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Sally Roberts Dilemma

What the Hell is Stable Disease?



A discussion on ‘Stable disease or ‘disease free state’

Oncology nomenclature seeks to describe different disease states in and around one of the most sensitive and difficult areas of medicine. It is difficult because, despite some staggering progress in patient outcomes in recent years, oncology remains one of the hardest areas to show real progress.  The reason for the difficulty in using recognisable terms is because cancer is not one disease but a multitude of disease factors all wrapped up in the term ‘cancer’.  The widest dictionary definition of the word cancer is, growth. It is estimated that the physiological processes that combine to create the conditions for tissue to ‘grow’ in an unchecked manner, may number over 200.

When this is placed into context, one can see why cancer is such a difficult physical anomaly to treat. It is amazingly complex and we are still scratching the surface in terms of our understanding of what cancer actually is and how we can treat it.

The unpalatable (for some) truth is that we do not yet know how to cure cancer. The notion of a cure invokes such emotional responses from interested parties, which include patients, friends, and patient groups to name a few. However, the scientific community remains steadfast in its desire to create treatment options that will make a significant difference to patient’ outcomes.

Here is the truth on the global effort to treat cancers. The scientific community’s realistic goal is to, in the short to medium term, turn cancer from an acute disease to a chronic disease. What this means is, as there is no cure for most cancers, the best we can do is to use treatment methods which in combination, slow down the disease process to a pace that makes the condition a ‘long term treatable condition’. The aim is to be able to put ‘brakes’ on the disease to turn into something that can be managed, rather like rheumatoid arthritis. Its not pleasant when somebody suffers but by careful management patients can achieve a quality of life which is something they find an acceptable ‘trade off’ between taking medication and the resulting outcome, whatever the outcomes are.

This has to be seen in context. The most difficult cancers to treat are tricky because they find collateral pathways to continue their ‘growth plans’ (the cancer cell) whatever treatment modality is used, the cancer can eventually find a way to achieve it aim of further replication. This is why survival (termed overall survival in cancer terms) is the Holy Grail of treatment. After all survival is the ultimate measure of treatment success and the ultimate need for patients facing life threatening health issues. Overall survival is an obvious measure of treatment success but as already stated, cancer is a complex disease to manage and sadly, overall survival is infrequently achieved. This means there has to be other measures of clinical outcomes outside of survival because cancer is incurable and we are seeking to ‘manage’ it as best we can. The main treatment milestones in most oncology studies are Survival (OS) Progression free survival (PFS) Stable disease (SD) and Progression (P) An explanation is offered below.

Overall survival

Overall Survival is the time that a cancer patient remains alive as a result of treatment for their disease. (Example shown later) This can vary from a matter of months to years depending upon which cancer is involved.

Progression Free Survival (PFS)

Progression Free Survival is different to Overall Survival. This term refers to the period within a disease journey, where a patient enters a period where they have not achieved ‘cure’ as they still have their disease but as a result of treatment or sometimes naturally, the natural progression of their disease has halted for a period of time where the disease doesn’t get any worse, hence the term Progression Free Survival.

Progression Free Survival is usually a finite period of time within the treatment/disease journey and in most cases, usually ends with signs that the symptoms of the disease return signaling the end of this period (PFS)

Stable Disease

Stable Disease is a term, which indicates the state in which a cancer has been treated and clinical signs of disease do not appear to ↑ or ↓ in extent or severity. Stable disease can vary from study to study and ranges from weeks or  months to years (infrequently) This term is quite often confusing to lay people but it is a very valuable state to be in if you are a patient undergoing treatment. Patients can gain an acceptable quality of life in Stable Disease during their cancer journey.

Progression

Progression is the term used when clinical indicators suggest the tumor is once again active. This means the treatment has either stopped working, or it is still working but the cancer has found an additional pathway to start growing again. This usually means adding further treatment lines or an adjustment to dose. Frequently, progression means that treatment has achieved as much as it can and will probably mean that active treatment is of limited value at this stage.

Objective response rates

This term refers to the % of patients who actually demonstrate a response to any therapy they have been subjected to. Any patient who has demonstrated any type of tumor response has received an Objective Tumor Response. Clearly the higher the percentage figures the more patients will be likely to get a response from the treatment.

Palliation or palliative care

This term refers to the stage where all active treatments have been explored and for whatever reason, have ceased to bring any meaningful value to the patient. Palliation is the managing of patient’s pain and psychological states when active treatment is no longer appropriate. 

A properly constructed clinical study in oncology will normally feature these terms as they are the standard terms used to study and determine if a treatment has value. New treatment needs to meet the standards set out in the Study Protocol, which will usually be comparing one drug (an older or contemporary with a new or proposed drug)

If new treatments have not been through this rigorous process they have not shown that any treatment observations were as a result of using the drug as opposed to chance or previous treatments.

ASCO 2012 Cancer conference

Cancer Milestones 1894 - 2020

The graphic is difficult to read http://www.nejm.org/doi/full/10.1056/NEJMra1204479?query=featured_home&

The chart shows the major oncological milestones between 1984 to date. The pivotal steps in cancer care are highlighted. Of note, there are no references to Antineoplastons as a major breakthrough in metastatic disease. In fact, there is no mention of them per se.

