Nitroglycerin and cancer drug therapy

Following on from the paper on the anti-parasitic drug mebendazole (which I first discussed on this site a while ago) and the antacid cimetidine (paper not yet published), I've been working on another ReDO paper on the drug nitroglycerin. Like all the repurposed drugs we're looking at in the ReDO project this one is commonly used clinically for non-cancer uses, in this case it's a drug used to treat heart problems and blood pressure. Available as tablet you stick under the tongue, or a spray or even a transdermal patch, nitroglycerin is a drug that has been used for over a 100 years as a vasodilator - in other words it relaxes the blood vessels. It's partly this property that makes it interesting in terms of anti-cancer treatment.

Like other tissues, tumours need a blood supply for food and oxygen, and it is well-known that they release chemical signals that cause new blood vessels to form. This is the process called angiogenesis, and for many years scientists have been looking at ways to disrupt the process - with drugs like avastin (bevacizumab) developed to stop this happening. The idea is that with no blood supply tumours can't grow. However, even when angiogenesis does take place and tumours sprout the blood vessels they need, the vessels that are formed aren't normal. The blood supply is chaotic and the vessels are much leakier than normal. Back in the late 1980s some scientists started looking at how we could use this to our advantage. The idea is that you take advantage of the leakiness by using drugs that leak out into the tumours rather than spreading throughout the body (as normal chemo does). Hiroshi Maeda and his co-workers termed this the 'enhanced permeability and retention' (EPR) effect.

Nitroglycerin enters the picture as a way of making the leakiness worse by relaxing the blood vessels, thus encouraging large drug molecules to leak into the tumours. And once they've leaked out, the chaotic structure of the vessels means the drugs are retained in the tumour where they can have an effect. It is, in theory at least, a way of targeting anti-cancer drugs to the tumours and not to the rest of the body. It's an elegant idea and has lots of experimental evidence going for it. And the evidence includes some small trials in humans - primarily in lung and prostate cancers. There are more clinical trials on-going, and we can but hope that their results encourage more work in this area. To really work well we need to team up the nitroglycerin with some reworked chemotherapy drugs that are specifically designed to work with the EPR effect.

Gina Pantziarka 1964 - 1994

Everyone has a cancer story. Mine started in the summer of 1994. My wife, Gina, had given birth to our second child – George – a year previously and had been suffering a bit from the blues. She’d been feeling tired, low, generally out of sorts. It was hard to pin down any particular thing that was wrong, she just felt exhausted all the time and there were these odd symptoms that seemed to come and go. For example her menstrual cycle seemed to be out of whack, or at least there were a couple of times when there were unexpected bleeds mid-cycle. Was that the sort of thing that happened after giving birth, didn’t it just take time for things to settle down again? In any event a couple of visits to the GP didn’t suggest anything other than a mild bout of post-natal depression. In the summer we were due to go on holiday to Cyprus, it was where she was born and we always holidayed there so that she could get to see her parents and her sister.

Normally she really looked forward to going on holiday, but this time she was just feeling worn down. Something wasn’t right, but she was only 29 years old and had no history of illness. She’d put on a fair bit of weight in the previous few years but other than that there was nothing to cause concern. A week before we were due to leave I suggested she go back to the GP and explain what was going on. The doctor seemed to be a bit perplexed and hesitant and suggested that some investigations might be in order. It was all a bit tentative. How urgent should these investigations be? Gina wasn’t really sure how concerned the doctor was, so I called the GP to ask the question directly: did we need to postpone our holiday? And the answer was clear enough, there was no reason not to go on holiday.

We spent two or three weeks in Cyprus. Gina’s parents were over-joyed at their new grandson and thoroughly besotted with their grand-daughter, now seven. It was a tiring holiday in many respects. We did a grand tour of family on both sides and for a while Gina seemed back to her old self – always smiling, chatting and enjoying company. Towards the end the tiredness was edging forward again, not that she complained much, though she did let on to one of her cousins that it had been a bad year so far and she couldn’t wait for it to finish and a better year to start.

Report from Metronomic Chemotherapy Conference

Chemotherapy remains at the core of much current cancer treatment. Along with radiotherapy and surgery, it’s one of the big three that nearly every cancer patient has to face in the treatment of disease. Many of the ‘classical’ chemotherapy drugs have been in clinical use for decades now, and you would think we would know all there is to know about how best to use them. Unfortunately it appears not... 

The most common approach to chemotherapy is the multi-drug maximum tolerate dose (MTD) protocol. Here you take a set of drugs that work in slightly different ways and then blast them into the patient in a fixed pattern and at the highest possible dose. These cocktails are incredibly toxic – they knock out cancer cells but at considerable collateral damage. Patients lose hair, suffer sickness, loss of immune system, suffer damage to the heart and other organs. It’s a horror and nobody looks forward to chemo. On the plus side there is often a considerable amount of tumour kill, at least at the beginning. But very often tumours develop resistance, the drugs stop being effective and the side effects continue.

