Radiotherapy: State of the art

Radiotherapy: state-of-the-art
Presenter: Gillian Whitfield

Thank you for the invitation to speak and I think this is probably something completely different. I’m not sure if there are any other radiation oncologists in the audience, so this may be a little bit of a primer. I don’t have any disclosures. I treat neuro-oncology and skull base tumours in all ages, paediatric and adults. I treat with conventional fractionated radiotherapy, linear accelerator based stereotactic radiotherapy, and in the last year with proton therapy.

I will start with a case, an example of a lady with a sphenoid wing meningioma who was referred to our service in June 2012. In 2011, the previous summer, she presented with critically worsening intracranial pressure and she’d had emergency surgery. You can see in the presentation scan, that she had a great deal of oedema even in proportion to that moderate sized meningioma, and she went on to have several more procedures up to March 2012. Following that surgery, the intracranial disease had been completely resected but she was left with some residual in the infra temporal fossa, and that was the reason she was referred for radiotherapy as well as the fact that the histology was Grade II. She had homonymous hemianopia from presentation.

I will dwell a moment on what we consider the indications for radiotherapy to be. In Grade I tumours, there’s generally no great urgency to irradiate but we consider radiotherapy for inoperable tumours, particularly if they’re progressing or the patient is symptomatic. Subtotally resected tumours, again we wouldn’t necessarily go straight to radiotherapy but it can be considered on progression, as well as options of reoperation being considered. Also for recurrent tumours.

But in Grade II tumours it’s different. Even after complete resection, we know that there is a significant recurrence risk, which in different series lies somewhere between about 40 to 60%, predominantly in the first five up to ten years following surgery. Actually, we don’t really know because there is no good randomised data at the moment to what extent radiotherapy can influence that natural history. However, there is a trial ongoing, the ROAM trial which is open in the UK, Europe, Australia, and New Zealand, which is looking at immediate post-op adjuvant radiotherapy versus observation in completely resected Simpson I to III Grade II meningiomas. I think that must be a difficult trial for patients to consent to, but it’s recruiting well and hopefully it will get us a good answer to that question. Although some patients are observed after subtotal resection, generally there is a strong case for proceeding to radiotherapy.

For Grade III tumours, even after complete resection from a radiotherapy perspective, we would think that radiotherapy was definitely indicated. Going back to our case, this lady elected to proceed to radiotherapy. On the left picture you’ve got the planning CT scan and you can see that she’s had a cranioplasty and an orbital reconstruction. On the right, on the MRI you can see the disease of the skull base. From a radiotherapy perspective in a case like this, we would aim to treat not just the residual disease, but also the tumour bed, the area at risk of harbouring microscopic disease, and that’s because we normally only get one shot at doing a course of fractionated radiotherapy. It’s very difficult to irradiate again right next to an area that you’ve irradiated, and as I said we know that even if you’re completely resected in Grade II, you’ve got a high recurrence risk.

On this CT scan, we can observe the different target areas for radiotherapy. In the orange zone, we would include the gross residual tumour volume (GTV) but also the post-operative tumour bed. In addition, we would treat the GTV with a margin to what we call the clinical target volume (CTV). This CTV -coloured in dark blue- is the volume beyond what we see that is thought likely to harbour microscopic disease, and the margin would be different between a Grade I, II and III tumour. For instance, in Grade II, we would typically extend that 5 mm into brain parenchyma or perhaps 10 mm if there’s frank brain invasion, and typically say 10 mm along the dural bone or soft tissue margins, none of which has a good randomised evidence base.

Finally, there is a third target area, coloured in light blue. This is what we call the planning target volume (PTV). When we actually want to treat that dark blue clinical target volume, we have to allow for all the slight uncertainties in the radiotherapy planning process, including slight variation in the patient’s positioning day to day, slight inaccuracies in the CT-MRI co-registration we’ve used for planning, and there are some other minor uncertainties in the physics of the radiotherapy delivery. So we plan the treatment to that larger planning target volume.

When we do the planning, we have to think about all the nearby radiosensitive organs at risk and for the sphenoid wing, we are close to lots of radiosensitive normal tissues. There is a list here of the things that we think about: lenses, corneas, retinas, lacrimal glands, optic nerves and chiasm, and hypothalamic pituitary axis. Nowadays we often think about the hippocampi as well which is a relatively recent thing, but there’s evidence that they’re perhaps more radiosensitive than a lot of the other brain tissues in terms of neurocognitive function. And the brainstem.

