Online survey: Improving outcomes for patients with advanced cancer

The Rarer Cancers Foundation has asked AMMF to help with an on line survey – they want to do all they can to support the NHS in ensuring that people with rarer and less common cancers have the best possible care and treatment. To do this, they need to know more about people’s experiences and what they value when they have advanced forms of cancer.

An on line survey has been prepared to collect this information from patients, their family members, carers and others who have an insight into this area.  Your feedback is vital and will collectively help to make a real difference to the outcomes for those with advanced cancer.

Closing date is 30 Jan 2012, so please do take the time to take part.

If you have any queries or need help with the survey, please contact Debbie de Boltz at RCF on 07889 726269

https://www.surveymonkey.com/s/Patients_views

AMMF is delighted to have become a member of Cancer52, the organization providing a “common voice for the less common cancers”.

Cancer52 is so named because 52% of cancer deaths in the UK are from the less common cancers (although in 2010 this proportion increased to 53%). Despite this figure, the less common cancers remain severely under represented and under funded across all areas, including policy, services and research.

Cancer52 is an alliance of over 40 organisations working to address these inequalities and to improve outcomes for patients with these highly challenging diseases.

Together we have a more powerful voice.

AMMF was delighted to report a few months ago that it had been agreed with Imperial College that the charity would fund a Research Fellowship for a year.

Dr Abigail Zabron has now begun her research work and has written to AMMF introducing herself, describing what led her to embark on cholangiocarcinoma research, and outlining what she hopes to achieve.  I’m sure we all wish her the very best with her research.

AMMF's Helen Morement (l) with Dr Abigail Zabron

“It is a great privilege to accept the support of AMMF in the form of a Research Fellowship to study cholangiocarcinoma.

I was originally drawn to science by an innate curiosity about how things work in the world around me, and this led me to study biology at BSc level at Bristol University, and to follow this with a PhD at Emmanuel College, Cambridge, studying the molecular pathways by which different parts of the plant cell communicate with each other.

During this time I realised my interests lay in applying a scientific understanding to patient care, and I then retrained as a medical doctor at the Royal Free & University College Medical School, and have deeply enjoyed my work ever since.

It was in my first year after qualifying, when working for a hepatobiliary surgeon, Professor Brian Davidson at the Royal Free, that I came across patients with cholangiocarcinoma, and began to appreciate the particular difficulties, especially for the patients and their families, of dealing with a disease so difficult to treat, and about which so much remains to be discovered. So often we as doctors cannot even offer any explanation about why this has happened.

After taking up a post as a Gastroenterology Registrar at Imperial AHSC, where there is a particular clinical interest and expertise in biliary tract cancers, these difficulties have been brought home to me again. I am sure there is so much more we should be able to do, and that a better understanding of this disease is core to moving forward in improving treatment. As a scientist, trying to unpick the genetic, environmental and life-style factors which combine to allow the disease to develop is truly fascinating, but the importance of improving the situation for my patients gives this a real imperative for me as a doctor.

This Research Fellowship funded by AMMF allows me to step away from my clinical training for a while, and to concentrate on research full time. I have been fortunate in joining Dr Shahid Khan and Professor Simon Taylor-Robinson’s Cholangiocarcinoma Research Group at Imperial College London. I hope my work during this fellowship will add to our understanding of this disease, so that we may be better able to predict, prevent or treat it in the future, but also help in developing new understanding and diagnostic tests in the shorter term.

For example, our group has recently identified possible protein “fingerprints” in blood samples of patients with cholangiocarcinoma. I am currently exploring the best way to take this work further in order to identify the proteins that result in these patterns, using the proteomics facilities available at Imperial College.

My previous pilot work using different proteomic techniques has shown that we can identify specific proteins in bile fluid itself, reflecting different diseases around the bile ducts, and I am applying the same techniques to bile from patients with cholangiocarcinoma. With this in mind, I am currently collecting bile from patients with blocked bile ducts from all causes, to be able to compare this with bile where cholangiocarcinoma is present.

I hope once enough samples are available and analysis complete that this will help us understand better the biological differences between a normal bile duct and malignant tissue, and enable the future development of effective diagnosis and treatment.”

