The Latest Treatments for brain tumours

The Latest Treatments for brain tumours
This article by Madeleine Kingsley centres on an interview with Dr Henry Friedman (Duke Medical Centre in America), one of the world’s foremost brain cancer experts on the latest brain tumour treatments. At the end there is a link to Part 2, which looks at the coming  treatments and centres on an interview with UK expert Dr Mike Brada.
CANCERactive was founded when Catherine Woollams and her father realised there was far more to beating cancer than a few drugs, some radiotherapy and surgery. The things they discovered, they simply wanted to pass on and CANCERactive and  icon magazine were born. In the first magazines, we featured brain tumours but, then, that is the cancer Catherine had and it was ’incurable’. Eight years later it is time to review how treatments have progressed. In Part 1 of this review Madeleine Kingsley interviews top US brain cancer specialist Professor Henry Friedman on the current state of play. In our next issue of icon, in Part 2 Madeleine will follow this up with an interview with the UK’s Mike Brada and a look at what treatments are just around the corner.
By Madeleine Kingsley
For all the ongoing challenges of treating brain tumours, the picture seems a good deal more positive than it was 10 years ago when icon and CANCERactive founder Chris Woollams embarked on his tireless research quest to help his daughter Catherine who, at 22, had been diagnosed with an aggressive brain tumour a grade 4 glioblastoma. Chris launched this magazine after discovering how incredibly hard it was to source the scattered and often inaccessible information needed to optimise quality of life and survival. He pledged then that no one on the cancer journey ’should die of ignorance’ and recognised at once that knowledge should offer empowerment, not just problems and morbid statistics.  As Catherine put it: ’Dad, I’m not interested in cancer. I’m only interested in living.’
There is no denying that the decade of medicine that’s passed since the icon launch has delivered no cure and no magic bullet for brain tumours. The much-publicised deaths of Beatle George Harrison, of politicians Mo Mowlam and Ted Kennedy, and all the unsung losses of those close to us, remind us why Geoff Pilkington, Professor of Neuro-Oncology at the University of Portsmouth stresses ’We need to do much more.’
Every year in the UK, some 4,500 people are newly diagnosed with a brain tumour (including both primary and secondary masses). The number of adult sufferers has been rising by around two per cent annually since the mid-nineties. More men under 45 and more women under 35 die from a brain tumour than any other cancer. Only 14 per cent of sufferers reach that significant five year water mark after diagnosis. And at present, only 0.7per cent (note that’s less than one per cent, not 7 per cent) of national cancer research is currently spent on brain tumour work.
Remembering Catherine, it seems important to report that although not won, the war against brain tumours now has considerably more weapons in its armoury. It’s important too, to pass on the message of hope now coming from experts and survivors alike. Singer Russell Watson is touring again after a second, more aggressive brain tumour resection and he actually credits surgery with enhancing his voice. Rob Daly, father of our teenage diving Olympian Tom Daly, does not expect his cancer to prevent his poolside presence in 2012.
Hope is perhaps less prevalent here, where the Mail on Sunday recently headlined a brain tumour story ’The cancer we may never cure’ and too many consultants are still to ready to pronounce the devastating worst-case scenario. From the States, Professor Allan Friedman, co-Director of the Preston Robert Tisch Brain Tumour Center at Duke Medical Center, North Carolina posts an upbeat response: The odds are in our favour for major achievement and long-term answers, he maintains. His colleague and co-director, neuro-oncologist Dr Henry Friedman (no relation) concurs: We know that a brain tumor is unlike any other disease. We take an aggressive team approach to find answers and provide hope. We play to win. We want survivors.   One Duke patient, Amy McClure Pomykal (see complementary story) is doing well nine years after diagnosis, during which time she has given birth to two healthy babies. Another, musician David Bailey, died recently after being given six months to live more than 14 years ago when he was 30 and had just had surgery on his glioblastoma multiforme. That was before Dr Henry Friedman returned his call (even though, Bailey recorded in surprise, it was 10.30 at night) to say ’You’re too young to die, come down, page me and I’ll see you immediately.’  In the terror and confusion of new diagnosis, when your previously assured future flies apart and a black, Bosch-like pit seems to beckon, it makes a world of difference to be heard as a human, not just a case number - to feel that you matter to a confident consultant who stints no time, no effort. 
