‘It is not necessary, in order to make great progress in the cure of cancer, for us to
have the full solution of all the problems of basic research... the history of medicine
is replete with examples of cures obtained years, decades, and even centuries before
the mechanism of action was understood for these cures’ - Sidney Farber, United States
Congress, 1971
In 1971, when President Nixon declared war on cancer, 1 in 30 of us would develop cancer
in our lifetime. Today that figure is 1 in 3.
Longer lifetimes account for a large part of this change, but dramatic changes in our
food chain and lifestyles contribute to this epidemic, with the world health organisation
forecasting a 75% increase in cancer cases by 2030. Conversely, the cold fact is that
despite trillions being spent on research, we have not cured a single cancer since the
1970s. If this is a war on cancer, then we are staring defeat in the face. We are little
closer to overcoming metastasis or malignancy, the holy grails of oncology, than we were
50 years ago. Is it possible that a tiny colony of malignant brain cancer survivors, the most
deadly of all cancers, hold the key to a dramatic improvement in all cancer therapies tomorrow?
Could the next great stride forward in the field of oncology be simply a change in strategy
as opposed to a new drug or technology? And what happens if that change in approach directly
contravenes established medical practice, and the entire clinical trial structure we
have built for testing cancer treatments?
I think that many of these brain tumours and other kinds of cancers are treatable. I just
think that a mountain of evidence is being over looked.
If you face this disease and say from the get go that it is incurable, you will always
be right, all your patients will die, and you have no business treating those patients
in the first place.
They’re trying to protect people. They inadvertently get into a situation where they kill people.
I would not be alive today if I had listened to the only to the advice of my oncologist.
Because as one point he told me that, ‘Well, you should try to consider just staying home
now and playing with your little daughter while you can and not pursue any aggressive
treatments’ … but I decided otherwise.
Surviving Terminal Cancer
The Everest of oncology
The brain poses unique challenges for clinicians: due to its control of every single process
in our bodies, it is very difficult to remove meaningful parts of tissue without removing
meaningful functionality from the human being. This limits the reach of surgery, radiotherapy
and multiple biopsies, some of the most efficacious tools at the oncologists’ disposal today.
Furthermore, the brain sits flush within a fixed volume cavity - the skull - and so the
swelling that is the by-product of carcinogenosis is frequently the primary cause of death in
brain tumour patients as inter-cranial pressure builds relentlessly. Finally, clinicians treating
the brain face a unique impediment in something called the blood brain barrier: a natural
and virtually impenetrable biological coat of armour which protects brain cells from
infections circulating in the body. If we didn’t have such protection then a simple
cold could easily end our life. However, when placed in the context of cancer, this protective
coat of armour makes it difficult to get chemotherapy into the brain. These three aspects of neurology
make clinical practice in the field of neuro-oncology the most severely challenging of any in oncology
today. Compared to other cancers, brain cancer has a very low profile, and yet it claims
more young lives than any other cancer. Nobody survives it’s most aggressive and lethal
form, glioblastoma multiforme, referred to in medical circles as ‘the terminator’.
Part of this is because of the difficulty we just described in treating the brain. But
brain cancer itself is differentiated from more common cancers by it’s cellular heterogeneity:
this means it’s highly differentiated cell populations are inherently complex and varied,
and so simple targeted treatments affecting only some areas can not impact it’s overall
ability to mutate and proliferate. A complex problem calls for a complex solution, and
biological heterogeneity demands therapeutic heterogeneity: or more simply brain cancer
is telling us that each patient is has a different disease, and that they need a different cure.
This genetic instability is the hallmark of all cancers. In this sense, cancer is the
most terrestrial of diseases, starting as a simple malfunction of a living organism,
it demonstrates the same remarkable capacity for adaptation and change, that has defined
of all the great survivors of evolution. It is this ability to modify it’s DNA structure
from generation to generation that results in the phenomenon referred to as drug resistance
- the principal barrier to treating cancer. All of these facts, the limitations of traditional
intervention methods when dealing with the brain, cancer’s most sinister characteristics,
and then additional problems specific to brain cancer, are acknowledged and agreed upon by
every hospital and every expert in the world. The tragedy for brain cancer patients today
is that the care they will receive does not come close to reflecting the scientific knowledge
now at our disposal. This is where the problems facing brain cancer, if they could be solved
today, could revolutionise the treatment of all cancers tomorrow.
‘A round trip to Hades’
In southern California an academic and scientist has dedicated his life to pursuing better
outcomes for brain tumour patients since being diagnosed himself in 1995 with the most aggressive
type of brain cancer, glioblastoma multiforme. Given only a few months life expectancy, Professor
Emeritus Ben Williams was an extraordinary patient, and now nearly two decades later,
he is an extraordinary survivor for patients, his book Surviving Terminal Cancer is a source
of frank assessment and logical analysis of all available treatment options, often lacking
from their own medical team. Every year, Ben updates this invaluable source of information
making it freely available to any patient surfing the internet via a national brain
tumour charity. His remarkable journey has taken him from moribund patient, to highly
respected survivor and patient advocate.
When I was diagnosed with brain cancer I knew almost nothing about the disease other than
that it is one of the worst medical diagnosis you can get. My first reaction when I heard
of that was to basically have a shiver down my spine because I knew I probably didn’t
have much chance of surviving. I hadn’t even heard of a glioblastoma at that point.
I was told that it was the worst kind of tumour you could have and that nobody survived it.
For the first couple of weeks after that I was just in shock. I mean there was no other
way to describe it.
Ben was told he could expect to live for 12-18 months if he was lucky, and that the chemotherapy
treatment available to him would not save his life.
For the first several months, most of my thinking was, you know well, I’m going to die. How
am I going to deal with it? And I thought a lot about death. The treatment was just
sort of something I was just following along because I didn’t know any better at that
point. There were no options that were presented to me. What you are faced with is well, I
don’t really have a choice. This is going to kill me and I better try and figure out
how to make that as easy a process as possible.
Like all patients Ben was prescribed the standard of care: immediate surgery, followed by intensive
radiation and chemotherapy.
When you receive a diagnosis that every one tells you is terminal - that no one survives
it - it’s impossible not to become depressed by that information. I mean I look at pictures
from that period of time and I mean, clearly I was depressed and it wasn’t until I began
doing research that said there was a possibility, that there are things you can do that would
be helpful and I began to think - well this is worth at least making the fight. And the
more information I began to find, the less depressed I became, and the more optimistic
that things were not nearly as terrible as everyone was telling me.
However, before the era of the internet, Ben’s task of educating himself quickly was considerable.
The first couple of months I basically did nothing else but reading. It was a crash course.
I knew I didn’t really have much time to do a comprehensive education so I was really
trying to find a shorthand account of what I was dealing with. Unfortunately most of
the articles were every bit as discouraging as what I had been told initially as they
almost all began with an introduction that said glioblastoma is universally fatal. But,
the more research I did, the more leads that I came across about things that had been ignored
and things that - at some early stage data from clinical trials that really hadn’t
gotten much attention but still looked quite promising and - it seemed like it was totally
sensible to try and add those things into whatever else I was being prescribed to do.
So I found, you know, several different drugs that had good evidence from medical literature
of benefitting people with cancer - some of them specifically with brain cancer but others
with cancer in general. I mean things like (immune stimulants) and things that were
used widely else where so that I found one mushroom extract that was used in Japan routinely
in almost all cancer treatment protocols and yet it is never mentioned in the United States.
It has zero toxicity. Why would you not use it? I mean millions of people in Japan use
it. That’s a big mystery to me. How you can just disregard something that has credible
evidence.
But Ben's line of thinking was met with surprising opposition.
My neuro-oncologist raised the question - well you don’t want to add these things because,
you know, they have a lot of toxicity and I thought, well not from what I know about
them compared to what you’re about to give me. And it turned out that while I had some
side effects of some of the things they were really nothing of major consequence so I was
right about the idea that they were worth trying.
With a PHD from Harvard and a chair as Professor of experimental psychology at the University
of California, Ben had the courage of his convictions, a critical tool the vast majority
of patients lack.