The following is a brief summary of Tyson and El-Serag’s paper reviewing scientific literature up to and including March 2011, entitled “Risk Factors for Cholangiocarcinoma”, which was recently published in the journal Hepatology.

(The following technical translation of the published paper has been prepared for us by Dr Ruth Corrigan MA (Cantab), and a link to download the full paper can be found below the summary.)

Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. People below the age of 40 are rarely affected, and most people are diagnosed in their 60s. Worldwide, CC accounts for approximately 10%-25% of all hepatobiliary worldwide, although there are considerable geographic variations in the incidence of CC, largely attributed to geographical variations in known CC risk factors (particularly parasitic infections, see below). However it is important to note that for the majority of CC cases in the Western world no risk factors are evident, and thus these cases are classified as “sporadic” cholangiocarcinoma. Much research is still required in order to find out more about why CC develops. This paper aims to summarise what is known about CC risk factors to date.

In this paper the authors review 63 scientific articles relating to risk factors for the development of CC. In general, risk factors for diseases are identified using one of two methods: either by comparing people with and without the disease of interest and looking for any differences between the groups which may be linked to the development of the disease in question, or by looking at people with and without proposed risk factors and comparing how many from each group develop the disease of interest. This paper looks at the conclusions of many of these studies to provide an overview of our current knowledge of risk factors for CC.

Initially this paper reviews the evidence for known CC risk factors, for example parasitic infection of the biliary tree (prevalent in South East Asia) and the autoimmune disease primary sclerosing cholangitis. Next the paper highlights possible CC risk factors such as inflammatory bowel disease, diabetes and obesity and summarises the evidence for each.

It is important to note that although risk factors can be identified at a population level, that is to say “people with primary sclerosing cholangitis are more likely to develop CC than those without”, it remains almost impossible to identify individual risk factors in patients diagnosed with CC, that is to say “this patient developed CC because..”.

Known Risk Factors For CC

The following risk factors are all accepted by scientists to increase the likelihood of developing CC:
Parasitic infections

Biliary tree disorders including bile duct cysts

Primary sclerosing cholangitis

Bile duct stones

Toxins

Conditions are considered risk factors for a disease if numerous studies by different groups of scientists have come to this conclusion. Some examples of such work in relation to CC are described below.

Firstly, studies from Thailand have found that people with CC were between 5 and 27 times as likely to have antibodies indicating infection with the parasite Opisthorchis viverrini than similar people without CC. Similarly, patients with bile duct cysts (arising due to a developmental abnormality of their bile duct anatomy) are reported as having a 50 fold increased risk of developing CC compared to those with normal bile duct anatomy. Equally a study of Chinese patients found that those with gallstones high up in the billiary tree (before the left and right hepatic ducts join) were also 50 times more likely to get CC compared to those without. Furthermore a Japanese study found that people exposed to the radiographic contrast agent Thorotrast were 300 times more likely to get CC than those who were not exposed, strongly implicating this toxin in the development of CC.

However, it is important to note that although such conditions are consistently linked to a high risk of CC, the percentage of CC cases which can be attributed to each of these known factors is unknown, and likely to be low. For example, it has been estimated that only 10% of CC can be attributed to primary sclerosing cholangitis, even though up to one in three of these patients will develop CC.  In practical terms this means that many risk factors are yet to be identified.

Possible Risk Factors For CC

The involvement of some factors in the development of CC is currently unclear, as the conclusions from studies are either conflicting or there are too few studies to be certain. Such factors include:

Inflammatory bowel disease

Choledocholithiasis and cholangitis

Hepatitis B or C and cirrhosis

Diabetes and obesity

Alcohol use

Smoking

Genetic factors

Before discussing these potential risk factors the authors of this review suggest that CC ought to be considered as two entities; intrahepatic and extrahepatic CC, based on whether the cancer affects bile ducts inside, or outside of the liver. This is because they suggest that some less well established risk factors can be more strongly associated with a particular subtype of CC.

With regard to the proposed risk factors listed above, current research as included in the review is summarised below.

Inflammatory bowel disease (IBD). Several studies have investigated the link between IBD and either or both intra- and extrahepatic CC, with mixed results. Conclusions are further complicated by the fact that primary sclerosing cholangitis is itself more likely in people with IBD and it remains unclear whether any link between IBD and CC is in fact due to the increased risk of primary sclerosing cholangitis in IBD patients.

