Following on from the last post, which looked at new research on a way to overcome multi-drug resistance (MDR) in cancer cells (MacDiarmid et al., 2009. Nat Biotech 27:643), I thought I'd try and find some information on both the prevalence of MDR, and the effectiveness of current chemotherapy treatments.
This was partly inspired by an article by Mike "Health Ranger" Adams comments in a national newspaper, where he basically says that Patrick Swayze was killed by the chemotherapy, and not by the cancer itself (goto article)
So according to Macmillan Cancer Support, there are over 200 types of cancer and over 50 different chemotherapy drugs currently in use. The main effect of these drugs is to stop cancer cells dividing by interfering with DNA replication. For example, cisplatin, a commonly used drug in chemotherapy, causes the DNA to cross-link or stick together irreversibly. The result of interfering with cell division is that either the cell will commit suicide (apoptosis) or at least stop growing. The aim is to either kill the tumour or prevent further growth so it can be operated on. Chemotherapy is often used as an adjuvant with surgery, to try and kill of any cancer cells that may remain after the tumour has been surgically removed.
Unfortunately, cancer cells become resistant to the drugs used on them. The response to this has been to increase dosages and/or use combinatorial therapy (several drugs at once). As most drugs have some kind of side effect, increasing the drug load will increase the toxicity to the patient. The side effects of chemotherapy are generally due to its effects on cells which have high rates of division, such as bone marrow (which makes blood cells), hair follicles, and the lining of the mouth and digestive system. In younger people, it may also affect the germ cells, reducing fertility. The loss of bone marrow cells is the most serious, as this can lead to anaemia and infection from lack of red and white blood cell production. Basically the drugs are non-selective, once they are in the blood they will have an effect on any cell which divides. This is why therapies which use a targeted delivery system such as the one I discussed earlier are really important if we want to fight cancer. At the moment, the strategy is largely, give the patient drugs for a certain period of time, then stop the treatment to let the patients own (non-cancerous) cells recover, while hoping that all the cancer cells have been killed.
How do cancer cells become drug resistant? The main mechanism seems to be by pumping out the drug molecules from the cell. Essentially there will be a mutation leading to over-expression of one of the ATP-binding cassette transporter proteins, which are able to pump out a wide variety of foreign molecules from the cell. The two main ones identified are p-glycoprotein (or MDR1, this was targeted in the MacDiarmid minicell study) and MRP (Pajic et al 2009 Cancer Res 69:6396, Cole et al., 1992 Science 258:1650). Other mechanisms could include activation of DNA-repair pathways or enzymatic pathways that break down the drugs, although these are mostly unknowns.
So the point of this post was to find out the effectiveness of chemotherapy. A fairly recent study looked at 5-year survival rates after cancer treatment with or without chemotherapy. Chemotherapy was found to only increase survival by 2.3% in Australia and 2.1% in the USA, which is not much, but better than nothing (Morgan et al., 2004. Clin Oncol R Coll Radiol 16:549). For comparision, 5-year survival of cancer without chemotherapy is 60%, this varies a lot according to the type of cancer.
There a numerous papers comparing the effectiveness of treatment with and without specific drugs for various different cancers. One suggested that chemotherapy for elderly prostate cancer sufferers may not increase survival rates (i.e. lifetimes) but significantly reduced pain, i.e. gave a better quality of life (Mike et al., 2006. Cochrane Database Syst Rev. 18:CD005247). This theme was found in the other studies I looked at. Humber et al. suggested that increasing the dosage of chemotherapy against womb cancer does not improve survival but worsens the side-effects (Humber et al., 2005. Cochrane Database Syst Rev 20:CD003915). finally, a study looking at the effects of using the drug gemcitabine after surgery to remove pancreatic cancer found that the drug prolonged the cancer-free period after the surgery, but ultimately did not result in an extended lifespan when the cancer recurred (Ueno et al., 2009. British J Cancer 101:908).
The case for chemotherapy then - it may slightly improve your chance of survival, but more importantly, make your final days a bit more comfortable. However, just pumping more and more drugs into the patient is not going to help.
Back to the article by Mike Adams. Swayze died of lung cancer, which is notoriously untreatable. What drug therapies we have do not work very well, one study gave the figure of just two months of extra life following chemotherapy for small-cell lung carcinoma (Suglan et al., J Clin Oncology 20:3750). To repeat what I said above, this is maybe better than nothing. And without testing the drugs, on patients who are dying and are desperate for anything that works, we would not have found out the things we have. The key thing here is though that I have not found any evidence that chemotherapy actually reduces chances of survival for cancer patients.
It seems clear to me that the future of cancer therapies must reside in targeted therapies, such as the minicell strategy I am currently getting very excited by. To be fair to the health ranger, I should have a look at "alternative" therapies for cancer (i.e. not from Western medicine). Maybe next time.
Rob 28/9/9
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