I realised fairly early that medical practice is standardised for everyone and pays almost
no regard for the individual variability of patients. When I first asked my oncologist
- my neuro-oncologist - if I could add the first agent that I used - it was high dosage
Tamoxifen - to what he was offering in terms of a chemotherapy program. He just out right
refused. He was unwilling to bend and we had a major altercation over the phone and it
ended up with him basically saying that we couldn’t work together and so whether he
fired me or I fired him, I was without a neuro-oncologist at that time. But fortunately my neurosurgeon
intervened and convinced my neuro-oncologist that maybe they should let me do a little
bit more in terms of participating in my own treatment program than they would ordinarily
do. Eventually we got along quite well but I never did really tell him everything I was
doing after that. Going against the advice of my doctors was really initially an act
of desperation. I mean, I wasn’t concerned about offending them, I was concerned about
staying alive and so I was going to use anything I could get my hands on, and if that made
them angry, well that was too bad. At one point I was going down to Mexico, to Tijuana,
to obtain a drug normally used for acne which also had been shown to have some treatment
benefits for glioblastomas. I had to go to Mexico because the drug required a prescription
and I knew it was going to be a great difficulty obtaining it here so I was taking that all
along without the knowledge of my neuro-oncologist. The irony was that when I eventually told
my neuro-oncologist what I had done, he said to me ‘that was a very nice study that MD
Anderson did’ – he knew about it all along, but it was not a part of the standard treatment
and so he’d never even mentioned the possibility. In most cancer treatment protocols there is
a standard treatment that the oncology community has agreed upon and they don’t deviate from
it except in the context of clinical trials. That realisation, the beginning of my deep
anger about how the medical system was working - It made absolutely no sense to me not to
use everything that might have a benefit as long as the toxicities were acceptable. Why
wouldn’t anyone want to add them? It seemed to me totally irrational that people didn’t
use everything that was available.
With this strategy Ben constructed a cocktail of drugs around his chemotherapy. When his
MRI scans began to show his tumour gradually reducing in size, and eventually disappearing
altogether 6 months later, it was clear that something very unusual was taking place.
After my first round of chemotherapy I did get a small amount of shrinkage in my tumour.
That was a tremendous weight that was lifted off of me. I mean I didn’t feel of the kind
of depression that I had felt up until that time. I mean, I was ready for the battle at
that point because it didn’t seem hopeless. So I started adding even more things at that
point. And then after the second round of chemotherapy I had a lot of progression in
the tumour, and then after the third round of chemotherapy, a lot more. Then I had a
clean MRI after the fourth round. And I’ve got clean MRIs ever since. People are always
raising the question - so this might have worked for you, but maybe you were just a
rare case that responded to chemotherapy’? Did any of these other things that you added
make a critical difference? The hallmark of my case was that the chemotherapy did work
for me. I mean, I had something was different about how I was getting the chemotherapy and
the things that went with it, and I had deliberately focused on that. I mean, I though seriously
about where the resistance to chemotherapy came from and how one might overcome it.
Now retired, Ben spends a great deal of his time responding to the desperate enquiries
of patients who have read his book, offering impartial advice whilst never advocating specific
treatments.
We’ll never know for sure why I’m still alive. Certainly I did things that were unusual,
but, you know, I might have done things that were unusual in terms of the characteristics
of my tumour. I don’t think that’s an argument I take seriously now because I have
advised a lot of people over the years to adopt a similar approach. They didn’t do
exactly what I did, but they added as many things as they could to the standard treatment
- and many of them have had very good success. The irony is that almost all oncologists agree
that multiple agent approaches are going to be necessary to actually cure anything. And
so, no one really is disputing that. The question is what goes into those cocktails and what
kind of criterion of evidence that you have to have for putting those cocktails together.
To this day Ben still self-administers a maintenance therapy: a daily cocktail of vitamins and
supplements designed to try and create as hostile an environment as possible for cancer
to face in his body.
Logic Dictates
On the east coast of America, an advocate of combination therapies is Dr Raymond Chang.
Pioneering the integration of oriental and western medicine, his book Beyond the Magic
Bullet poses an uncomfortable question for the oncology community.
Oncology thinking somewhat followed infectious disease treatment thinking because the first
original breakthrough in achieving a cure for any disease came in the infectious disease
field whereas possible with the discovery of penicillin and so fourth. Single antibiotics,
single chemical (*) were able to eradicate – cure, literally - serious medical conditions
like tuberculosis, like syphilis. That was then applied to cancer with the same logic
behind it… well if we find the right chemical, maybe we can eradicate cancer just like we
can eradicate tuberculosis… and then that mode of thinking dominated (*) therapy for
over a century at least. We think that most diseases, if you simply find the right key,
you should be opening the door, and the reason why the door remains locked - the cure remains
locked - is because we don’t have the right key. So we should keep looking for new keys
or try to improve the key that we have and we will eventually open the door. What if
this door has multiple locks? When you keep looking for one key, it’s not going to open
the door no matter how hard you look. It will never, it will fail, the whole strategy of
research will fail! Then maybe the way of thinking is wrong. It’s not that we need
better drugs, but we need to know better how to deploy what we have already. If we have
‘cure’ or ‘control’ already in our hands except that we’re not using things
properly.
As proved to be the case with childhood Leukaemia and aids, it was the combination of existing
treatments that delivered the breakthrough. Today infectious disease treatments follow
this logic.
Hepatitis C, hepatitis B - chronic viral infection - HIV obviously. They are all attacked with
multi(*), multi agent, multi target approaches – and with success. Cancer treatments are
kind of behind… again. So hopefully it will follow the lead of the infectious disease
practitioners.
The idea of a cocktail approach to cancer treatment has gained adherence amongst the
oncology community.
I think that if we are going to try to treat this disease we need to be using combination
therapy from the get go. Single agent therapy is not likely to be very effective with a
disease with so many molecular (*) underlying its ability to be invasive and resistant to
therapy.
What you want to design for a problem like cancer is not a drug or an intervention. You
want to design a solution - because that’s what patients want. So it’s a lot like your
computer: there’s amazing components in there like your microprocessor or your hard
drive, but individually they aren’t worth anything to you until they are put together
into an interoperable system that becomes your laptop that’ll do word processing or
send emails… Now that’s of value to you. Today in drug development and in clinical
research we need to be thinking of those kinds of integrated, interoperable solutions.
With glioblastoma we’re really climbing a mountain. Every therapy that we see a modest
success for gets us a little bit further up the mountain then we set up a new base camp,
and then we come up with a another therapy that gets us further up the mountain, set
up a new base camp. The concept of synergy is really important here because what if we
could just get further, faster?
An example of why it is that combining different treatments together is in fact the development
of what is now the standard of care: It used to be that you used to receive radiation first
and then wait a month or so, and then start on your chemotherapy. The new protocol is
that you have the radiation and the chemotherapy together. It has produced a better outcome.
Clearly the change of putting them together simultaneously as opposed to sequentially
was a step in the right direction.
Current management of brain cancer as well as many other cancer conditions involves a
multi disciplinary approach where surgery is deployed, radiation is deployed, chemotherapy
is deployed, and targeted therapies are deployed. So one can argue that it is already, in a
way, it’s already mixed or cocktails and not just one single therapy… But, much more
can be done. Many other drugs can be used without much toxicity without much even cost.
Simple, simple drugs.
Although there is general consensus of the advantages of the cocktail approach, there
is disagreement about how much information is needed to start combining untested treatments
together. How far and how fast this can be taken for individual patients is the fundamental
issue.
The big problem with cancer treatment is that the tumour develops resistance. I mean, you
know, so it’s usually that the treatment is only partially effective in the beginning
- at best - and what you then get in an evolution of resistant strains of the tumour, and so
the more you treat it, the more resistant it gets just through the process of evolution.
The biggest risk in all of this is you’re going to be dead very quickly from your tumour
unless you do something other than what is being offered from the conventional medical
treatment.
We always balance the potential gain with the potential toxicity of an agent and making
a decision whether to include it and if so, how to include it and when to include it…
but we’re not treat colds, we’re treating glioblastoma… and what risks you might take
with a cold are going to be far less than the risks you are willing to take with someone
with a glioblastoma when you know the natural outcome is so dire.