However, there is an alternative approach to using these drugs called metronomic chemotherapy. This involves giving considerably lower doses of these drugs but much more frequently. Here, instead of blasting the patient with chemo and then leaving them for a couple of weeks while they recover from the blast – time in which the tumour can also recover – you give a steady drip-drip of the drugs instead. The side effects are considerably lower and quality of life is much higher – especially as the drugs are usually given in tablet form on an out-patient basis.

A new surgical technique for bone cancers

When it comes to bone cancers – such as osteosarcoma or Ewings sarcoma – surgical removal of the tumour-bearing bone is part of the standard treatment. Chemotherapy is part of the treatment, and sometimes radiotherapy, but resection of the bone is at the core of any curative program.  In days gone by this used to mean amputation of a limb, but these days a lot of work goes into limb-sparing surgery. And of course for those cases where the tumour is not in a limb, amputation isn’t an option any way.

In practice this means that very often surgery involves not just the removal of the effected bone, but also taking bone from another part of the body and slotting it into place a replacement. In my son’s case, George had three separate operations to treat the osteosarcoma in his jaw. The second and third time the ‘new’ mandible had to be replaced with a ‘newer’ one – in the end bone taken from his leg, his hip and a rib all to craft new jaw bones. While his was an extreme case, it shows what surgeons are capable off – but also gives an idea of how much trauma is involved to the patient. Some of the operations took more than 12 hours to complete. 

But what if there is a way to reduce the scale of the operation? What if the surgeons didn’t need to harvest new bone to replace the diseased one?

Surprisingly, such an approach does exist. It involves removing the diseased bone – making sure there are good margins as normal – and then the bone is treated to definitively kill the tumour cells. This is achieved by placing the resected bone in liquid nitrogen or bombarding it with very high doses of radiotherapy. Then the treated bone, now stripped of disease, is replaced in its original position. No need therefore to operate on other parts of the body to harvest bits of bone. No need for extensive remodelling.

Does this radical new treatment work? Recent papers show that the results are very good – there are lower rates of complications, low rates of disease recurrence, and of course lower risks of infection and faster recovery times.  For example in one study, published in the Bone and Joint Journal (http://www.bjj.boneandjoint.org.uk/content/96-B/4/555.abstract), no recurrences are reported at all in the grafted bones. 

That’s the good news. For patients in the UK the bad news is that this procedure, which was first used in Japan about 10 years ago, is not available. I remember asking for this for George, but got a blank look in return. So far as I know this is still not available in the UK – though I’d love to find out that someone, somewhere in the NHS has started doing this. It would make a huge difference to those people who’ve got primary bone cancers or bony metastases.

The Case of Ashya King

The sad case of Ashya King, the five year old with a brain tumour who was taken from hospital by his parents, has generated huge amounts of publicity in the UK and has focused attention on the issue of cancer treatments available abroad that are not easily accessed or available in the UK. I write as someone who has faced this problem with my own child, George, and as someone who has helped other parents access treatment abroad. In this country it’s extremely difficult to criticise the NHS, it’s seen as a betrayal somehow, yet there are serious problems which have to be discussed. I’ve written before about the abysmal figures for osteosarcoma in this country, figures which lag behind some of the other countries in Europe. It’s a similar story with some other cancers, particularly some of the rarer cancers.

In the case of Ashya King, the family wanted their child treated with proton beam therapy, but it’s not the only instance of treatments which are available abroad but not in the UK. There are numerous kinds of ablation treatments in use in other parts of the world which are not often used in the UK – cryoablation, radiofrequency or microwave ablation and so on. In some cases there is treatment in the UK at one or two centres and only for one or two cancer types, whereas in the other countries they treat a wide range of cancers and at more centres.

The hard part comes for parents who’ve identified a treatment and then try to get approval and funding to get that treatment. This is incredibly hard to do. Socially we are not used to demanding things from doctors – we are brought up to be respectful and not to question. It takes a lot of guts to actually disagree and make a demand. If you are lucky you’ll get a hearing, but more often than not you’ll be turned down, fobbed off or made to feel stupid. Persuading your doctors is one thing, assuming that you get through that hurdle – and many people don’t – the next step is to get funding. Again there are some fantastic cases where everything works and people are referred abroad for treatment. In many more cases there’s no funding. In which case people have to fall back on savings, on family and friends, even on taking out loans and new mortgages. Not only is this hard on families financially, it takes time and energy that should be focused on the child not fighting the system.

So, never let anyone tell you that everything is wonderful in children’s oncology in the UK. Especially now, with this case in the news and at the start of Childhood Cancer Awareness month. There are some fantastic people there, some great doctors and nurses, but also a system that is monolithic, moves at a snail’s pace and is resistant to change. And don’t underestimate the bravery and courage required to be a parent of a child with cancer who has to fight that system.