As a cancer scientist, a common question I get is “When are we going to cure cancer?”. It sounds like a simple question, but the truth is pretty complicated.The first thing to point out is that finding a cure for cancer is extremely unlikely. Cancer is an umbrella term for over 200 different diseases (1000s of different diseases if you include sub-types). Although these diseases have many outward similarities (all grow uncontrollably and have the potential to invade and spread), the biological mechanism is different for most cancer types. The simple answer is that we may find cures for various cancers, but each will need their own research and treatment strategies.To understand cancer you have to understand that it is a disease of evolution. Over the past 4 billion years we have evolved from a single celled organism to the dominant mammals on the planet. This process is driven by random alterations and mutations of our DNA. Each of these mutations has the potential to change our genetics. If that change gives an individual an advantage over the rest, then that individual is more likely to survive and to pass the advantage on to his or her offspring. This selective pressure to retain advantageous traits is known as “Natural Selection”.These random changes and mutations can happen every single time a cell divides. Our cells are actually astonishingly efficient at avoiding and correcting mistakes, preventing most events that could result in a tumour. However, trillions of our cells divide every single day, and not all mutations can be caught.Just like in our evolution, if a mutation gives one of your cells an advantage over the other cells, then this cell will survive over the cells around it. For example, if a mutation causes a cell to multiply out of control, it will outgrow those around it and form a tumour. Moreover, tumours can often result from unique combinations of mutations, which will drive their growth in a different ways.If you take a step back and think about that, you can begin to see why a cancer can be so hard to treat. It is a corruption of our own cells, genetically almost identical to healthy ones, similar enough to make it hard to target, different enough to drive the disease. Most drugs we try to use will have difficulty differentiating between cancer and healthy cells, and as a result will cause terrible side effects.To make things even more complicated, as the tumour itself grows it accumulates more and more mutations. Some of these mutations will cause further advantage over other cells within the tumours, and form their own little part of the growth, meaning that the cancer can be made up of many cells that are genetically different.
This brings us back to the idea of natural selection: when we find a drug that works for a tumour, we are applying a selective, evolutionary, pressure. If any of the different cells in the cancer allow it to resist the therapy, then that cell will quickly take over, giving rise to a chemo resistant cancer (pictured).Tackling this problem requires an understanding of the various mutations that are causing the cancer to grow. This understanding allows us to design drugs towards these specific mutations, a process we have already started. If we can then recognise what mutations are present in a specific tumour (using techniques like liquid biopsies, which we have written about before), we can use this new generation of drugs to target all of the different mutations present. This may, for the first time, allow us to design a treatment specifically aimed at stopping resistance arising.Vast resources are now being invested in developing these targeted therapies. There already have been some significant successes. For example, breast cancer, lung cancer and melanoma patients can now get different drugs depending on the mutations present in their tumours. It is unlikely that we find one drug that will cure cancer, but research in this direction will help us to refine treatments and ultimately improve patient survival.
The cost of a cancer breakthrough
A new combination of drugs marketed by Bristol-Meyer Squibb has been hailed as a breakthrough in cancer treatment. Almost every media outlet carried a story about the results of a trial that were announced at a conference in Chicago yesterday, with the usual hype. The results are quite remarkable. 58% of metastatic melanoma patients treated with this new drug combination saw their tumours shrink, with the tumours stable or shrinking for a median of 11.5 months. This is amazing when you consider that metastatic melanoma was thought to be largely incurable as recently as 5 years ago. The drugs are each a form of immunotherapy. This refers to a therapy that works by making the patient’s own immune system attack the tumour. In this case, the combination targets two separate mechanisms tumours use to avoid the immune system. Firstly, one drug (Ipilimumab) targets CTLA-4, which is made by the tumour to suppress the immune system. The second drug (nivolumab) targets a protein called PD-1, which prevents the immune system from killing the tumour cells, even if it does recognise them as bad.This is quite a significant breakthrough in the treatment of melanoma but it does come at a cost however. The treatment has significant side effects, with over 80% of patients experiencing these. Furthermore, 55% experienced severe side effects, and 36% of patients had to stop treatment as a result.There is also the issue of cost, a problem I have discussed in a previous blog. Ipilimumab has already been approved by NICE at a cost of at least £42,200 per QALY. Nivolumab hasn’t yet been appraised by NICE, so it’s cost per QALY isn’t available, but in the US it is slightly more expensive than Ipilmumab, costing roughly $150,000 dollars per patient per year. As a combination, it is estimated that it will cost patients in the US $295,000 per year. This may well prove a stumbling block for an already creaking NHS. However, as both Merck and Roche have their own versions of these drugs, the hope is that the competition will force the manufacturers to drop their prices. Whether they will or not remains to be seen.Unfortunately, this breakthrough isn’t the cure that some articles say it is. Between cost and side-effects, there will be problems prescribing it to many patients. It is a welcome advance however, and does herald the development of immunotherapy as another arm in our treatment of cancer.Edit (03/06/05): The $295,000 figure comes from adding the list price of the two drugs. Some outlets are reporting that a discount may be applied to that, making the drug considerably cheaper, potentially bringing it closer to $200,000 per patient per year. While this is a significant discount, $200,000 per patient per year is still a staggering cost. To put it in perspective, if every patient with late stage melanoma was given this drug, Bristol-Meyer Squibb would make over $2,000,000,000 per year from it. When you consider that this is from only the late stage patients, with only one type of cancer, you can see why some people have a problem with the pricing of this and other drugs.