On this slide, I show you what their tolerances are, not because you will want to remember any of this, but just to point out that when we give fractionated radiotherapy, typically in 1.8 to 2 Gray (Gy) fractions, the tolerances of these structures are much higher than if you were to use a single fraction stereotactic radiosurgery approach. But nevertheless, some of these structures still have a tolerance below the dose of radiotherapy that we would wish to give, and for that reason in a radiotherapy plan we have to modulate the dose to be as high as possible in the tumour bearing areas but lower in the areas of these radiosensitive normal tissues.

For example a couple of the lowest tolerances to radiation are the lens, where over about six to ten Gy you’re at risk of cataract, and the lacrimal gland where around about a mean dose of 25 Gy you’re at risk of getting a long-term dry eye. The optic nerves and chiasm are actually relatively tolerant up to about 55 Gy, but that is probably for an uninjured optic nerve and chiasm. There is evidence from treatments of pituitary tumours where perhaps the chiasm has been compromised either by the tumour or the surgery, that in that situation the tolerance may be lower. There are reports of visual loss down to as low as about 48 to 50 Gy, so we’re always a bit more cautious in patients who’ve either had surgery in the region of the optic nerve or potentially where a tumour might have compromised the optic nerve.

It’s worth pointing out that some of the tolerances are really not well known yet. At present, we have very little idea what the tolerance of the hypothalamus is, and that’s something we really need to tease out now that we can do more precise radiotherapy and we can modulate the dose to quite a high degree, how sensitive is the hypothalamus compared to the pituitary – we really don’t know. In terms of the hippocampi, we think they probably have quite a low tolerance but there is very little data. These are all areas that we need to know more about to optimise radiotherapy in the future.

Once our patient had chosen radiotherapy, we proceeded with the planning. This is a plan back in 2012 when we tended to treat mostly with static beams. Nowadays we more often treat with an arc therapy, treating the patient in a continuous 360-degree arc, but we still use this static field treatment as well. The prescription dose is 54 Gy in 30 fractions. In the planning, you can observe that the dark orange areas, which are getting at least 95% of the prescription dose, mostly conform very well to the tumour area, however in left slide, you see that the dark orange area is slightly baggy around that pale blue area that we are trying to treat, and actually with arc therapy we can often get much better conformation of the high dose volume to the target area we’re trying to treat. The arc technique does result in a larger spread of the low dose, although the total amount of unwanted radiation you deposit beyond the target volume would be similar among all these techniques.

A word about radiotherapy doses. They do vary a little bit around the world, perhaps tending to be a bit higher in some of Europe than we typically use in the UK, but actually the doses presented here are similar to North American doses. Typically for Grade I tumours, we would treat to about 50 to 54 Gy, Grade II 54 to 60 Gy, and Grade III at the moment most places would treat to about 60 Gy. There has been an EORTC trial which was mainly observational, and included a dose escalation arm for the more aggressive tumours, in which they gave a further boost up to 70 Gy and we’re awaiting the results of that, to know whether that was beneficial. But in general, it’s worth saying that the prescription dose is not necessarily determined just on the basis of grade, we take into account other factors: how the tumours has behaved, where the residual tumour is. If there is residual tumour right next to critical organs at risk like the chiasm and the optic nerves, you’re not going to be able to take that area next to chiasm and optic nerves to the highest doses anyway, and that’s the area the patient is then most likely to relapse, and it may not then be beneficial to take other parts of the volume to very high dose. We also think about patient age, the youngest patients and the oldest patients are perhaps at most risk of having some of the late effects, particularly neuro-cognitive late effects, so it’s a risk adapted approach.

About how effective radiotherapy is, there’s no really good quality randomised data unfortunately. These are retrospective studies compared with what we might expect with surgery alone. In Grade I tumours, the local control at around five to ten years is generally very good, usually around about 90% but we do know that over time that falls off. I usually tell patients that by about twenty years post-treatment that may have fallen off to about half to two-thirds of patients still having local control.