It is clear that cocktail therapy represents an excursion into the unknown, with corresponding
uncertainties about the risks involved.
Some of these cocktails involving 10 or more substances can have life threatening complications
and for the safety of the patient it would be much better if the physician knew about
it and could appropriately follow. There can be some aggressive attitude of some physician
starts experimental treatments especially with free purpose, non approved drug cocktails.
And I can very well understand that patients may try to avoid this conflict with a treating
physician and I think that the solution is on the side… lies on the side of the physician.
Resistance
Treating malignant brain tumour patients is not easy for physicians. Most do not become
doctors to watch all their patients die. At the sharp end of this scale lies paediatric
neuro-oncology. In Belgium, one man’s professional crusade against brain cancer has led to his
university hospital becoming the most advanced centre in Europe for immunotherapy in brain
cancer. When not fund-raising out of hours to support his research programmes, Professor
Stefaan Van Gool is on the very front lines of neuro-oncology, taking the fight patient
by patient.
Personally I think the prognosis of the patient is the worst when the doctor does not treat.
There is nothing. If there is one thing frustrating that is that you want to fight for your patient
but that you face borders that are aimed to be protecting patients, but are sometimes
also not protecting patients because they block progression. Evidence based medicine:
you do an intervention, compare to control - but if this intervention consists of five
new factors… that will be a hard one to do, but maybe these 5 (*) factors are needed
to make the progression. That’s the difficulty more and more. You have to fight against all
the barriers with (*) committees, with regulatory authorities, which makes thinking out of the
box more and more difficult. If we come too much into fixed system: phase one, phase two,
phase three, phase four, and that’s it. That will reduce progression - certainly if
you want to elaborate multi model, more holistic approaches. That’s very difficult and unfortunately,
at the moment, it becomes more and more difficult.
The reality facing the vast majority of patients, is that their doctor will not engage with
any experimental therapy outside of a clinical trial, even in the context of a terminal diagnosis.
We wanted to try and understand the reasons behind this seemingly unnecessary resistance.
Realistically there are other practices beyond medicine. It has to do with capitalism, it
has to do with health care structures, systems and so fourth. Mono therapy is easier to carry
out. If something goes wrong, it is clear what’s wrong because you’re giving one
treatment at a time so if the patient has a server side effect it’s that treatment
- it’s that drug. Regulatory wise, it’s very difficult to get studies going involving
multiple agents, because let’s say if you’ve got five agents - instead of testing one thing
at a time then you have to test A against B plus C plus D plus E or, A plus B against
C plus D plus E. There are then, to the power of five, so many different variations possible.
That means you have to do so many studies. Practically it’s almost impossible to study
these things if it becomes complex. So a simple monotherapy approach is easier, cleaner for
management purposes - but it may not be as effective. It is unconscious because doctors
don’t necessarily think about it, but they implement it in this fashion. This is the
way how studies are done. You don’t put patients on three new X, Y, Z unknown new
treatments at the same time because the issue always comes up that well, if it works, what
did it? Then we don’t know. That is not acceptable to science. You have to be careful
that the doctors need to be scientific… but when you’re treating the patient, is
it for science or is it for the patient? Sometimes we forget.
Other obvious candidates for cocktails are natural compounds. These naturally occurring
substances cannot be protected by patent and so no one company can gain a monopoly over
their supply. Totally non-toxic, and with years of data to prove its efficacy in cancer
care, curcumin should be an obvious adjuvant for any cancer protocol, and yet it is rarely
used in western medicine. We travelled to the world’s largest specialist cancer hospital,
MD Anderson in Houston, where the series of laboratories dedicated to natural compounds
are testament to the holistic vision behind the Texan project.
As of today there have been over 150 clinical trials that have been completed. And the answer
is yes it works and it down modulates bio-markers. You know, there are only 20-25 driver genes,
and that I have taken all those driver genes and asked ‘are they down modulated by curcumin?’
Because that is what the drug industry is targeting…and the answer is yes: curcumin
alone, has over ninety different targets, ninety different targets, it is not just a
mono-targeted. So this is what the drug industry calls a ‘dirty drug’. Any drug that hits
more than one target is a dirty drug for them, they don’t like it. There are only two rules
of the game that I have learnt from my days in Genentech (and there is no third that I
know of) .. Safety: number one, whatever you’re giving to the patients should be absolutely
safe, it shouldn’t hurt them in any way. Second is the efficacy. There is no third
rule, and curcumin meets both of them.
But as any cancer patient will testify, there is huge opposition from the medical establishment,
towards adding natural compounds to traditional cancer treatments. The reason most patients
are given, is that it ‘may interfere with your treatment’ although only in rare cases
is there any evidence to support this claim.
In medicine today, there is a buzz word and that is called ‘targeted therapies’. Targeted
therapy means you pick a single gene, a single protein, and you try to find an inhibiter.
That is what they call a ‘magic bullet’. They have come up with a lot of magic bullets.
Only thing is, these are not bullets and these are not magic, so there is a lot of frustration,
asking where did we go wrong? Where they did go wrong was thinking that cancer is a single
gene or single protein - a single target disease. By now, we are living in the era of ‘omics’:
genomics, proteomics, metabolomics, and all of that is out there to tell you that cancer
is a multi-genic disease. No matter which direction I look at, people’s mind is set,
and their mind is set on targeted therapies. They want a targeted therapy, if it is not
targeted they are not interested, period. It doesn’t matter whether it does anything
good for the cancer or not, they are not interested… and that’s where I face the biggest resistance.
I have people tell me point blank in my face, right here in MD Anderson. They say, ‘well
Dr Aggarwal, anything you do with respect to natural products I don’t believe even
one bit of it. They don’t even want to read… and we publish in the same journals. We are
most highly cited. People don’t want to read. There’s this, you know, in born bias.
My problem with the ethics of oncologists is that they want to pre-empt the decision
and they don’t their patients have any leeway in making a decision that sort of kind of
moves them in the direction of alternative medicine. It’s a real concern on their part.
I mean, professional reputations can quickly be ruined if you’re viewed as one of those
kooky guys who goes around trying to throw out anything under the sun into your treatment
protocol.
History is littered with scientific breakthroughs that were castigated for their implications
for the prevailing status quo. When Copernicus introduced his heliocentric theory to the
world, the shock to the belief system reverberated for centuries afterwards: Gallileo Gallilei
was persecuted for his acknowledgement of Copernicus’ theory and his pursuit of a
new rational science in its wake. Even Gallileo’s presentation of his new invention, the telescope
and it’s irrefutable new evidence, could not dampen the fervour of his condemnation.
In the nineteenth century, Ignaz Semmelweis, a relatively unknown doctor, a Hungarian practising
in the venerated hospitals of Vienna at its empirical peek, noticed an alarming correlation
between the new practice of pathology, and the advent of a series of deaths of both mothers
and babies in the maternity wards of those same hospitals. His suggestion that perhaps
his fellow surgeons should consider using chlorine to wash hands before operating on
patients, was met with vicious resistance. Unable to substantiate his theory scientifically,
Semmelweis was ostracised professionally by his peers for daring to question the status
quo. He died 15 years later in a mental institution, a broken man, yet a century and a half later
he is venerated as a national hero in Hungary, where statues and coins carry his legacy as
the father of sterile medicine. Today, the Semmelweis reflex is a term used to describe
an illogical and exaggerated response to a challenge to the prevailing dogma. Unfortunately
- the Semmelweis reflex is alive and well in today’s medical establishment: Barry
Marshall, a little known doctor from Western Australia, had identified a bacteria in the
early 1980s that indicated stomach ulcers were caused by bacteria. This was heresy to
the established thinking in the field of endoscopy, which was convinced that stomach ulcers were
caused by stress. As a result Marshall’s thesis was not published in any medical journals
and sat on the shelves gathering dust while hundreds of thousands of patients across the
world had their stomachs removed, unnecessarily so according to his theory. With the bacteria
in question only able to develop in primates, but with testing on primates prohibited, the
successful animal experiments that the medical establishment deemed pre-requisite for Marshall
to progress to human trials, could thus never be completed. So locked out of both animal
and human experimentation, but convinced of his theory, Marshall chose to experiment on
the one human he did have legal access to: himself. In front of an audience of stunned
peers, he downed a petri dish full of bacteria grafted from a patients’ stomach, and claimed
to have infected himself with a stomach ulcer. The proof duly came, as did his cure without
the need to remove his stomach, swiftly followed by an avalanche of awards and praise from
the establishment, culminating with the Nobel Prize in 2005. Beyond the more obscure issue
of medical hegemony, lie more obvious reasons for why combination therapies do not reach
patients.
