One of the most contentious issues for people dealing with Li Fraumeni Syndrome is screening – the active program of checking for cancers before any symptoms become evident. The idea is simple enough – if we can catch cancer before it develops and spreads then the hope is that there is more chance of successfully dealing with it. On the face of it this should be a straightforward question to answer, but in fact it’s an area that is frustrating and complex.
Given the inherent risk associated with radiation for people with LFS, some of the normal tools of screening, such as chest X-rays or CT scans, are not recommended for routine use. The aim then, is to find a screening protocol that balances the extra risks involved with the potential benefits of early detection. In practice this has meant an emphasis in particular on MRI scanning, which can scan the whole body and brain without the risks posed by CT or PET/CT. But even with this restriction, there are clearly many possible protocols which can be developed and which are currently being tested in clinical trials across the world.
Possibly the best known is the ‘Toronto Protocol’, developed at The Hospital for Sick Children for adults and children with LFS. A key point about this protocol is that it is very active – it involves regular MRI and ultrasound scans, blood tests and urine analysis, breast examinations and even colonoscopies. The full protocol is available online at: http://www.sickkids.ca/pdfs/Cancer-Genetics-Program/35386-TP53TorontoProtocol.pdf. This runs in parallel to the golden rule for people with LFS: Regular evaluation with family physician with close attention to any medical concerns or complaints. This last point is essential for families with LFS – it should mean immediate access to doctors, and testing, should there be anything that could be a symptom of cancer.
The key question about the Toronto Protocol is does it work? Is all the screening worth it in catching cancer early and in making a difference to outcomes? An initial answer was provided in 2011 with the publication of the initial findings from the study of the protocol. This compared a small group of 18 LFS patients on the protocol with another group of 15 patients not on the protocol but undergoing ‘wait and see’ observation (which is still standard practice for most patients). The paper, ‘Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study,’ published in top cancer journal The Lancet Oncology, concluded that: 3-year overall survival was 100% in the surveillance group and 21% (95% CI 4-48%) in the non-surveillance group (p=0·0155). That was a pretty stunning result, but it was hedged with caveats, particularly with the relatively small number of patients involved, and the fact that the two groups were not evenly matched in terms of age and other characteristics. While the data looked convincing to many people, for many clinicians there really wasn’t enough data to draw firm conclusions.
The Toronto Protocol isn’t the only one being studied, however. In the UK the SIGNIFY study has been exploring the use of whole-body MRI. One of our own Trustees, Lara Veitch, was an early beneficiary of SIGNIFY. And as we heard at the LFS UK 2016 event, the results of this study are almost ready for publication and look to be broadly positive. In France there is a similar study called LIFSCREEN, at the Institut Gustave Roussy in Paris. It should be noted that the SIGNIFY trial did not include children, whereas the LIFSCREEN study includes children over the age of five. There are other studies on-going in Australia and the US, and these are closer to SIGNIFY and LIFSCREEN than the Toronto Protocol in that they are primarily about whole-body MRI.
While we’re waiting for these trials to complete and report their results, the Toronto trial has recently published an update on progress since 2011. As before the comparison is between patients on the protocol and those under observation. The paper, ‘Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study’, has again been published in The Lancet Oncology. With a longer follow-up and an increase in patient numbers, the result is still clear: 5 year overall survival was 88·8% (95% CI 78·7–100) in the surveillance group and 59·6% (47·2–75·2) in the non-surveillance group (p=0·0132).
What this all means is that clinicians are slowly building towards a consensus that active screening is better than the traditional wait and see approach. There will be arguments about which particular protocol works best, but it’s hard to see that there will be disagreement that some regular scheduled whole-body and brain MRI scans (at the very least) provide a survival value in the long-term.
But this brings us on to the next issue, which is how do we make sure that all patients get this screening protocol? A screening protocol can be expensive, especially something as comprehensive as the Toronto Protocol. It’s worth noting that the most cited reason for patients declining screening mentioned in the updated Toronto paper was lack of insurance coverage. In the UK it’s the case that different patients get different levels of surveillance. In part this is because there is no standard protocol in place – we hope that this is a key change that arises out of the SIGNIFY study, once the results are published.
In the UK the lack of screening is such a real concern that one family have started an online petition in a bid to raise awareness and encourage the authorities to provide additional screening. Importantly, the screening has to include children. This is a key difference between SIGNIFY and some of the other screening trials – we hope that once a recommendation is made that it does include children. If you haven’t signed the petition, please do so – we need to be pushy on this because early screening can save lives.