Choledocholithiasis and Cholangitis. In a similar vein, although both the presence of gall stones in the common bile duct (choledocholithiasis) and infection of the common bile duct (cholangitis) have also been associated with increased risk of CC in at least 3 studies it is unclear how much this is due to an increased risk of primary sclerosing cholangitis in these patients.

Hepatitis B or C and Cirrhosis. The link between hepatitis B or C with CC is equally unclear. Conflicting studies from Asia find that hepatitis B (but not C) is associated with CC, also that hepatitis C (but not B) is associated with CC, and that infection with either virus is not associated with CC. However, in European studies both hepatitis C infection and liver cirrhosis have been linked to an increased risk of developing CC, but hepatis B has not. Finally, three studies from the United States find that hepatitis C infection is associated with an increased risk of intrahepatic CC, whereas no studies have implicated hepatitis B in the development of either subtype.

Diabetes and Obesity. With regard to diabetes, the field is split, with four studies (including two large American studies) finding a potential link between diabetes and CC, but at least four finding no significant association. Again, there are studies suggesting both that obesity is and is not linked to the development of CC, but the evidence to date is too sparse to be suggestive one way or the other.

Alcohol Use. The role of alcohol use in the development of cholangiocarcinoma is similarly disputed by several studies. However, since some studies reviewed find a significantly increased CC risk of 2-15 fold in those who drink heavily compared to those who do not, the authors of this review consider it likely that heavy alcohol use is associated with an increased risk of CC.

Smoking. Interestingly, at best, smoking is only a weak risk factor for CC, but again, conflicting data from a variety of studies, some of which failed to quantify the amount of tobacco smoked mean that no firm conclusions can be made.

Genetic Factors. Finally, numerous studies have implicated many different genes involving enzymes responsible for the disposal of waste products, DNA and the immune response in the development of CC, however more work is needed to draw out consistent findings from such studies.

Summary:

In summary, with the exception of CC in countries where liver flukes are common, most cases of CC are not associated with one of the established risk factors for the disease. This is especially true in the Western world where the majority of cases of cholangiocarcinoma are classified as “sporadic”, that is to say that the causal factor is unknown. This suggests that other risk factors must exist and raises the possibility that some of these could be associated with particular disease cases. To date, data regarding the role of IBD, obesity, smoking and genetic variations is not strong enough to prove or disprove an association with CC. However, current evidence is suggestive that diabetes, heavy alcohol intake and HCV (in Western countries) may be associated with increased risk of developing CC. Given that CC in different parts of the biliary tree may have different risk factors the authors of this review also emphasize the need for a clear and consistent method of classifying cancers of the liver and biliary tree system.

El Serag CC risk factors review

At the meeting with CRUK on Wednesday 21st September, to discuss the proposal that AMMF financially support the ongoing BILCAP trial, one point that came across very clearly was the painstaking care which which trials are organised and conducted and how everyone wants results as quickly as possible.  However, in order for outcomes to be credible and dependable, results must be meticulously gathered and analysed and that, throughout any trial, the patient’s quality of life is always uppermost in everyone’s minds.

During the meeting various questions were raised and, in each case, the CRUK representatives answered them as fully as possible.  Where they didn’t have answers, they promised to find out.

A quick resume of the BILCAP trial – This trial is comparing surgery followed by capecitabine treatment with surgery alone for cholangiocarcinoma or gallbladder carcinoma.  The trial is building on experience from other studies in an attempt to give robust, practice-changing evidence for the effectiveness of using chemotherapy after surgery.
(As referred to below in the text – the BILCAP research team have recently presented their work at ASCO, and their very informative poster giving all details on this trial to date has now been given to us – pdf available below.)

Q.  Why is capecitabine the chemo of choice for the BILCAP trial?

A.  Previous studies have shown that cholangiocarcinoma can be sensitive to chemotherapy.  A number of small studies in people who have undergone surgical resection suggest that the drug 5-fluorouracil (5-FU) may be helpful in prolonging survival from cc.  Leading on from there, capecitabine, which is an oral form of 5-FU, is now being used in a far larger study, BILCAP, which it is hoped will give the conclusive proof required to change clinical practice.  (This pill form of 5-FU chemotherapy means that patients can take the treatment at home, avoiding the need for hospital visits, which is an important consideration in terms of quality of life.)