If you have: a drug A from company A, and a drug B from company B, and a drug C from
company C, it is extremely difficult to get all three of those drug companies together
to agree to use their drugs to treat a particular disease process. It’s much easier if the
drugs all come from one company… and that is a fundamental challenge that not just neurosurgical
patients with glioblastoma face, but all cancer patients face. And from the company stand
point one could make a good argument that it’s reasonable and understandable that
this is the case because they invest hundreds of millions, sometimes billions of dollars
to develop that drug, and as that drug comes to market it goes to the FDA, the application
of that drug to other disease processes in combination with other drugs could cause a
lot of problems for them. So it’s a very difficult thing to address.
On top of the reluctance of western medicine to consider natural products as they cannot
be patented, for the very same reason, drugs whose patent has expired are similarly discarded
as they cannot guarantee a return on the investment required to run a clinical trial. This results
in a large number of drugs with strong laboratory evidence for anticancer properties never getting
anywhere near patients. In some cases, even when human trials have been run it is still
not enough to bring the drug into the mainstream treatment.
A very nice example is the use of the old malaria drug which is dirt cheap, Chloroquine,
for brain cancer where nice trials have been carried out showing improvements up to 50%
survival time when it’s added to standard chemotherapy. It has almost no side effects.
It’s one pill a day. It does not mean the patient has to suffer going to the hospital,
get a drip, any of this. It’s dirt cheap. Why not? Well, FDA has not approved its use
for this condition - for one. The information is not widely disseminated. There’s no big
drug company behind the manufacture of chloroquine to market it for this use. Nobody makes much
money if suddenly every brain cancer patient starting taking chloroquine, it adds very
little to the bottom line of any particular business or company.
So it is more and more important for us to look at these drugs that have been left on
the shelf, that big pharma wants nothing to do with, but we don’t initially have the
time or the resources to provide the data managers, the IRB fees and start up fees that
it takes run a good clinical trial.
Aside from the influence of the medical world status quo, and the economic reasons hampering
development of combination therapies for cancer, there is a strong feeling amongst the patients
we interviewed as to why oncologists are unwilling to deviate from established best practices,
even in the context of terminal disease.
One of the problems from a patient’s perspective is that they want as many drugs as possible
to facilitate long tern survival, and that’s a very reasonable request from the stand point
of a patient. If you have cancer, you hear a certain drug might be effective in your
particular type of cancer, you want to access that drug. You hear that another type of drug
might be effective, you want to actually just go ahead and combine those drugs, and so fourth
and so on. From a patient’s perspective, you are entitled to pursue any type of therapy
you want to. From a provider’s perspective, from a neurosurgeon, a scientist, from a a
neurosurgical oncologist’s perspective, we have to be very, very careful about what
we recommend to patients in terms of going after therapies that are unproven.
Doctors are judged by so-called standards of practice in the community. So, if in California
this is the way we do things, here, in LA, this is the was we do things… and you do
it differently and the patient gets hurt, and you’re in court, they will summon your
peers and say well, how do you do things usually? And every body says ‘I don’t use Temodar,
I don’t do Temodar + chloroquine
This issue of liability is one of the silent enemies in the war on cancer. Drs and hospitals
who would willingly take more risks for their patients who have run out of options, are
discouraged from doing so by fear of malpractices suits. This fear of prosecution is not limited
to doctors, but runs deep through the entire system, dissuading individuals and teams from
doing anything outside of the box for their patients.
The specialists are at major cancer institutions that does not treat patients as individual
unlike what patients may think. They treat as a group. They can call it a team approach,
but they treat by committee, literally there is a committee of doctors who review cases
– it’s called a tumour board – and almost, you can imagine, 6,7 specialists at the centre
every week, sit down and go over new cases and decide ‘this is what we’re going to
do.’ Now, that also creates an issue because then everybody has to agree for one, then
of course what everybody agrees on in any bureaucratic structure has to be the lowest
common denominator. Okay? But that’s the safest way for the doctors and the hospital
because if there was a problem, and if the was a charge, they say well, ‘six specialists
had a committee meeting on the same week – and we all agreed… you want to sue six of us?
And we represent the hospital are you going to sue the whole hospital for this decision?
every one of our patients get exactly the same thing. What’s wrong with this? We are
following the guide lines from the American cancer society’. So, everything is therefore
protected, protected, protected… for liability reasons. So it’s fool proof. If you try
to be individualistic, stick your neck out, give chloroquine because there’s a paper
that says give chloroquine, and something goes wrong, you don’t have anything backing
you up in the court of law. It’s much safer to follow a protocol. A protocol is one thing
at a time until it’s proven otherwise. The proof may never come because there is no funding
to try to prove these things. Who gains from proving them? Who is going to fund the proving
of this? These are much larger issues that I think will hamper developments of true cocktails
unless there is radical changes in health care systems and social systems. It may not
come.…
Lightening doesn’t strike twice
Ben's Williams book is nothing more than a blueprint for anyone who wants to follow a
more pro-active approach to their own treatment. One such patient was Richard Gerber, a fellow
American academic living in Italy, who was diagnosed with the same lethal brain tumour
a decade after Ben. Given just months to live, Rich had nothing to lose.
During the chemotherapy and radiotherapy that I had – although it was very exhausting
– I started reading at night, articles and journals, and I realised that therapy was
not going to really make my life any longer so I started doing research into alternatives,
and little by little, on the internet, I came across this name ‘Ben Williams’ who had
written a book. I ordered the book. And it basically is teaching people to take their
matters into their own hands and to be their own doctors in part. So far, this cocktail
approach that he writes about in his book has proved efficacious for me. I wasn’t
just blindly following Ben. In fact, I wouldn’t have followed Ben at all if his arguments
weren’t logically convincing.
In common with Ben, Rich shared a scientific background, he is an expert at developing
solutions for complex problems.
I took what we call a ‘black box’ concept that is glioblastoma is a very, very complicated
phenomenon. Nobody knows: how it works, how it grows, how it gets started, how the therapy
works, and papers are published on very specific subjects and very specific genetic pathways,
but there is no integration of this information. So, my approach was based on finding as many
agents which could block assorted pathways which activate glioblastoma, and doing it
all at once so that the glioblastoma would have less of a chance to mutate and escape
via a path way because I would already be blocking that pathway.
Of course, assembling and consuming an unsupervised and untested cocktail of drugs and neutraceuticals
is daunting even for someone with an in depth appreciation of their disease. One of the
patients we interviewed equated it to playing Russian roulette whilst on death row.
My doctor was a very sympathetic oncologist, but she was very ‘by the book’. She didn’t
want me to do anything else. Coming up with my own notions I suggested to this doctor
that I would like to take melatonin. I tossed this out as sort of a test because at the
time I was actually taking 10 or 15 other pharmaceuticals but I thought I would start
small and she didn’t want to hear about it. She told me not to take melatonin, that
it would just confuse the matter. At that point I realised that I was on my own because
if I couldn’t confess to my doctor that I was taking melatonin, how could I confess
to her that I was taking chloroquine and (*) and other pharmaceuticals. I didn’t add all
the ingredients at once. I added them incrementally. I basically included any ingredient, be it
a supplement or a pharmaceutical that was active against cancer and didn’t interfere
with the other ingredients. The pharmaceuticals had to be dosed correctly, and the dosage
I used was that carried out in the research paper on cancer that I found. You have to
read very closely these articles to get the correct dosage – but it’s there.
At its peak his cocktail numbered over 25 different components, and in order to access
them all, Rich broke every rule in the book: From feigning symptoms of other ailments in
order to access non-cancer drugs that he believed may also act against his disease, to forging
prescriptions.