Professor Henry Friedman’s Progress Report
As far as primary brain tumours are concerned, Dr Henry Friedman says that the major gains of these past 10 years ’have, for the most part, come not from refinements in the technology per se of surgery and radiotherapy, but the ever-increasing awareness that a major resection (compared to a sub-total, or minor resection), together with a precisely delivered radiotherapy, whilst not curative, increases the duration of survival and the quality of life. This data is more than 10 years old, but it remains the foundation on which we should continue to remember to build for the therapy of malignant glioma.’
As to the additional modalities that have generated so much enthusiasm in recent years, Dr Friedman says ’There is no question that Temodar (Temozolomide), which was a British-synthesised compound, has proven to provide a modest benefit to patients with malignant glioma. I don’t think it is the definitive answer but it does provide a better outcome in many patients than they’d see with chemotherapy alone.
(Temozolomide is an alkylating agent that works by stopping cancer cells from making new DNA. If they can not make DNA they can’t split into two new cancer cells.)
Is there anything else that’s come down the pipeline? Certainly I believe that in the past 10 years there have only really been three drugs that have emerged. One involves a delivery system a wafer called Gliadel.  Gliadel has had a lot of mixed publicity but to my mind it does still contribute to an increase in survival in patients with malignant glioma. The wafers are introduced in the tumour cavity during surgery and can take the brain tumour drug Carmustine, a mustard gas derivative known by the trade name BCNU, straight to the target, rather than administering the drug intravenously, resulting in its dilution and wastage around the body and breakdown by the liver. BCNU is an alkylating agent attacking cancer cells in the resting phase before re-growth and cell division.
A research report from Dr Friedman finds a 27 per cent survival increase three to four years post surgery. 
And I believe that the role of Avastin, though not approved in most European countries (Switzerland alone has sanctioned its use), has been shown to increase the quality of life and the progression-free survival of brain tumour patients. It has a better response rate than anything else that’s ever been found for patients with malignant glioma.
The trio of drugs Gliadel, Temozolomide and Avastin are the only three that have been approved in the United States in the last 30 years. (BCNU and CCNU were approved earlier) Gliadel and Temozolomide have contributed to variable increase in the survival of patients with newly diagnosed disease while the data for Avastin is so far confined to recurrent disease. Dr Friedman (who makes it clear that he is a consultant and spokesman for both EISAI, which now makes Gliadel and for Genetech, which makes Avastin) explains that studies in progress are now evaluating the potential benefits of Avastin in the newly diagnosed brain tumour patients both in the States and in Europe. It is very interesting, he reflects, that the European neuro-oncology community took the rather unprecedented step of leading the denial of Avastin for approval in recurrent malignant glioma even though it was advanced to trials evaluating its activities in patients with newly diagnosed malignant glioma. This seems at face value rather puzzling. If Avastin is not good enough to approve for recurrent disease, then how could one reasonably justify its evaluation in the newly-diagnosed? When you ask the neuro-oncology community in Europe, then they say ’Well it didn’t go through the appropriate trials in Unites States (comparative randomised phase 2 trials). It was approved on sub-optimal data’.  Well if it was so approved and indeed, in England, they are now doing studies that ask the question, why would you even have the nerve to evaluate it in newly diagnosed patients when you don’t have convincing proof in your own mind that it works in recurrent disease? That’s a question worth posing.
So here, it seems lies a key difference between the oncological outlooks of America and Europe. There’s a certain degree of European nihilism, Dr Friedman suggests, that is less operational in the US.  One could argue from the European standpoint that there is more rigour attributed to trials than there are in the States. I think that would be wrong. I just think that the European community tends to be more pessimistic than the European community.  Is this pessimism, icon asks, in the best interest of patients?