Q.  What happens if a patient’s cc recurs whilst on the BILCAP trial?

A.  They will be offered “treatment as indicated”.  On further questioning as to what this meant, it would seem that if the patient’s consultant felt there was another treatment that would be helpful, then that would be offered.

Q.  This is a lengthy trial – will there be interim results?

A.  The primary aim of this large trial, involving 360 people who have had sugery for biliary tract cancer, is to see if capecitabine will extend survival compared to surgery alone – the effect of the treatment on the percentage of people surviving for five years or more after their diagnosis, and on the length of time before the cancer returns.  If they can show that the drug treatment has a positive effect on any of these, it could lead to a change in the way cc patients are treated here in the UK and internationally.
The trial has been running for several years, with 234 people enrolled to date.  All patients will be followed up for up to 5 years, so it may be some years until the final results are known.  Although everyone wants to know the results, and there are some interim results available, it is considered very important that the final results are known before the true effects of the drug treatment can be fully interpreted, and so its impact can be understood.
The BILCAP research team recently made a presentation at the 2011 ASCO conference (The American Society of Clinical Oncology) – a link to a pdf of their informative ‘poster’ is below – reporting that recruitment for the trial is going very well.  A small interim analysis of survival and toxicity data was also presented.  The survival analysis was performed at a very early stage and doesn’t really give any indication of what will happen in the longer term.

Update 07.10.11 -

What is the longest length of time a patient has been on the trial? There are patients who have now been followed up for five years.

Q.  What are the toleration/toxicity levels of this trial?

A.  As reported at the ASCO conference, the side effects of the treatment were mainly as anticipated and of a low grade – hand/foot and GI toxicities being the most prevalent – meaning they could be dealt with easily.  (The patients are asked to complete a form after each round of treatment, and the percentages of the various areas of side effects can be seen on the poster.)

Q.  Have many people withdrawn from the trial?

A.  The CRUK representatives couldn’t answer that, but promised to find out.

Update 07.10.11 - 

What is the number of people removed from the active side – because it has been intolerable?   They are unable to supply this information, but re-iterated that the side effect profile suggests that the treatment is very well tolerated.

We did talk about the ABC-03 trial – and, briefly, this is the information we now have on it:

Most biliary tract cancers are inoperable, mainly because they are diagnosed at an advanced stage.  In a previous sudy, ABC-02, the combination of cisplatin and gemcitabine was shown to give extended survival in patients with advanced, inoperable cc over gemcitabine alone.  However, to try to improve outcomes even further, the ABC-03 trial has been set up with a further drug added to the combination – cediranib.

Cediranib is an “anti-angiogenic” drug.  This type of drug works to prevent cancers from driving the growth of new blood vessels to provide the high levels of oxygen and nutrients they need.  Cholangicarcinomas usually build up a dense network of blood vessels around themselves, so it is thought that cediranib could be a useful addition to the armoury.
If the results from this trial are positive, plans are that a larger trial would be developed.

BILCAP ASCO Poster 27May 2011 FINAL VERSION 1 JUNE (2)

AMMF’s Imperial College Meeting Summary

On Thursday 28 July, a gloriously sunny day in London, AMMF representatives, Helen Morement, Noel Corrigan and Dr Ruth Corrigan, met with the Imperial College cholangiocarcinoma research team to find out what is currently happening in the world of cc research.

Imperial’s cc research team were out in force – Professor Simon Taylor-Robinson, Dr Shahid Khan, Dr Abigail Zabron, Dr Chris Wadsworth, Dr Verena Horneffer van der Sluis, Dr Mohamed Shariff, Dr Nimzing Ladep and Research Nurse Co-ordinator Mary Crossey – our discussions were certainly wide ranging and a summary of the topics covered follows:

Dr Abigail Zabron – Research Fellow

l to r: AMMF's Helen Morement, Dr Abigail Zabron, Dr Ruth Corrigan

We were delighted to meet Dr Abigail Zabron, who will be taking forward the preliminary work on proteomics and genetics of cholangiocarcinoma from this October, funded by AMMF.  All Dr Zabron’s work will be directed to sporadic* cholangiocarcinoma, which is the type that is increasing in incidence here in the UK and in the USA. Dr Zabron is highly experienced in this field and is dedicated to her work.  A fuller profile will be coming soon …

(*Opisthorchis – liver fluke – induced cc is the most prolific kind in Thailand where there is the highest incidence of cc in the world, and also appears in other countries – research is being carried out into this specific type of cc in various centres, too.)