There were moments during my cocktail therapy when I thought I was doing too much, and I
was getting out of my own comfort zone which is nothing like medicine, but, I realised
that the alternatives were very small: either I tried something much more radical than the
standard of care, or I would die. And when you’re faced with that kind of decision,
why not use more ingredients?
Long term survivors of malignant brain tumours are extremely rare. What makes Ben and Rich
even more unusual amongst this tiny data group, is that they have never had a recurrence - their
cancer has never come back.
A glioblastoma can’t really be cured. Never. I never think about cure and I don’t talk
to anybody about cure. I think that every year that you live without a recurrence is
great. I think Ben Williams now has lived eighteen years without a recurrence if I’m
not mistaken. I’ve lived six and a half years without a recurrence. At that point
you can say that we’re under control, but you can’t say that we’re cured because
there is always a possibility that it could come back.
Ethics in question
After the horrors of the human experimentation that characterised the holocaust, at the Nuremberg
trials the international community laid down the founding principals of a clinicians ethical
obligation, initially referred to as the Nuremberg code and later ratified in the Declaration
of Geneva as an extension of the Hippocratic Oath. Building upon these foundations, the
world of medicine unilaterally subscribed to the Declaration of Helsinki in 1964, and
its primary revision in 1975 that introduced the principal of ethical review by an independent
committee. In doing so, the global medical community enshrined the moral truth that ‘concern
for the interests of the subject must always prevail over the interests of science and
society’. Can we honestly say that today’s double-blind studies on terminal cancer patients
adhere to this principal?
Frankly, that I don’t know how a neuro-oncologist could go home and look themselves in the mirror
at night given what he knows and the outcome of his patients are. I just don’t think
it’s even ethical. I wouldn’t be able to live just presiding over patients, just
giving them radiation and chemotherapy and at the same time, knowing that they are all
going to die.
I think the general concern in the oncology community is that this is a terminal disease
and when diagnosed with a GBM you are going to die. I think that philosophy is kind of
counterproductive to doing anything meaningful, so I think our goal is to put patients on
clinical trials to press the field forward, but when you can’t do that, to do something
better than a standard of care which is palliative.
What we are fighting against is the negligence that physicians are not aiming to inform themselves,
that they are not forming an opinion themselves.
If you face this disease and say from the get go that this it is incurable - you will
always be right, all your patients will die and you have no business treating those patients
in the first place.
I think it is one of the toughest situations in everyday clinical work. This is a point
where it is really necessary to really explore the patient’s wishes and really find out
if the patient is willing to take an additional risk for a chance, for a possibility of having
a better (*). The problem is that a patient who is asked to take an additional risk for
a chance to survive will almost always say yes.
So the central issue is the question of protecting patients rights at both ends of the spectrum:
whilst uninformed vulnerable patients need protection from unreasonable offers of experimental
therapy at one end, equally should patients at the opposite end of the spectrum, who do
not wish to accept a palliative standard of care, be denied the right to fight for their
lives? When their doctors refuse to co-operate, these patients inevitably find themselves
outside of the medical system. We wondered how many other cancer patients have embarked
into unchartered territory of self-medication, without their story ever coming to light.
In California, we heard of another desperate struggle against terminal cancer. But for
Neil and Margo Hutchison, there was no happy ending. neuroblastoma, a rare cancer of the
nervous system, claimed the life of their eldest son Sam aged just 8 years old.
He was a very active little kid. Loved sports, loved anything with balls, loved trucks, he
ran like the wind, we was a funny, great fantastic kid. When he was four and a half we were at
a soccer game and he sat down and said ‘my legs hurt’, and he always used to jump out
of our van and he started to sit down to get out of our van so we that something was definitely
wrong. We decided to get some blood tests and an X-ray and he was diagnosed with neuroblastoma.
55:38 N: Sam began one of heaviest chemotherapy regimens used in medicine with accompanying
stem cell transplant that meant he lost his hearing and would be sterile for the rest
of his life. But with such a high grade of malignancy Neil and Margo were told Sam had
very little chance of surviving.
Well first off, I mean, you’re shocked, I mean, I think even parents of someone diagnosed
with paediatric leukaemia would just, you know, – it has a very high survival rate
– you know, it still it punches you in the gut, but when they sit you down…
You’re just… yeah, you’re in shock for months.
After the shock dissipates, the dislocation between the patient’s perspective and that
of their medical teams was a common factor in all the cases we covered during filming.
It is clear that while the Hutchison's have both a deep respect and appreciation for the
doctors who treated their son, they had also come up against the same compassionate fatalism
that proved so unpalatable to Ben Williams and Richard Gerber.
I think that one argument that we used to have with doctors when we talked about issues
like this is, they’d say… I’d say like ‘hey listen, throw the book at these kids,
it’s non toxic, get them in there, throw cocktails at them and see how they do.’
Their argument back to me would be like well, ‘if some child survives we don’t know
why’, and I’d say ‘yeah, but that’s a medical, scientific perspective. From a
parent perspective we don’t care why. He’s alive and we’ll figure it out’. If we
keep doing it we’ll figure it out. We’ll back door the answer. Somehow, someway, some
shape or form. The scientific community wants to know why.
They believe in what they’re doing and, know you, they want something that’s science
based. They want a clinical trial. They want the proven results. That takes years to get
that kind of data, and these kids don’t have that kind of time.
And you’d see the data, you’d see child after child die and you’d have that mental
calculus going in your mind all the time because you don’t want to harm your kid either because
the Hippocratic Oath is apparent: First do no harm. It’s not about that…
Right, and so it’s not like you’re making crazy, uneducated, you know, ‘we’re just
going to try anything’ decisions but…
You are absolutely right but like okay, but I know this outcome. I don’t know what this
is going to be, but I know where this is going.
Given that the probability that the patient is going to die is astronomical – it’s
almost 100% – what harm is there is adding other ingredients to the therapy?
Why on earth would you possibly oppose it? And the only answer to that is well, that’s
not part of the standard care and we’re afraid that if you use anything other than
the standard of care that somehow we’ll make things worse in a way that we don’t
understand. That’s not an acceptable position in my view.
For the vast majority of patients, it is also an unacceptable position. The advent of the
internet has seen a growing underground network of patients and carers supporting each other.
This film is a direct result of such a community.
We had, you know, the whole community of neuroblastoma parents who were medical doctors and things
themselves, and what we tried to do was read the preclinical data, you know, and we were
just trying to stay ahead of the curve and kind of predict where things were going to
go clinically. You know, you see a single agent clinical trial and you know the data
for that or you talk to – it might not be published data – but because we are neuroblastoma
community we know that 10 kids are on it and they all progressed. There’d be publish,
preclinical data saying that ‘hey, the next trial that’s going to come up is going to
be adding this second drug’, and so we would get the second drug, and that was very common
place.
High profile survivors like Ben and Rich find themselves inundated with requests for their
advice, and having experienced the despair of falling outside the medical system themselves,
they can appreciate the desperation of patients with no where to left to turn.
I’m an engineer, and many engineers carry out risk benefit analysis naturally and routinely
in their work. In terms of the cocktails that I had identified, I did my own independent
research, evaluated what the potential benefits were compared to the side effects, and it
was quite clearly something that ought to be tried. With the benefit of hindsight and
the reflection of where I am relative to the prognosis, I am concerned that this approach
could not have taken place sooner. Many of the doctors feel that they are not able to
engage in these off plan treatments, and perhaps those that are outside the normal sphere of
training because they tend to feel that the Hippocratic Oath limits their ability to do
that in the principle of ‘do no harm’. But I believe that there are equally sins
of omission as there are of commission.
There is no doubt that in the future we’re going to be looking at multiple therapies.
The question that arises: doesn’t the patient have the right to go an pursue combination
therapies and put them all together in a way they think and their doctors hope will facilitate
a long term cure? The problem again comes back to the issue of toxicity. Unless you
carefully study these combination therapies, you may be doing more harm than good in many
cases, and although that there is clearly the impetus to move forward with combination
therapies, they need to be studied.
