. The Tobacco Industry Research Committee (TIRC) was set up and vigorously defended itself and beat down statistical evidence when ever it arose.  IT constantly argues over terminology about cause and utility of statistics and how incomplete medical science was, etc. It sought to discredit the scientific community. 1954

12. Due to pressure by Cancer and Lung societies President Kennedy assigns his Surgeon General Terry Smith to investigate a ling between smoking and cancer and health.  A report was released to every major radio and news station declaring a strong link between smoking and numerous health related risks in 1964.

13. The FTC (after much fighting by the tobacco companies, etc.) came out with their first warning ever on cigarette packs stating, “Caution: cigarette smoking may be hazardous to your health”. 1965

14. After a serious legal battle, TV station in the US were required to allow for ‘proportional airtime’ that showcased the dangers of smoking alongside the “Marlboro Man and Virginia Slim’ commercials. 1968

15.  Tobacco companies angry/upset with the ‘proportional airtime anti-smoking adds’ decide to remove cigarette smoking ads from TV altogether in 1971.

16. As a result of very aggressive ads targeting women, female smokers go up from 15 to 36% of all women who smoke from 1940 to 1944.

17. From a total of over 300 product liability cases taken to court against tobacco companies, not a single one had resulted in judgment against the companies.

18. Game changing court case where Cipollone family was awarded ‘negligible’ damages at $400,000 from the Cigarette company for withholding so much information about the risks of cancer and was 20% responsible for her death.  Although, a small slap on the wrist, this lead to a huge wave of court battles and tons and tons of bad publicity for years to come against tobacco companies and exposed their ‘torrid cover up’. 1987

19.  After facing litigation from entire states, the major Tobacco companies agreed to a landmark global agreement called the ” Master Settlement Agreement” in which the 4 major tobacco companies settled with 48 states.  The largest settlement ever recorded had transpired in 1998.

Tobacco smoking is now a major and mostly unregulated cause of death in Both China and India.  Cigarette smoking is now rising in many former soviet union countries as well as Asia.  Tobacco companies are plying their trade now in countries where they can still make huge profits.  Warnings are still lacking and enforcement is almost all but absent in many of these countries. 2000’s

Thank you and I hope you have enjoyed reading this.  Smoking is NOW YOUR responsibility not the company who sold you the cigarettes.  If you smoke you are asking for cancer and there is no denying it.  Sure it is hard to stop, but please do…its in your hands!

For more information see…. Cancer Made Simple