BARCELONA—This year's European Society for Therapeutic Radiology and Oncology Congress saw an even greater emphasis than usual on education. There were several translational sessions, and lots of revelations about which targeted drugs could be used as radiosensitizers if only the pharmaceutical companies would think of them that way.
I hadn't been to ESTRO for a few years now and I was astonished by the range and excellence of the science at the meeting: More than 50 clinical trials, randomized clinical trials and sessions on translational medicine, imaging for therapy and molecular imaging, as well as sessions on collaboration on genomes and doing sensible things about prediction of outcome from radiotherapy or radiosensitivity.
All this was integrated with debate about how many fractions for this cancer, how many fractions for that cancer; achieving the same sort of outcomes with less inconvenience for the patient—fewer visits to the hospital, fewer problems finding a parking space, etc.
If you look at the activities of ESTRO over the last 29 years, what stands out is the organization's astonishing achievement in educating young radiation therapists, radiation technologists, and physicists. By the end of the year they will have completed 32 educational sessions, not just in Europe but also in China and Australia. And with about 100 oncologists at each one, thousands of people have attended these ESTRO educational meetings.
Similarly at this conference, there was a big emphasis on education, with a dozen educational sessions, repeated so that people who had to go to parallel sessions did not miss out. They really were impressive, organized for young radiation oncologists who were specializing in particular kinds of cancers and for radiation technicians and nurses alike.
I knew they were coming but what I wasn't expecting was the large number of translational sessions whose headlines were very similar to those you'd expect to see at ESMO. There was a whole session on HDAC inhibitors, as well as epigenetics related to particular strands of DNA important in management or outcomes of radiation.
PARP Inhibitors as Radiosensitizers?
I didn't know that the epidermal growth factor receptor was actually predictive of radiation resistance, and I didn't know that the PARP1 inhibitors were already being tested as radiosensitizers.
It is also becoming obvious that PARP is an important area for interaction between the lab and the people working on developing medical and radiation oncology approaches to BRCA1- and BRCA2-mutated patients, whether they have breast cancer or ovarian cancer.
There was a real plea from the translational scientists, and some of the clinicians, that a number of drugs that have been developed by academics and pharma—sometimes together—have been discarded if they didn't work as cytotoxics and not thought of as potential radiosensitizers. Masses of work will have been done to find out what the mechanism of actions are, but all is wasted unnecessarily, should the possibility of local action with concurrent radiotherapy not be explored.
For instance, mTOR inhibitors are just as interesting for the radiation biologists as they are for medical oncologists, yet there are clear problems in educating some of the decision-makers about progressing new molecules as radiosensitizers in their own right.
I recall being involved at the Cancer Research Campaign (CRC, now CRUK) in the development of temozolomide, which was an innovative drug made by Malcolm Stevens and his team and then licensed by CRCT to Schering-Plough. We thought of this as a cytotoxic drug with a different mechanism of action, and indeed it was, but it was 10 years before it was realized that in fact it was a radiosensitizer as well.
Temozolomide is now part of the standard treatment of certain gliomas, and we now know that outcome depends on methylguanine methyltransferase.
A very interesting proposal was promoted here at the meeting, an idea that was launched earlier in the year with the help of a grant from the US National Cancer Institute. Professor Catharine West, from the Paterson Institute, Manchester, UK, has been working for a long time on hypoxia genes, trying to find out which patients should have their radiation schedules altered based on the degree of hypoxia in the tumors.
There are now an abundance of hypoxia genes and Dr. West is still working on this, but she is also leading the new International Radio Genome Team or Radio Genome Project. This seems to be, again, a highly logical and sensible, timely thing to do.
All this information, within the Human Genome Project, is rightly exploited to find druggable targets at the cellular level for development of new therapeutics. Dr. West points out, however, that we have never seriously dissected the genome from the point of view of radiobiologists; we have never looked to see whether there are genetic signatures in there that will predict for radiosensitivity and hypersensitivity of normal tissues to radiation. Imaging techniques are getting better and focusing radiation beams more precisely on to tumor cells, but any spill onto normal tissue remains serious. Dr. West maintains that the degree of hyper-reaction of patients' normal tissues around a cancer when given some radiation treatment will be genetically determined.
The Radio Genome Project is therefore inviting people all over the world who are putting patients into clinical trials involving radiation therapy in some form or another, to store a sample of blood so that genomic studies can be coupled to radiosensitivity data.
Prediction of radiotherapy outcome may well be another benefit from this approach, so it's really a novel approach, and it seems ESTRO is fully behind it.
A first for an ESTRO meeting was an entire session on molecular imaging. It's remarkable to see how imaging technology is advancing so fast and converging with molecular pathology at such a rate that some clever molecular imaging can pick up targets that previously only the pathologist could spot with particular antibodies, molecular probes, or immunochemistry techniques.
Targeting was a buzzword at ESTRO, and some of the very clever ‘knives' demonstrated can image and then ablate an early T1 or T2 lung cancer through the same machine.
The term “radio-surgery” is being used to describe the actions of devices such as CyberKnife, Gamma Knife, RapidArc, and Tomotherapy. All these approaches have one thing in common—they are aiming to be much cleverer at targeting tumor tissue and staying targeted through different sessions and fractionations. Most of them use fewer fractions and two or three of these interesting knives can take account of movement such as respiration so that the lung cancer doesn't slip out of the targeted area.
The last really big area of great interest alluded to above is reducing the number of fractions of radiotherapy. Standard radiation of the whole breast post-lumpectomy would be six weeks. It's quite clear now that more and more of the top institutes are running trials that point to adoption of three weeks of radiation, claiming equivalence with five or six weeks.
Fewer & Fewer Fractions
In breast cancer it's quite likely that in a couple of years we will be talking about five fractions of postoperative radiotherapy given Monday to Friday in one week. This will be a dramatic improvement on the current patient experience, which is tedious and extremely tiring.
The most extreme development of that logical process—taking fewer and fewer fractions and higher and higher doses—is the partial breast irradiation with intraoperative radiotherapy. Two examples of this are the TARGIT trial, reported in The Lancet and the ELIOT trial from my institute (European Institute of Oncology) in Milan, not yet reported.
There is some concern that results are being reported too early for such an important area of research. The developments are so appealing to patients that some are now demanding the treatment, thanks to the publicity, without the results of the clinical trials being known. It's so much easier for a patient with breast cancer to wake up after surgery and find that the tumor is removed and the radiotherapy has been given.
Smart RT for Prostate Cancer
And just a final note about prostate cancer because the same thing is happening there. At the moment, the news headlines are describing the advances of prostate surgery using robotics. However, here at ESTRO we have heard that the radiation therapists are also busy developing smart radiation therapy for the prostate. There are now protocols testing five, four, or even three fractions using the ability of those clever “knives” to sterilize the prostate with, hopefully, even fewer side effects.
There are no completed head-to-head comparisons yet for early prostate cancer treated with either the best surgical approach or the best radiation approach. But several trials are ongoing.
What—as I asked a couple of experts—does the patient do in the meantime? Patients have to make up their own mind, having heard the positives and negatives from the surgeon and the radiation therapist and then decide for themselves in the absence of an evidence base. Not very satisfactory, but the evidence base will eventually be available from these randomized comparative trials.
In summary, the entire field is moving very fast and in a very good direction—namely cutting down the amount of treatment for the patient, whether he or she has breast, brain, or prostate cancer. It means more investment in imaging and targeting and the clever instruments that can carry out the smart radiosurgery.
But at the end of the day, providing that equivalence and maybe even superiority is achieved in some of the anti-cancer outcomes, a reduction of side effects is going to be of great benefit to the patient.