However, for the reasons outlined in this film, there is a distinct lack of clinical
trials investigating a cocktail approach to cancer. Instead, it is normal practice to
expect patients to forgo curative treatment in the hope that their sacrifice will someday
benefit someone else in their same position.
If you go to a major medical centre where they are doing clinical trials, the trials
are not really a hundred percent intended for the patient, they’d be intended for
a future patient, it’s intended for science - or for a drug company - but, it’s intended
to find out more about the drug, it’s not intended to cure the patient. Patients are
not aware of that. For science it is important to study things singly because otherwise it’s
confounding. We cannot deal with multiple unknown variables. You throw five drugs that
we don’t know much about t somebody and they get better, we don’t really know what
happened. Which one of A, B, C, D, E did it? We don’t know. You want to find out how
a drug works… that’s in scientific spirit. That’s great for science, but there is some
conflict with clinical care which is with a different intention: you want the patient
to get better.
When looked at closely, the history of cancer tells its own story: In another era, when
doctors were more empowered to pursue patient survival as a primary objective of clinical
care, dramatic progress was achieved in a relatively short period of time. One such
doctor whose belief system is entirely geared to patient outcome was a young haematologist
working at the newly formed National Cancer Institute in the early 1960s. Emil J Freireich
was certain he had figured out a way to send leukaemia into permanent remission. But he
faced enormous resistance for attempting to combine highly toxic chemotherapy agents.
When I started treating leukaemia - I have a slide of a quote from an article that was
written by a guy named Arthur Haut, who was one of the senior physicians at the number
one haematology department in the world in 1955 when I went to the cancer institute.
The quote says… just what you said: giving these drugs , 6MP, methotrexate, prednisone
to these children is just prolonging their suffering, it has no effect on their survival.
And he was on our consultant (panel) and he told our advisors that Freireich should no
be allowed to poison these dying children –to let them die.
Undeterred by fierce resistance from his professional community, Freireich questionably pushed ahead
with the assistance of some desperate parents, and the rest is history. Today, a giant in
the field of oncology after blazing the trail towards cure for childhood leukaemia, and
in the process inventing the platelet transfusion, at the age of 87 Dr Emil J Freireich has half
a century of outstanding achievement in clinical practice to reflect upon.
See I’m a devotee of the Hippocratic Oath. That’s why it’s on my wall. Every physician
in the United States, and I think in England and in Europe, who graduates from his medical
training swears by the Hippocratic Oath. Now what’s the essence of the Hippocratic Oath?
Now what’s the essence of Hippocratic Oath is that, as a physician, I will always do
whatever I can to help a person who is ill and consults me.
For cancer patients staring death in the face, the chilling realisation that despite a palliative
standard of care, they must wait for their cancer to inevitably progress before their
doctors will engage with experimental treatments, defies belief. In the vast majority of cases,
only then do experimental treatment options become available to patients. We asked Dr
Freireich if in his opinion, this broke the Hippocratic Oath…
It certainly does. Is there ever a circumstance where a patient should be denied treatment
which could – in someone’s imagination – help him survive his disease? And the
answer is no.
System Failure
Would the things we did in 1960 be possible in today? The answer is, unequivocally, capital
‘N’, capital ‘O’ – NO!
By obliging doctors to follow rigid protocols, our system for validating cancer treatments
is not only failing patients, but it is also failing the innovators who are developing
treatments: a hidden consequence of forcing patients to wait for cancer to reoccur before
giving them access to experimental treatments, is that potentially promising treatments are
first tested only on these ‘recurrent’ patient populations, who already have genetically
mature cancer, and thus are far less likely to respond to the drug or treatment than an
early stage patient. This means potentially life-extending treatments for the newly diagnosed
are discarded forever because they cannot show effect first on moribund patients.
Reforming regulations is the most important thing we can do in advancing health in the
world. The AIDS patients told us how to solve societal problems for specific diseases. See,
the AIDS guys were homosexuals and they were used to being politically active and they
were organised, and when the FDA said you have to do a randomised trial where you get
treatment you know won’t work and compare it to treatment you think will work… they
said ‘hell no!’ and they marched on the hill and they won. My personal view is that
that’s the way medical problems should be solved. First we need the knowledge, then
we need the social solution.
ACT UP - the AIDS coalition to unleash power - was a direct action group widely credited
with instigating the rapid acceleration of AIDS research that transformed the once deadly
virus to a chronic condition in little over a decade. Larry Kramer, New York City playwright
and author was a founding member, speaking in the late 1980s as the AIDS pandemic gripped
the world in the face of institutional and political indifference, his words echo violently
in the ears of cancer patients today: ‘placebo studies were not designed with terminal illness
in mind’ he said and the ‘academic mechanism of testing drugs is becoming life-threatening
rather than life-saving’, it’s ‘genocide by neglect’ he claimed. As a result of ACT
UP’s unprecedented lobbying of congress and the FDA, which included emptying urns
onto the white house lawn as per the will of their members’, today’s life saving
treatment for AIDS is given to patient’s despite it never having passed a randomised
phase three clinical trial: How many cancer patients must die before the regulators recognise
this needs to be adapted to oncology in the same fashion?
All they have to learn to do is balance benefits against risks. If you have nine drugs that
are going to cure glioblastoma and you have a patient that is 100% likely to die… lets
give them the nine drugs! Who’s against that? You can’t do anything risk free. That
does not exist. You can’t walk across the street without taking a chance. You can’t
wake up in the morning, you can’t eat food. I mean, it’s nice to do as well as you can,
but you can’t be insane and we are insane now. The regulatory process is insane. They
are trying to protect people. They inadvertently get into a situation where they kill people…
but that’s not their intent. We’re just human unfortunately.
For patients and carers, once these inefficiencies come into focus, the incentive to adhere to
the rules of clinical trials evaporates along with the validity of the precious data the
trial produces.
Do you want me to be totally honest? Yeah, sure, neuroblastoma patients ship drugs. We’d
ship drugs by fed ex. We’d find clinical trials and we’d be on a single agent and
we’d – other parents on the other trial would send us their drugs and we’d send
our drugs. We had viruses from Israel that other parents had given us that we’d tried
and… that’s what we did. There’s a whole black market and grey market of drugs because
parents are so knowledgeable. I mean, there’s Doctors, PHDs, MDs that have children with
neuroblastoma and it’s a very tight community and they would do anything for anybody. In
fact, we, you know - that’s what we did - created our own clinical trials for the
most part.
In randomised phase 3 trials, you have the additional disincentive of placebo control
for half the patients. A quick glance at the appalling enrolment rates around the world
and we can see that patient’s vote with their feet.
It’s so obvious that if the FDA allowed us to be rational about treating cancer patients,
we could move them all one hundred times faster. As we did with AIDS, because what happened
was, the drug was good and the patients didn’t have to die to prove it. And as you said in
the beginning ‘you need to do a randomised phase 3 clinical trial’ No! if you have
phase two evidence that’s clear, if you have an objective response, objective survival,
objective progression free survival, that’s it… The truth is in itself. You don’t
have to do comparison, you have to have the truth, you have to have reproducibility, you
have to have a lack of bias, and what you’ve got there… that’s the answer man! The
AIDS guys did it. The cancer patients have to do it. We have to force congress to change
legislation so that when a doctor and a patient agree that the benefits succeed the potential
risk… that should go. Whatever way we make it, that’s got to go.
New horizons
In all of the clinical trials to date, there really hasn’t been much progress. Meanwhile,
those people however are dying. Yes, people live a little bit longer with the standard
approach that we have now, but it’s not much. And so, I would say this approach is
not working. It’s time to try something else.
