World Congress on Gastrointestinal Cancer 14, Barcelona, Spain

An improving outlook for liver cancer patients

Dr Graeme Poston – University Hospital Aintree, Liverpool, UK

There is a huge problem out there that many cancers will spread to the liver. Up to about twenty years ago, once it was in the liver, that was it, nobody would anything, you would get offered best supportive care. For most of the first decade of those twenty years chemotherapy was fairly ineffectual, it’s only in the last ten years that we’ve actually seen chemotherapy agents have some impact on cancers that have spread to the liver or started in the liver. Now what we know is that if you can remove a cancer from the liver, whether it’s a primary liver cancer or a secondary liver cancer, certainly you will prolong survival and there’s a chance of cure. The chance of cure is about one in three and that means being alive, disease free, ten years later. It’s the only modality surgery which offers the chance of cure to patients who have got cancer in the liver. Now at present only about 20% of patients whose cancer has either spread to the liver or started in the liver are suitable or amenable to surgery, surgical resection. We do have other treatments though, oblation therapies, which we did in the past with alcohol injection and then we did freezing therapy, we call that cryosurgery, then we used a thing called radiofrequency which heated them. Now we use, literally, microwaves and a microwave probe which you can put into a tumour, we can destroy a tumour in two or three minutes in the liver. They increase the options for patients who have got cancer in the liver but the majority of patients still are not amenable to surgical intervention.

Now the one major step forward in chemotherapy which has really helped us, the liver surgeons, has been the ability to convert patients with inoperable liver tumours, be it primary and more commonly secondary or metastatic cancer in the liver, to operability by shrinking the tumours down in size and therefore allowing us to preserve healthy liver which wouldn’t be possible if the tumours were too big. That started about fifteen years ago, the first data came through with oxaliplatin in secondary colorectal cancer and then more recently we’ve seen big steps forward with the use of Erbitux in KRAS wild-type colorectal cancer spread to the liver where we probably can convert a third of those patients who are inoperable and incurable to operability with curative intent. Now that does mean that we, the liver surgeons, have to work actively with the medical oncologists in multidisciplinary team working. The problem, and it’s not just a European problem, it’s a global problem, is that very few countries actually work that way. It’s a legal requirement in the United Kingdom, Ireland, France, Belgium, Spain and Scandinavia but in many other countries, and some major European countries like Germany and Italy, it is not a legal requirement. So doctors in those countries are operating on their own, in the dark, whether they be a medical oncologist or a surgeon there’s no requirement to interact with other disciplines. So outcomes, by necessity, will be poorer when that actually happens. So the major thrust of what we’re talking about tomorrow morning will be the multidisciplinarity of this, not just focussing on the surgery but how the surgery integrates into the other oncological disciplines, predominantly medical oncology and chemotherapy and biological therapy, but also things like radiotherapy. We’ve now got Cyberknives which will help improve the chances for patients with liver cancer. In the past we couldn’t use traditional radiotherapy but Cyberknife is a new option for us. Also working with our colleagues in radiology who can destroy tumours in the X-Ray Department now just by burning them out or putting catheter tubes via the artery into the tumour and literally putting the chemotherapy into the tumour directly, we call that arterial chemoembolization. Again, this is changing the face of oncology as it affects the liver.

At what stage should liver surgery be considered?

I chair the Quality Standards Committee of the National Institute of Clinical Excellence in England and we are making it a legal requirement, as of next April in England, that all patients with liver cancer must have their scans looked at by a liver surgeon. We’re not saying every patient must come and see the surgeon but we are saying that the patient who has cancer involving the liver, confined to the liver, those scans must be looked at by a liver surgeon. The reason is that the general surgeons and the general oncologists don’t understand the liver, they don’t understand the anatomy, they don’t understand what’s possible. Even now we’re seeing something like 50% of patients who are suitable for this kind of surgery not even being considered for it and being condemned to palliative chemotherapy and they’re dying in eighteen months without anybody even thinking that surgery might be an option for them. This will be a legal requirement in England next April, all hospitals will have to report to the Department of Health on what happens to these patients once they’re diagnosed with liver only cancer and if they don’t refer them, the Chief Executive’s neck is on the block for this. So this will be a quality standard that NICE will impose next year.

What are some of the trends in treatment?

We have been looking at various things, I’ve been involved in a very big trial that’s been running in Europe for the last fifteen years where we looked at, for instance in secondary colorectal cancer in the liver, a combination of chemotherapy first and chemotherapy afterwards. Our initial trial results, which we reported in the plenary session at ASCO five years ago, looked very favourable. We thought we were improving three year progression free survival in our chemo patients after surgery by 9%. Unfortunately, when we reported earlier this month at ASCO on the five year overall survival figures, the survival benefit had fallen overall to only 4%. Now, you’ve got to ask yourself if you’re a cancer patient, are you going to put yourself through six months of fairly intensive chemotherapy if your chance of being alive at five years is only 4% greater than if you didn’t have six months of your fingers getting very numb with the oxaliplatin and the problems of chemotherapy side effects? And that’s a difficult question. The difficult area for us has been that we were hoping, over the last five or six years, that the new monoclonal antibody targeted therapies like bevacizumab, cetuximab, would also help to improve survival figures but in the stage 3 colon cancers, the primary colon cancers, the results have not been good with the addition of biologicals. We are looking at them in stage 4 for liver surgery, those results are awaited but I’m concerned that we may well find that in stage 4 we have the same problem - that they don’t turn out to be as good as we hoped they would be. But we still have a lot of work to do integrating the medical oncology aspects of this, the chemotherapy or the biological therapy, into the surgery. We must never forget that the majority of patients, despite the surgery, will recur and need more treatment in the future. That would be combined therapy – we can re-operate on the liver for some people, we can further oblation, we can certainly go back to the chemotherapy, either using the earlier agents and reintroduce them or introduce a second or third line of therapy as necessary. I have got one patient who has had six liver operations in the last ten years and is presently disease free. Now clearly he’s got interesting biology but this is what is now feasible and we can keep people alive. It also introduces the concept that some of these cancers become a chronic illness, like diabetes. The diabetic who doesn’t take their insulin will die within two or three weeks; if they take their insulin their life expectancy is relatively normal. Some of these cancers become a chronic illness and as long as we can keep re-treating or maintaining the patients on their therapy, they get on and lead normal lives.