Source NEJ of Medicine

ANP Phase I Japanese study in 1995

Burzynski The Movie

Coverage of the Burzynski Clinic in Houston continues unabated with the debate raging over if, as some Burzynski supporters believe, there is health value to be gained from attending his clinic and following his treatment regimes. In the social media there are many comments expressed regarding the Burzynski movie which seems to have created headlines amongst the non-scientific population



whom desire only to see/hear headlines before making their minds up regarding the validity of the this subject matter at hand (does Burzynski have a cancer cure and has he been the subject of Government orchestrated underhand dealings) The snapshot trailer of the movie above has an advertisement feel to it and the headlines would not be out of place if Grisham had launched a press review of his latest piece of fiction. The sponsors are two media organisations who, some would say, have a vested interest in hyping up the movie for ratings.

The key to how valuable an analysis this movie is of treatment that the Burzynski clinic offers lies buried within the data.

Most lay people will not be a) interested and b) have the knowledge and understanding of medical data to be able to objectively appraise the information contained within the movie. After discussion of the data there is the issue of, as the movie and Burzynski supporters believe, there is a conspiracy to suppress the notion that this lone Doctor has uncovered a ‘cure’ for cancer.

To look at this fairly it requires a discussion about the two points raised (data and conspiracy theories) To summarise this does not do the subject due respect but, mindful of the non-scientific nature of some readers, a summary seeks to merely ‘touch’ upon the data and what it means.

Data

In the developed world, all new medicines are required to undergo a rigorous process of validation to prove, as far as is possible, that the new medicine does in fact do what the developer says it will do and that it can do so effectively and safety. Finally it is the responsibility of the developer to contrast the new treatment with existing treatments which have already been through the evaluation processes as described above. This process usually has 4 stages but the first three are key (Phase I to 3) Essentially Phase 1 data is designed to evaluate;

• The safe dose range
• The side effects
• How the body copes with the drug

• If the treatment shrinks the cancer

Phase 1 is concerned mainly about finding a safe dose and an understanding of any side effects associated with the new drug. It is worth noting that 90% of new treatments do not progress to Phase 2 such is the difficulty in proving new compounds have any treatment value.

Phase 2 studies follow on from Ph1 if the analysis of the data encourages further work (i.e. a safe dose has been established with an acceptable safety profile) the purpose of Phase 2 studies is to develop the experimental treatment a little further by seeking to understand a little more about the drug.

Phase 2 studies;

• If the new treatment works well enough to test in a larger phase 3 trial
• Which types of cancer the treatment works for
• More about side effects and how to manage them
• More about the best dose to use

Phase 3 studies

This is an important Phase (probably the most important) as this is where the early work in Phases 1&2 is really put to the test. This is where there are larger patient numbers and a comparator (a drug to compare against the new treatment) is evaluated. Drugs which get to this Phase can still fail. It is only when bigger patient populations are introduced that ‘key facts’ about the experimental drug becomes known. It is largely as a result of the Phase 3 studies that Health Care regulators around the world make their decisions about if an experimental treatment gets licenced for widespread use.

It is worth taking note at this point that most clinical developments (particularly new chemical entities) take about 8-10 years to get to marketing stage (where Doctors are allowed to use the treatment)

If you wish to read a broader description of the clinical trial process, this link takes you to a Cancer charity which explains Cancer to patients

http://cancerhelp.cancerresearchuk.org/trials/types-of-trials/phase-1-2-3-and-4-trials#phase2

Discussion on Burzynski data

Now that the clinical trial process has been described we are able to view where the Antineoplastons therapy that the Burzynski clinic features in the movie, is in its development and hopefully understand the arguments with a little more clarity.

The Burzynski clinic has completed Phase 1&2 of its clinical trial process. Let’s recap what this means. The new treatment that the Burzynski clinic has been working on has demonstrated to have found a treatment where a safe dose has been identified (Phase1 trial) it then entered Phase 2 trials where the study seeks to understand a little more about the treatment on a slightly larger patient group. The Burzynski clinic has completed the first 2 Phases and now is required to put the treatment to the biggest and most important test by going into Phase 3 studies (the stage where licences are determined) This is by no means approval or permission to be in general use. Remember also that drugs will also fail at Phase 3.

Critics of the Burzynski development of ANP’s point to the fact that after carrying out clinical trials for almost 30 years (this figure is disputed by Burzynski supporters but to be fair, let’s say its 25 years) that key data should now be available. Remember that its takes around 8-10 years to get NCE’s (new chemical entities) to the clinic (where Doctors can use on a general basis) so the question arises, what has been happening in the Burzynski clinic to take this long to prove his treatment works? Critics say that he has had 25 years and has still not proved his treatment works to a level where it can be licenced for widespread use.