Traditionally, regulatory bodies have made decisions that have been based on population
studies. So if you think about it for a moment… We introduce a drug into a large population
in which we know there are many variables in that population - people are different
– and we can’t control for those variables, we don’t know what they are sometimes, we
just know they exist. So the way we dealt with that in the past was to create this statistical
model of randomisation and, in fact, blinded randomisation so we cover our eyes, and we
flip a coin, and we divide people up, and we look for an outcome, and when we get an
outcome we put a statistical number on it, and that gives us some assurance that yes,
that was really due to the drug and not something else. Do we need that today? If I could go
into that population and I could - today - tell you about those variables - which I couldn’t
before - because now I understand those genetic, molecular make up of their individual cancer,
and I also under stand their genetic molecular make up of them, as a person, and now I can
refine those populations. Do I still need to put a blindfold on and flip a coin? Or
can I begin to be much more rational about who I would treat with a particular drug and
who I would not. That is the adaptive trial design. That is what cancer is teaching us
and telling us what we can now do, so we don’t need to depend upon that old model. We can
be much more sophisticated, much more rational, and we will get answers faster, we’ll be
much more certain that our answer is in fact correct, and we will be able to allow patients
to have access to lifesaving drugs quicker, faster, and with more assurance that they
are going to help them and not hurt them.
We accompanied Ben to University of California Moore’s Cancer Centre to meet one of a new
generation of oncologists engaged in an ambitious program of personalized medicine...
There’s two issues. One is, you know, what are the best combinations for each particular
patient? Because, I think we all know that glioblastoma is a different disease in every
single patient. If you took a hundred people in a room there’s probably fifty diseases,
and so what we’re finding is that single drugs seem to work better in some patients
than others because of the genetic make-up of the tumour, and so when you talk about
combinations it’s even more complicated. But we actually have a project where we’re
taking all the genetic information from each patient, putting it into a computer, and coming
up with an answer to what drugs would be most effective to each patient. So, it’s really
a personalised medicine approach to understanding the genetics and using that information to
find the best combinations.
So as we move towards personalised medicine where patients will receive combinations of
treatments, and that these combinations should reflect the genetic characteristics of different
patients, then the only logical conclusion to be drawn is that until we dismantle the
sanctity reserved for large-scale, randomised phase III trials, we will never see meaningful
changes in patient survival.
Personalised medicine is the mantra. The irony is that the practices up to now are directly
opposed to doing it. You can not – for most of the randomised trials that are done, even
though you get a significant result – tell an individual patient what the chances of
that treatment working for them will be. Right, I mean, so, if you can’t do that, what you
started out… I mean the purpose of what you started out to do - you’ve failed. You
need more homogeneous patients so that you can actually say for this group of fairly
similar patients this particular treatment will work. Well, you’re never going to do
randomised trials once you start thinking in that framework of needing homogeneous patients.
Well if we don’t change the regulatory process, what we’re already seeing is the biomedical
research enterprises collapsing. We’re seeing investments beginning to dwindle because quite
frankly if you’re a venture capitalist or an equity investor, you have far safer, quicker
opportunities for a return on investment than to engage in hoping that a molecule - that
you’re going to be willing to fund very early in it’s development – some how or
other is going to make its way through a 10-15 year process at the cost of over a billion
dollars to ultimately be able to give you a return on that investment. So we’re seeing
negative consequences of not doing something, and at the same time we also have the realisation
of the incredible opportunities if we would do something and therefore, change has to
occur.
Acceleration
At the current rate of development of combination therapy, testing combinations one by one,
it will take decades, and possibly centuries to deliver more expansive cocktails to the
clinic. In the face of a clinical trial system that is clearly failing, a new line of thought
is gaining traction in some oncology circles. One man who is not hiding behind protocol,
is Marc Halatsch. He founded the International Initiative for the Acceleration of Glioblastoma
Care as a framework to combine expertise and engineer a treatment he feels will have a
better chance of combating cancer’s genetic instability. This radical work involving untested
drug cocktails does not sit comfortably within his scientific community, nor the pharmaceutical
companies Marc would normally enjoy sponsorship from.
We have to (*) the protocol and that initially involved 17 drugs. All of these drugs were
chosen to act in (*) against glioblastoma to inhibit or suffocate signalling pathways
that are important for glioblastoma. We consciously avoided to identify new targets for the glioblastoma
treatment. We were referring to drugs that are approved are marketed for years for other
non-oncological indications and for which a reasonable safety profile is already available.
So, the accelerated improvement means that we are using drugs, that we want to use drugs
that are already available today, for which we already have experience with human use
rather than identifying a new molecular target and validating a candidate track for years
and years and then possibly finding out that it doesn’t work. We have a rational basis
that these compounds are effective, that they can be effective, and that they have reasonable
and justifiable risks even though we do not know how these risks adapt when these substances
are combined.
During filming we were contacted by a senior drug researcher for Glaxo-Smith-Klein in Cambridge
England, who had been diagnosed himself with a high grade, inoperable brain tumour. He
refused to come on camera, even with his identity hidden, but he was interested in Marc’s
paper, referring to the science behind it as ‘beautiful’. But when he travelled
to a major centre for brain cancer in London, in the hope of finding a forward thinking
clinician who might prescribe him the experimental protocol, he was told the study was ‘unscientific’.
He died in 2014 leaving three young children.
Well if people say the paper is unscientific… I think that it’s a judgement that cannot
be accepted because the paper is certainly not unscientific. It is making a proposal
based on a set of hypothesis, and all of these hypothesis are based on preclinical data,
on what we think is robust preclinical data. What we can say for sure is that the recent
architecture of medical research for glioblastoma patients has failed to bring out substantial
improvements for these patients and we don’t know if you can do it better, but… we want
to try.
It is no coincidence that cancer cocktails are first coming to light in the arena of
brain cancer. The limitations of surgical intervention in the brain provide the impetus.
There’s a shift going on right now in a lot of oncology where you may want to biopsy
a cancer, treat for four weeks with a mono therapy (one drug), re-biopsy that cancer,
see if the genetics have changed, treat again with a different drug for some period of time…
and so as the cancer shifts and mutates, you’re changing your therapy accordingly.
If you don’t do that you may be treating according to a profile that is simple outdated
because a tumour is a dynamic. The biological situation may already have changed.
Now we can’t biopsy like that in the brain. You can do that in the lung, the breast and
other answers… bone marrow. So we have to figure out how’ll overcome those genetic
changes that will occur with treatment.
Well I believe, in the absence of bio-marker profiles, it is very important to have a pragmatic
approach and to hit multiple targets at once so that even if there is a change in the profile
and some pathways may compensate for other inhibited pathways, you have a high chance
of maintaining a higher therapeutic pressure against the tumour. In general, multi agent
protocol can be defended by pointing out the heterogeneity of the tumour, and if you have
a set of drugs that act in concert then you have a simple rule, and the rule is, the more
drugs you have the better you probably will be able to address heterogeneity of the tumour.
This is an example of the new rational science of treating cancer, based on the lessons that
cancer itself is teaching us. Yet what Marc and his peers are pioneering, is in reality
revolutionary. The pharmaceutical companies that own the drugs he is using have refused
financial support for his research, and he is risking his professional reputation in
medical circles by even publishing this paper. Cocktails are considered radical because if
such an ‘unscientific’ approach were to work for patients, it would equate to opening
Pandora’s box, with the associated danger of patients no longer being willing to accept
current medical practices. Few oncologists would be willing to support such an investigation,
John Boockvar in New York, was an exception.
The idea of carpet bombing a cancer is an appropriate idea where you just bombard the
tumour with multiple agents that will come at it from different signalling pathways,
much like they do with HIV medicines, and it will take that kind of approach to see
– I think – good outcomes. Of course our delivery mechanisms, our ability to get these
drugs into tumours has to be better, our immune systems in these patients has to be augmented,
improvement in immunotherapy will be an important adjunct to any treatment, because if we cant
identify mutating cells or cells that are distinct you have no chance… because chemotherapy
is only going to do so much without destroying the natural body.
Never say die
Of all the patients we met during filming, one man’s story stood out for his exceptional
courage and determination in the face of imminent death. Anders Ferry is still fighting his
disease today, 15 years after being diagnosed with terminal cancer at the age of 32. His
remarkable struggle for survival has encompassed 6 recurrences and 5 neurosurgeries including
some ground-breaking therapies and interventions. Unable to travel alone, Anders and his father
Arne travelled to London at their own cost from the far north of Sweden, to share his
story in this film.