Dr Friedman also points out other promising protocols that are on the way: Vaccines look to have potential, but have not yet been through truly randomised phase 3 trials that could unequivocally prove the benefits. One-armed studies, however, suggest that vaccines represent a very exciting new arena of research that will hopefully in coming years wind up giving us better weapons. There’s also potential in Cilengitide, (an integrin inhibitor that is anti-angiogenic, developed by Munich University and the drug company Merck) which is undergoing some early trials and looks like it may well be a drug that has benefit in this patient population. It certainly bears evaluation.
So the good news, Dr Friedman sums up, is that there are new approaches and new compounds that are moving forward, that lend us the potential for better outcomes. In general most centres in the United States are seeing longer survival. They are either getting more supportive care, or they are getting better results because of the actual care itself.  I don’t think I can answer that question. It may be that we are giving more focused attention to the patient’s need than one saw in the past more attention to the side effects of chemo, the side effects of tumour I do think we take better care of our patients now and that there are more weapons to use in providing ancillary help, whether this be anti-depressants, or in our philosophical approach. There are altogether more weapons out there and we are, unequivocally, going to see better survival of these patients. If we continue both to push ahead with this optimistic approach and conduct the trials to advance the field, we’ll do better still.
Why is science not seeing more, faster progress?
Compared with other cancers, brain tumours are very diverse and their biology highly complex: So, as Geoff Pilkington, Professor of Neuro-Oncology at The University of Portsmouth, explains, the challenges of treatment are particularly tough: Surgery cannot guarantee removal of the whole tumour. It’s ’a bit like removing a spider from jelly; you get the body out, but a few legs often get left behind.’ Radiotherapy can sometimes provide a cure, but can also invoke new tumours at the site of radiation. It can also cause residual damage to surrounding healthy tissue, disabling patients or triggering developmental problems in children. Chemotherapy does not cure and even where it does shrink the tumour and extends life it too often makes the patient feels worse and attacks the immune system. In the head there is also the additional problem of delivering drugs directly to tumours, as they must first penetrate the blood brain barrier.
These were the difficulties Geoff Pilkington one of the UK’s most eminent scientists in this field - outlined in his Mail on Sunday feature. But he never intended the ghost-written piece to suggest the negativity of its title. His prime intention, he stresses, was to gain recognition for what could be achieved in the brain tumour field given money and tenure opportunity for young scientists. Also essential in his view, is real co-operation between biologists and the pharmaceutical companies at present dedicated to promoting their own individual drugs.  After four decades of research, Professor Pilkington (now intent on securing continuity and expansion of his research when he retires in five years time) knows as well as any man alive how much more must yet be done. But the message we need to get out should be upbeat. The issue is that it’s taking so long to translate what we do in the laboratory to trial stage. This is still a grossly underfunded discipline, despite the emergence of some 20 wonderful charities which are now beginning to co-operate rather than work in isolation.
Changes of approach needed both biological and organisational
The reason that the survival curve has not headed further upwards is that we are not taking sufficient heed of the biological nature of brain tumours, says Professor Pilkington. We tend to use a one-hit alkylating agent - the sort of drug that attacks the nucleus of cells. Temozolomide is the latest generation of these and is perhaps better than the former PCV drug regimen, offering better quality of life because patients can take it orally at home. We’re looking at these single agents largely because drug companies want their quid pro quo and, understandably, will only go down the line that produces gain. If we could only get the drug companies to work together with each other as well as with tumour biologists, collegiately rather than independently, then the various approaches could be more effectively evaluated in concert. There are currently a few different approaches either trying to kill cells through the nucleus or the mitochondria the energy-metabolising centre or by depriving the tumour of its nutrient and oxygen supply by depriving it of its blood vascular supply (anti-angiogenesis therapies).
Anti-angiogenesis tumour kill or tumour spread?