Further concern arises from the fact that the Burzynski clinic charges such high fees for inclusion in their clinical trials. Estimates vary but figures of £200,000 ($313,000) seem to be consistent. This is highly unusual as clinical trials around the world do not charge for trials. If they do it is only small fees. We have to ask ourselves the question, why are patients charged such high fees when the treatment has not been proved to work? Remember drugs have to have completed Phase 3 studies to be able to receive a licence. The Burzynski clinic treatment has not completed any Phase 3 trials since it began its clinical trial programme. Burzynski clinic supporters say the fees reflect the fact that the ANP trial programme is self-funded so Dr Burzynski has to charge high fees. Patients have questioned these fees especially as Dr Burzynski is reported to live in a $6,000,000 mansion and makes political donations regularly. Patients also ask, if the fees are so high because of having to self-fund the trial programme, how much money has been paid by patients in the 25 years he has been doing his trials? And why are there no Phase 3 results yet?

The last question is often answered by Burzynski clinic supporters by citing the FDA Conspiracy against Dr Burzynski. They say he is unfairly dealt with and is being supressed in conjunction with what they call ‘Big Pharma’ (major Pharmaceutical companies) to make sure he doesn’t ever get a licence for his Antineoplaston treatments. There is no evidence that can be found to substantiate this claim. In fact, if the Burzynski treatment had shown, through the clinical trial process, that it had enough potential to be used world-wide, a major corporation would have stepped in to fund this by now. For all the negative press that ‘Big Pharma’ receives from the Burzynski clinic supporters, the major oncology companies have a long history of partnering with developers like Burzynski when they can be sure that the treatment has real potential. This appears to be the major problem for the Burzynski clinic. They have not, despite the hype surrounding the movie, been able to show the world via the appropriate clinical trials (haven’t got to Phase 3 in 25 years) that the treatment meets the accepted criteria required for the medical establishment, major corporations as investors, independent patient liaison groups and most importantly the patients themselves to be able to make this treatment available around the world.

Conspiracy theorists will argue that the Burzynski clinic is being supressed at the same time the relatives and patients, desperate for a last chance to beat nature at its own game and gain extra years in the face of a terminal illness, will grasp in their desperation at anything that might give them more time with their loved ones. They will do almost anything to achieve this goal which includes trying to pay fortunes for an experimental treatment that hasn’t, as yet, been able to satisfy the world of its value. It is easily understandable why patients would want and need to believe the contents of the Burzynski Movie. However, as is the case in life, the spirits of the desperate desperately and broken are susceptible to any suggestion they can cheat nature. The Movie doesn’t advance the academic case for the ANP treatment as much as patient’s, carers and the medical world want and need.



Bursynski supporters getting out of shape on minutiae

It’s been an interesting few days on Twitter observing the machinations of so called ‘supporters’ of the maverick US Cancer cure Physician, Stanislav Bursynski. You may recall that this is controversial Doctor who uses film crews and patient testimonials as major platforms in his promotion of his clinic and specifically his ‘wonder drugs’ in for form of ANP’s. Other Clinicians use the time honoured tradition of arranging comparative and reproducible experiments which, when conducted and monitored properly, allow close scrutiny and debate over any new or improvement of a treatment.  There are plenty of pieces in ‘blogland’  on the suspicion with which his clinical development strategy is held but it is ‘supporters’ who seem to be the ones fronting the major defence of his efforts to ‘cure’ peoples cancer. A number of them probably think they serve the Bursynski Clinic well in its efforts to encourage more desperately sad and broken spirits to weigh over a lifetime’s savings fund to this clinic. With little evidence to show prospective ‘new’ patients other than carefully constructed websites and choreographed films, the clinic needs all the ‘foot soldiers’ it can get to advance the case for its existence. One might be excused for thinking these Bursynski advocates had some technical knowledge of the subject that they appear, on the surface, to know so much about and talk with such authority on. Here are a few examples of the science based medicine approaches they take to convince ‘new’ patients to consider this approach and how they engage with Health care Professionals who spend most of their working lives truly caring for cancer sufferers.

This is the level of science application behind the so called 'fans' of Bursynski. The concern is that if these people play even a fraction of a role in persuading patients to go to this clinic then it’s a scary thought. When pro Bursynski supporters get all out of shape in interactions with oncologists and other health care professionals, it is most likely because they cannot access the basic tenets being debated – we shouldn’t underestimate their lack of understanding because they are clearly influencing those with difficult and sensitive choices to make for themselves and their loved ones. This is one of Bursynski’s legacies in not publishing acceptable protocols and then carefully monitored and scrutinised trials. The confusion caused amongst well-meaning but misguided people leaves them in a vulnerable position.

Australian Drs, Scientists wage war on Alternative/Pseudiscience Medicine's

This reports the aim of a group of Australian Scientists to remove formal
University classes containing Alternative Medicine from the curriculum. It cites
the UK as another country which has made a similar move. Friends of Science in
Medicine (FSM) already has 450 members. They include Ian Frazer, the inventor
of the cervical cancer vaccine, and Sir Gustav Nossal, a renowned immunologist.
Among their group, 50 are international and they too hope to snuff out what they
refer to as modern-day quackery.

 http://www.theatlantic.com/health/archive/2012/03/australian-doctors-scientists-wage-war-on-alternative-medicine/253342/