We discussed with the group the pooling/sharing of information gained through research and from this discussion a couple of other topics came up:

Shared Samples for Research

Under a new scheme the government is financially rewarding centres who participate in a new shared sample scheme.  Research Nurse Co-ordinator Mary Crossey is involved in this on behalf of the cc research team which, on the face of it, should prove extremely useful in their research work.  However, collecting samples from various centres throughout the country is proving a bigger task than initially thought as a daunting amount of paperwork has to be completed every time.  Although initially seeming attractive, the costs involved in this make the ‘reward’ less attractive – so it remains to be seen if this will be a helpful move.

Research in Thailand

Professor Simon Taylor-Robinson visited Thailand earlier this year, and met with his counterparts to discuss research collaboration.  The collection of blood samples for use in UK research was agreed, and this has begun.

Transplantation / Visit to the Mayo Clinic

Many of us are interested in the progress of the Mayo Clinic as they are one of the few institutions in the world offering liver transplantation for bile duct cancer (for carefully selected patients, and following a strict protocol), using living donors as well as donated whole organs.  Here in the UK, transplantation is simply not an option for cc patients – with unclear/unproven statistics, lack of donor organs, and the cost to the NHS, being amongst the reasons cited for this.

(Dr Wadsworth’s award to undertake this trip came from St John Ambulance – amazing to learn that they support research amongst their other good works!)

Dr Wadsworth will be moving back into clinical practice later this year, but has done sterling work with his cc research – not least the microcoil probe which he has developed as far as he can and is now being handed over to Imperial’s superb Engineering Department for prototypes to be produced so that trials of its use can begin.

Treatment

Following on from our discussion about transplantation, we talked about other current treatments, including the seeming discrepancies between centres on the possiblity of surgery, and how in the US they appear more ready to undertake riskier procedures than here in the UK.  The general view was that many surgeons are concerned about their outcome percentages, which are now published, which makes them more cautious about taking ‘chances’.

CyberKnife

We discussed the use of the new, revolutionary radiotherapy technique, the CyberKnife.  However, the current thinking from the team seems to be that the jury is still out on this one re its use in the treatment of cc, because of the nature of cc tumours, and because they are often surrounded by such delicate structures.  It was felt that more evidence was needed before this would be taken on board for cholangiocarcinoma.

(This is, obviously, the opinion of the Imperial College team, the literature from The Royal Marsden Hospital re their CyberKnife states that it will be used on the liver – although we have asked and not had it confirmed that this would include cc – and we believe that this treatment is being offered to cc patients at private institutions.)

Risk Factors for Cholangiocarcinoma

Dr Khan also reported that the National Guidelines for Diagnosis and Treatment of Cholangiocarcinoma, which he has been working on for some time with a group of leading GI cancer specialists, is almost ready for publication.  We definitely look forward to that!

From AMMF’s point of view, we had a very productive meeting, covering a multitude of topics and receiving insightful replies to our many questions – and we are very grateful to the Imperial College team for their dedication and determination to seek out the answers we all hope for …

And finally …

One of the things Professor Taylor-Robinson mentioned in passing is that he is hopeful (very hopeful!) that current proteomic research will lead to cc being detectable in urine – via a simple dip test!  Which would have huge implications for the possibility of screening for cc, and could revolutionise the diagnosis process.  You heard it here first!!

Back row l to r: Dr Chris Wadsworth, Dr Mohamed Shariff, AMMF's Noel Corrigan, Professor Simon Taylor-Robinson, Dr Nimzing Ladep Front row l to r: Dr Shahid Khan, AMMF's Dr Ruth Corrigan and Helen Morement, Research Nurse Co-ordinator Mary Crossey, Dr Verena Horneffer van der Sluis and Dr Abigail Zabron

For details on research recently carried out at Imperial College on genetic risk factors in the development of cholangiocarcinoma, which was part funded by AMMF, please click to see AMMF’s Research Updates page:

AMMF’s Research Updates page