Here’s how anti-angiogenesis approaches work: A tumour feeds off the local blood supply from the surrounding brain, but the bigger it grows, the less effective its vascular supply becomes. So where the centre of the tumour lacks oxygen you get necrosis (death of tumour cells). The surviving tumour cells then send out a chemical messenger, VEGF (vascular endothelial growth factor), which recruits blood vessels from surrounding normal tissue. Researchers are trying to block the receptors on the cells which are required to activate this process because if you block the VEGF receptors you stop angiogenesis and the tumour dies. That’s the basis of how such drugs as Avastin and Recentin (marketed by two different companies) work. The big problem with that is that it’s being given to patients on the basis that, if deprived of blood, all the tumour cells will die. However, in a low oxygen concentration, a sub-population of tumour cells called cancer stem cells become activated.  What happens then is that this residual population of cells can refuel the growth of the tumour. In other words, by creating a low oxygen environment through anti-angiogenesis, you are producing the optimal environment for these cancer stem cells to proliferate, divide and migrate into surrounding brain tissues. And they are universally resistant to anything we have thrown at them to date.
The scientific sequence that could provide the answer
Professor Pilkington identifies that the next research task is specifically to address this stem cell population: If we are to use an anti-angiogenic approach we then need, downstream from that, an anti-invasion approach. So by depriving the tumour of its oxygen supply a large number of tumour cells will die but if we then use an anti-invasion strategy we can stop the residual cancer stem cells from invading into the adjacent brain. Since blocking cells from movement seems to increase cell division perhaps a cell-killing therapy which crosses the blood-brain barrier could then be used to deal with remaining tumour cells.
So if we utilise all the things we have at our disposal and put them in the right order so that we are second-guessing what the tumour is going to do next, we should be able to work out a reasonably successful multi-modality treatment. In short, although this is an over-simplification, we need to be able to control the biological behaviour of the tumour cells instead of just being able to whack them on the head and kill them.  At the moment the multiple therapeutic regimens we need don’t exist. They should do. People need to work together in effective co-operative research. We have to get the clinical folks to engage with those in the lab and vice versa to move things forward.
In my laboratories, he says, we are currently working on the blocking of molecules which are key to brain tumour invasion and which, in time, may prove to be of value as clinical targets for therapy. In addition, we are specifically isolating resistant cancer stem cells from brain tumours and trying to modify these cells to overcome their resistance to therapeutic agents. We are, more specifically, trying to develop a gene-based approach delivered to brain tumour cells by a specific virus in order to modify a molecule on the surface of these cells which will lead to tumour cell-specific death through the mitochondrial pathway. This project is still, however, in its relative infancy and the lab member engaged on this work only obtained her PhD in October so there is, perhaps, another three years required to fully develop the system towards the clinic.
Forward march.
Finally the UK has the mechanism for a united, committed approach to tackling brain tumour disease: In October 2010 an all-party government Brain Tumour Manifesto, bringing together for co-operative effort, the major UK charities Brain Tumour Research, Brain Tumour UK the Samantha Dickson Brain Tumour Trust to link with the International Brain Tumour Alliance. These bodies will now also engage with the British Neuro-Oncology Society, of which Geoff Pilkington becomes President next year. Getting everybody to work together is going to take a long time. But the more people collaborate, the more they will begin to sing from the same song sheet and the better the outcome. We have to speed things up with more government funding. Getting regimens from the lab into the clinic also requires drug companies to put in substantial sums of money and to work co-operatively. I would also like to expand Brain Tumour conferences to include scientific sessions for patients and carers. Anyone concerned needs a degree of clarity about what they are facing - why they are offered one approach and denied another. 
Is the patient situation really better in America? It’s easy to say that there must be something better on offer in the States, but mostly things are pretty similar on both sides of the Atlantic. However patients increasingly demand clarity from their clinical teams; from neuro-oncologists and from their clinical nurse specialists in Neuro-oncology. But with the enormous amount of complex and variable information available these days on the internet the scientists should also engage and embrace patient needs by demystifying the science and putting their research into context in lay terminology.
Readers Might like to look at ’Oncolytic Viruses’ in the Alternative Cancer Treatments section of this web site.
Part 2 of the above article is an interview with the UK’s Mike Brada on the coming brain cancer treatments. 


2011 Research
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