Well I have been experimenting with my own body and taking various odd combinations of
medications and non-mediations as well, under very uncontrolled circumstances. So this has
been a marathon for me and for my wife in particular. She has seen me through extremely
low points. The low points have been really low, close to death.
Ander’s original course of chemotherapy was stopped due to the development of a severe
rash, a result of sitting in a sauna trying to raise his body temperature in order to
increase the efficacy of the chemotherapy, Anders claims this rash released him from
a chemo educed mental-fog and afforded him the clarity to do some preliminary research
online. He immediately enrolled on an innovative American trial for an early immunological
compound. However, the compound was unapproved in Europe at the time, so he had to smuggle
the drugs through customs as battery electrolytes.
So I was doing very well on that treatment, but then after a couple of years they said
‘now we’re dropping the trial. Unfortunately you won’t get anymore drug.’ And I panicked
of course. I thought, well this is what has been keeping me alive for so long so I immediately
went into action to try to manufacture it myself. As a physicist and physical chemist,
it wouldn’t be difficult for me to actually create that molecule in the lab. So I pulled
all the patents and bought the chemicals, borrowed lab resources, and my mother volunteered
to be my guinea pig to try it first before I injected it myself.
At the eleventh hour, the founder of the drug company, who had got wind of Anders’ desperate
attempt to stay on the medication, called and insisted he did not use his own acetate,
instead sending him a life-time supply of the drug the next day. By this time, it was
becoming clear to Anders that this was just the beginning of his struggle, and that the
next challenge lay in combining different treatments.
Well I got the idea to do several things simultaneously when I read Ben Williams’ thoughts on it.
So I started adding little drugs that I could access, gradually building up to a protocol
that involved many drugs in a big drug cocktail. At its peak I was taking at least 8 prescription
drugs – off label… of course, they were not chemotherapies, but assigned for entirely
different diagnosis – and lots of nutraceuticals. The biggest obstacle to implement this protocol
has always been to actually find the prescription drugs. They are available but you need somebody
to write the prescription, and I have been lucky to have relatives and close friends
that could manage that for me. Sticking their necks out. And occasionally my treating oncologist
has written out a few, but very reluctantly, and has always been questioning ‘but why?
Is there any evidence for this?’ And I said ‘no, but there’s a potential in it.
Evidence is weak but there is some kind of hope. Let’s try it, I’m willing.’ As the alternative
of doing nothing, you just look at the statistics… every body dies within two years they said.
Well that’s not acceptable. By doing something proactively, possibly ruining your health,
getting terrible side effects, but also possibly getting real benefits, extending life. Like
I’m here now, a decade and a half later, I’ve got two little kids, a happy wife,
a beautiful wife. My little Lynae and Tim they are just my pride and joy of my life.
So, it has worked out well for me. Sure I have deficits, but I can live with that. Life
with deficits is still life.
On three separate occasions, Anders has fought back his cancer by combining conventional
surgery with innovative clinical trials, and extensive, specifically tailored cocktails
of off-label drugs and nutraceuticals.
Well concerning the oncologists, I said ‘I’m not really satisfied’ because when Anders
has his medication and it didn’t work and the protocol didn’t work, they said ‘sorry
we can’t do anymore. You go home and play with your girl’. I put the question, who
is responsible for their lives? Is it my son who is supposed to take the care in his hand,
or is it so that the oncologist must have some responsibility? He just can’t hide
behind the protocols.
Ander’s fight is one that is far from over, and yet he too spends a great deal of his
time advising other patients, sharing whatever knowledge or contacts he may have.
So ever since I created my internet persona – Andrew Yassin – and hit the internet,
I’ve seen so many people come and go on the lists. It’s terrible. Many people of
whom I’ve connected so strongly to, just pass away. It’s dreadful.
Do you think that those patients were denied something?
Absolutely, they were absolutely denied the best care that could have been provided. I’m
sure many more would have been alive – or at least had a much better chance to be alive
– if they had access to what I have been doing for instance. I am also sure that this
approach could apply to other cancers, not only brain tumours. I’ve seen effect in
advanced prostate cancers and breast cancers. If I create a prescription of various off-label
drugs there is a viable option of prolonging life for a long time, and that is also including
a creative and active life. I play my trumpet at international jazz festivals. Perhaps not
at the same level as I could before having all the surgeries, but still… it is a life
I enjoy and the kind I’m of proud of so I’ve done well.
Reflections
Already facing a terminal diagnosis, should cancer patients have to shoulder the additional
terror of unsupervised self-medication in search of a meaningful attempt at survival?
None of the patients we spoke to wanted to go it alone, they desperately wanted the reassurance
of professional medical supervision. Their courage has showed us that the impossible
is sometimes possible, that there could be a solution to problems we perceive as beyond
our reach.
I believe the medical community has an obligation to do research into the cause – the clinical
cause of patients who have undertaken self-medications, and who have reported extended life-span with
glioblastoma. I think it is an ethical obligation of the medical community to try to understand
what happened with these patients, how they did it, what their quality of life was and
how long they survived - these patients cannot be ignored.
As survivors today, patients like Ben, Rich and Anders stand as proof of principal. We
have the unprecedented opportunity to follow this lead, employing the gifts that science
and technology are affording us to actively embrace change. In the era of big data, Google,
and Apple, society can rationally ask the medical establishment to reconsider its confidence
in a regulatory structure that served us well in the past, but that appears slow, inefficient
and even inhumane in the context of terminal disease today. The quid pro quo, that can
secure the continuation of a scientific methodology and rational development of therapies, can
be the clinical data from EVERY patient. Retrospective analysis of this data in the era of genomics,
can deliver the precious information we are searching for in clinical trials, faster,
cheaper and more accurately.
Every professional I have ever talked to, every oncologist, every neuro-oncologist,
every radio oncologist I’ve talked to, believes that I am a freak chance, that my tumour would
have been put under control anyway, and that my cocktail therapy didn’t contribute one
iota to it. They also think that Ben Williams is a freak chance and that his 18 years would
have been given to him even without his experimentation, and anybody that lives a long time – longer
than average - and uses a cocktail approach is similarly dismissed as a freak chance.
But at a certain point, people are going to have to start looking at the evidence.
Some will dismiss this evidence as merely exceptions that prove the rule. But it is
hard to dismiss as coincidence Ben, Rich and Anders’ shared academic background and scientific
training, unusual or illegal access to prescription drugs, and the determination to overcome all
obstacles in the pursuit of their unorthodox cancer therapies.
I’m quite sure that if I hadn't done what I did I wouldn't be alive today. If I had
simply followed the prescription of my neuro-oncologist I would have been just another statistic,
namely I would have lived another 12-18 months and that would have been it. Because to my
knowledge he never had another long term survivor...
'Insanity is doing the same thing over and over again, and expecting a different result'
– Albert Einstein
The Repurposing of Drugs in Oncology is an initiative to provide oncologists with a robust,
independently researched database of old drugs that could be helpful to combine with existing
standards of care across all cancers, enabling them to prescribe off-label drugs with confidence
they will help and not hurt their patients.
With the support of a small charity in Belgium, Marc Halatsch and Richard Kast’s CUSP9 cocktail
of drugs is in final stages of approval in Germany for a phase 1 clinical trial for recurrent
glioblastoma. If the German regulatory authority approve this trial in spring 2015 as anticipated,
they will set a global precedent for other regulators to follow.
The film makers, together with the patients and some of the doctors featured in this film,
are working with a UK charity to open an international phase 1 clinical trial to investigate an expansive
cocktail approach for the newly diagnosed, as an adjuvant therapy to the standard of
care for Glioblastoma. It remains to be seen how such a proposal will be received by the
regulatory authorities across the world…
However, even if these trials go ahead, it will take vast sums of money and many years
to ascertain if they hold benefit for patients. Closing The Gap Now is an initiative to demonstrate
consensus within the scientific community that patients with a prognosis of less than
24 months should be allowed access to any treatment with phase 1 approval, in return
for donating their clinical data to an open-access research database. The scientific community
would then be able to obtain certainty about which treatments work for which patients much
faster, cheaper and more accurately than the current system allows. www.closingthegapnow.org
For brain tumour patients who wish to view extended interviews from this film please
visit www.virtualtrials.com