NCRI 2015

Advancing radiation therapy in pancreatic and liver cancer

Dr Theodore Lawrence - University of Michigan Health System, Ann Arbor, USA

I’m talking about future directions in the use of radiation therapy for the treatment of pancreas cancer and liver cancers. In the case of pancreas cancer I think the future lies in better combinations of molecularly targeted therapies combined with chemotherapy and radiation therapy. The standard treatment for locally advanced pancreas cancer, that’s what I’ll focus on in my talk, which is pancreas cancer that is in the pancreas, is not surgically removable but is not metastasised. So that’s one of the main places where radiation therapy can be of great value. Technical improvements in the delivery of radiation will be useful but the main focus of research should be on how to understand the biology of pancreas cancer and especially how to use new targeted therapies. I will focus on a therapy that is inhibiting the enzyme called Wee1 which affects how cells progress through the cell cycle. The basic concept there is that normal cells have two ways of protecting themselves from DNA damage, one is by arresting in the G1 checkpoint and they have a second way of protecting themselves by arresting at the G2 checkpoint. Most pancreas cancers only have one way of protecting themselves, they’ve lost that G1 checkpoint because they are cancer and they still have the G2 checkpoint. So this drug that we’re working with, AZD1775, inhibits the cancer cell from protecting itself using the G2 checkpoint so after chemotherapy and radiation it has no protection and we hope will be selectively sensitised. So I’ll be presenting some pre-clinical data on that and then also the beginning of a clinical trial.

What have you found so far?

So far it’s very early in our clinical trial, we’ve only treated fourteen patients but it’s very promising that this combination, or the standard approach using gemcitabine plus radiation which is used in many clinical centres around the world, but then by adding this new drug, AZD1775, it looks like we’re having better control of both the primary tumour. But just as importantly there seem to be fewer metastases developing so this agent both makes chemotherapy more sensitive, which I really won’t focus on today but does that, as well as the combination of gemcitabine and radiation makes that more effective for the primary tumour. So that’s one half of the talk.

The other half of the talk is much more focussed on the better use of technology for treating hepatocellular cancer, that’s primary cancer that starts in the liver. There the role of radiation therapy traditionally has been very minimal because initial approaches try to treat the whole liver. The whole liver is very sensitive to radiation so you can’t give a very high dose of radiation without injuring the normal liver, of course that’s not acceptable. So the techniques that we’ve developed at the University of Michigan, and other institutions have now developed as well, have used very focussed radiation right on the liver tumour. I think the most interesting part of what we’ve been doing recently is adapting the radiation course to the individual patient response. So I like to call this precision or personalised radiation therapy to pick up on the theme of precision medicine that has been mainly focussed on genomics but radiation therapy can be just as precise and just as individualised. So the approach that we’ve used is to break the treatment up into two parts. We initially treat people with very focussed radiation on the primary tumour and give 60% of our planned course. Then we wait a month to see how the patient responds to that and what we’ve been doing in a recently completed clinical trial is measuring the liver function of that patient one month after having given 60% of the treatment. If the liver has shown any injury we can then back off on the treatment; if the liver has not shown any injury we can give even more intense treatment towards the end of therapy. We measure liver function using a test called indocyanine green. This is a very classic test, we didn’t invent this, this has been used in tens of thousands of patients. It’s a chemical, indocyanine green, that’s injected into one arm and then one can remove a blood sample from the other arm and only the liver removes this indocyanine green from the blood. So if the liver is working well it removes it very quickly, if the liver is not working well it’s very slowly removed. So we can use this as a test of global liver function and see if we’re affecting the liver.

So what we can do with this approach is prescribe a dose of radiation that would not be safe for maybe 5% of patients but now we can know which 5% of patients would be too sensitive to receive that higher dose of radiation by measuring their liver function after some of the treatment has been delivered. Our newer protocols that we’re just about to start in this month will be looking at both the tumour, using dynamic contrast enhanced MRI, because we know that when there’s blood flow in the tumour that’s the active part of the tumour. So we’ll be targeting the active part of the tumour and will be sparing the parts of the liver that are functioning well which we’ll have detected by using perfusion MRI because we know from our previous work that perfusion in the liver shows the parts of the liver that are working. So by combining these two approaches, by using dynamic contrast enhanced MRI to target the active part of the tumour and by using perfusion MRI to protect the parts of the normal liver that are working and combining that with measuring the global liver function we can truly individualise radiation therapy for patients with hepatocellular cancer.

Have these methods been effective?

So that last method that I mentioned is a clinical trial that we are just about to start. The clinical trial that I described to you that we just have finished we’re now in the process of writing up but our results look very, very good, in which the control rate for tumours seems to be improved and the liver is not being injured. We’re about to have the paper published in The Journal of Clinical Oncology in the upcoming one to two months showing the original work that we did that compares this work to using radiofrequency ablation in a retrospective comparison, this was not a randomised trial. But this paper that will be coming out in the JCO shows that stereotactic body radiation therapy, this precise way of delivering radiation to the tumour, actually appears to be superior to radiofrequency ablation for tumours that are larger than 2cm. So we know even without all these refinements that I described to you that we’re about to initiate, we know even with standard stereotactic body radiation therapy we think we have an improvement over the prior standard approach of radiofrequency ablation.