Why are some drugs not provided on the NHS?
The decision not to provide a drug on the NHS can have a devastating impact on patients and their families, and often causes a negative public reaction. However, therapies are getting increasingly expensive (particularly cancer therapies) and NHS has a very limited budget. As a result, in spite of the impact on patients and public opinion, 36% of cancer drugs evaluated since the start of 2014 (see pie chart) have been rejected, usually on the basis of cost.Whether a drug is made available or not on the NHS is decided by the National Institute for Health and Care Excellence (NICE). This is an independent body that looks at the efficacy and cost-effectiveness of any new therapies, and makes recommendations based on their findings. In Scotland, there is a separate organisation (the Scottish Medicines Consortium) that makes the decision.The main metric that NICE uses to make these decisions is the Quality Adjusted Life Year (QALY). This takes into account the quantity AND quality of extra life given to the patient by a particular chemotherapy. So if a drug gives a patient an extra year of perfect health, it is given a QALY of 1.0. If the extra year is not in full health, it is given a value below 1 to account for this. For example, if a new treatment allows a patient to live for 2 additional years compared to the old treatment, but only with a quality of life weight of 0.6 (perhaps the patient is in severe pain as a result), then the treatment gives 2 * 0.6 = 1.2 QALYs to the patient.NICE has set guidelines on how much it can pay per QALY gained. That price is around £30,000, but can rise to £50,000 in some rare circumstances. Now compare that figure with the table below showing NICE recommendations on cancer drugs since the start of last year, and you can begin to see why it has had problems with some cancer therapies, with many drugs estimated to cost over the £30,000 threshold.
| Drug | Recommendation | Cost per QALY* | |
| Pixantrone | Optimised¶ | £22,000 | Link |
| Aflibercept1 | Not Recommended | £44,000 | Link |
| Pemetrexed | Not Recommended | £74,500 | Link |
| Afatinib | Recommended | £11,000 | Link |
| Bortezomib2 | Recommended | £17,800 – £39,600 | Link |
| Enzalutamide | Recommended | £22,600 | Link |
| Ipilimumab | Recommended | £28,600 | Link |
| Dabrafenib | Recommended | £11,000 | Link |
| Imatinib | Recommended | £16,700 - £30,000 | Link |
| Sipuleucel-T | Not Recommended | £48,700 - £512,000 | Link |
| Axitinib | Recommended | £33,500 | Link |
| Pomalidomide3 | Not Recommended | £50,000 - £70,000 | Link |
*depending on treatment ¶Recommended for a smaller group than applied for 1Aflibercept in combination with irinotecan and fluorouracil-based therapy 2Bortezomib in combination with dexamethasone, or with dexamethasone and thalidomide 3Pomalidomide in combination with dexamethasoneThis problem has been partially addressed by the creation in 2010 of the Cancer Drugs Fund, which provides funding for treatments that NICE haven’t judged on yet, or has deemed too expensive. This fund is due to finish in March 2016, but for the time being it provides an additional £340 million per year to pay for cancer drugs. The UK government have yet to comment on the long-term prospects of this fund.It must also be pointed out that this is not a problem with cancer drugs specifically. Many other diseases are facing the same problems. The cystic fibrosis drug Ivacaftor, for example, has had the same issues after it was priced as one of the world’s most expensive medicines (between £335,000 and £1,274,000 per QALY). Despite the cost, this drug is being used for a small number of patients in the UK. There was an extremely good article about the ethical concerns the over pricing of this drug in the British Medical Journal last year that I would encourage everyone to read it (available here for those with access, and by e-mailing us via the contact page on this site for those without).This all brings up another issue: are pharmaceutical companies over-charging for their treatments? According to a 2014 report, the cost of developing a new drug is now $2.6 billion (£1.7 billion), and takes over 10 years. The pharmaceutical companies argue that they have to make their drugs expensive in order to recoup their costs, and this is a valid point. This statement is slightly dented however, by the fact that the industry spends more on marketing than on research, a point well made by John Oliver in his show Last Week Tonight (below). Add to this the fact that the pharmaceutical industry makes a higher profit margin than any other industry, and the pricing of these drugs begins to look unreasonable. This issue is beyond the scope of this blog but you can find more information in this excellent BBC article.It is said that we are beginning the era of “personalised medicine”. Each person will receive a specific treatment for their cancer depending on the genetics of their disease. While this will mean more effective treatment of the disease, it also means that fewer patients will be getting any one drug. Cancer drugs will be used on smaller and smaller subgroups of people, which is likely to increase their price, as the cost of drug development is unlikely to drop. This raises difficult questions for an already struggling NHS. In a time of increasing drug prices and increasing cancer incidence, the challenge of funding these therapies will be a pressing issue for years to come.
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