What are your views on some of the adjuvant treatments?

In terms of liver surgery, the data so far have not been as good. So we did this trial, we called it the EPOCH study and published in The Lancet four years ago. Initially we thought the results were actually very good in terms of progression free survival, it was a 9% improvement. It hasn’t translated over into as good an overall survival figure which is what patients want. Patients don’t understand progression free survival, they do understand being alive or dead and that’s what overall survival means to the cancer patient. Up until now, the adjuvant therapies in my field have not been as good as they have been in primary bowel cancer and primary breast cancer. Now that may be that the patients who I treat have more aggressive disease because it’s already spread from the bowel to the liver and therefore it is a nastier form of cancer in the first place and therefore may not be as sensitive to chemotherapy or biological therapy as the primary tumour and the primary tumour that hasn’t learned to escape from the bowel or the breast. So that maybe why in my field the adjuvant therapies have not been as good as they have been at other sites.

What are some of the producers you use?

We do a number of things. Twenty odd years ago it was a horrific operation, we started with twenty pints of blood, another twenty pints of blood, and if we got the patient off the table alive we’re doing very well. It’s completely changed. With modern anaesthesia now these are bloodless operations. The safety of the operation is a lot safer than primary bowel cancer surgery where the mortality in Europe is still 4-5%, one in twenty patients die from the bowel cancer surgery, ours is 1%. We have international registers which we all put our data onto to compare ourselves to it. Most importantly though, particularly in Britain, we have centralised it. Only in England, for instance, there are only eighteen of 190 hospitals that will be reimbursed and we’ve said that to support a liver cancer surgery service you need a minimum of two million, and ideally three million, population base feeding into that. So out of every ten hospitals, one will be the designated liver centre and that’s where the patients who need this surgery go to. Now the operation, about 20% of them we now do laparoscopically, the keyhole approach to it, but 80% still require a big operation so it means your bikini days are over. But what it does mean is that actually with modern anaesthesia,  modern surgical techniques, the average stay is four days in hospital and because we don’t interfere with people’s bowels they’re eating and drinking on the same day as surgery and they bounce back very quickly. There’s a very important paper came out in JCO last year from a combination of the Bristol and Basingstoke group showing that the recovery to normal quality of life after liver cancer surgery was a median of 4-5 weeks as opposed to 4-5 months after bowel cancer surgery. So these patients bounce back very, very quickly.

Could you talk about some of the drugs used in liver cancer?

It doesn’t come into my field, we don’t use that in bowel cancer or in primary liver cancer. The drugs that are interesting in bowel cancer obviously are oxaliplatin, irinotecan, bevacizumab, cetuximab, panitumumab and then this year we’ve got very interesting data on aflibercept and regorafenib. Now, interestingly with aflibercept the data that so far have been presented from the VELOUR study show that it is basically very effective in people who have already had bevacizumab. Now it works by exactly the same way as bevacizumab, yet for people who progress on bevacizumab and then you introduce aflibercept, which works by the same mechanism, what you tend to find is that their response rates are much higher than chemotherapy alone, their progression free survival is better and their overall survival is better, that’s in second line. Now what is going to be very interesting is when we see it in first line. Regorafenib has only really been tested at the moment against best supportive care in third and fourth line patients but, again, there’s definitely a real improvement in survival. What we need to spend the next three or four years looking at is how we position those two particular agents in the marketplace for patients with metastatic colorectal cancer.

On top of that, there is another interesting development coming our way at the moment in being able to deliver very high dose chemotherapy right into the liver tumours themselves using what are called microsphere beads. These can be injected up the same catheter tube that you would use for doing coronary artery angiograms in the X-Ray department. These tubes are then placed by the radiologist against the tumour and then the beads which are impregnated with a tumour specific chemotherapy, in colorectal cancer metastases it’s irinotecan, in hepatocellular carcinoma it’s doxorubicin, are injected directly into the tumours and we’re seeing some very interesting results with this approach. It’s a bit like the therapy if not rather tenuous called SIR-Spheres where we use yttrium-90 radiotherapy in the same way, injecting them into the tumours in the liver. So this is looking very exciting. In hepatocellular cancer at the moment, the only thing we have out there is sorafenib and that really is only effective for a small group of patients with hepatocellular cancer but in combination with these new targeted therapies it’s beginning to look quite interesting. We’re running a trial called TACE-2 in the United Kingdom right now where we’re comparing sorafenib with targeted doxorubicin beads and we’re very interested in the results of this. It may mean that a combination of those two may make more patients with hepatocellular cancer, which globally is a major public health problem, operable or possibly even transplantable for new liver transplants.