The second point there is from one of the largest series, a series from Heidelberg of over 500 skull base meningiomas. They treated to a median dose of 57.6 Gy, this was a mix of various grade tumours. Again you can see that at ten years local control was good, about 90% for the Grade I tumours but worse for the Grade II (81%) and Grade III (53%) tumours, but still quite respectable compared to observation alone. The EORTC dose escalation trial I mentioned, also had an observational arm for some of the less aggressive tumours. For the completely resected Grade IIs they had three year progression free survival of nearly 90%, which I think is certainly better than observation alone in most series. The RTOG trial is a north-american trial, and their intermediate risk group was a mix of newly diagnosed completely resected Grade IIs and recurrent Grade Is. At an early time point of three years they have shown over 90% progression free survival at a slightly lower radiotherapy dose. We do know that for Grade III meningiomas, the outcome is poor and the European Cancer registry has shown five-year survival around  65%, which I think justifies aggressive use of adjuvant radiotherapy in these patients.

So coming back to this lady, she was treated in 2012 by one of my colleagues. Unfortunately she did develop a recurrence last year, both in the orbit, the cavernous sinus and the middle fossa floor. It was all in field of the previous radiotherapy treatment to 54Gy, which is within the range of 54 to 60 Gy that most people would treat a Grade II tumour to. So she elected initially to observe that and on two follow-up scans in March and September this year, that intra-orbital nodule was the growing part and the other parts appeared to be stable. She was beginning to develop some proptosis, so we discussed her in our skull base MDT and the feeling was that after the multiple previous operations and radiotherapy she had had, surgery would probably be a partial debulking and with a high risk to her vision. At that point we felt it was worth considering the radiotherapy options, as this lady now felt she would like to do something about it.

What are the radiotherapy options? One option would be to do a large volume reirradiation of the entire tumour volume previously treated, that would be to a palliative dose, with significant risk of toxicity. Another option would be to do a stereotactic single fraction radiotherapy to this nodule, which would be convenient but would have a high risk of early visual loss, given the previous irradiation of the optic nerve. An alternative would be to do a fractionated retreatment to the intra-orbital nodule alone, which would be less convenient, but would have a high chance of preserving her vision and that is in fact what she opted for. This shows the retreatment we did to a modest dose of 50 Gy in 30 fractions, with a small dose (1.67 Gy) per fraction which is very kind to the optic nerve. Overall we estimate with the previous treatments that she should have around 10% risk of visual loss at 5 years.

Lastly, ‘What about protons?’ In the UK, patients under 25 are currently already NHS funded to have proton therapy for benign meningiomas. We think that might reduce both acute and late toxicities. It could enable dose escalation which might improve tumour control, again there is no randomised data on that, but we might expect that. The problem is that we don’t really know the magnitude of the possible benefits because actually, as I’ve already pointed out, the data about dose-volume-toxicity for many structures, like the structures involved in neurocognition and endocrine function, are really not well enough known. We are looking at conducting a randomised trial for skull base meningiomas with proton therapy in the UK. And we are also looking at doing a lot of very detailed further observational work to try and tease out better the relationship between radiotherapy doses and toxicity. This slide is from colleagues in Austria: at the top – the dose distribution for a photon treatment-  and at the bottom, proton treatment, and actually it’s not the high dose volume that varies so much, but it’s the low dose bath to surrounding brain.

My key points are that with modern fractionated radiotherapy we are able to sculpt the dose very well to the tumour volumes, while modulating the dose to spare the normal tissues within that irradiated volume. After an interval, and with care, it is possible to reirradiate in some cases. We need to do comparative studies to work out the place of proton therapy in the treatment of these patients.

Q & As section

Question 1
We started to feel surgery is not really the answer and certainly doesn’t switch the process off at all. Have you seen cases of quite aggressive sphenoid wing meningioma where radiotherapy does appear to have actually switched it off or does it just slow it down in its tracks a lot, it doesn’t really turn it off?

Answer
Since 2011 I’ve seen patients where they have so far been controlled, but maybe their average follow up is five years. I’ve also seen examples of recurrences for the aggressive ones. I think for the aggressive ones the majority probably will eventually relapse but we can significantly improve the natural history. After an interval of perhaps five years, but actually for many patients it’s much longer, it’s possible again to do some further radiotherapy, which may at that point be more palliative but given the long natural history, that might be helpful.

Question 2
Given that the proton beam delivers the energy to the cells themselves much less bystander damage, do you think they’re going to be options of delivering it repeating that treatment or do we still have a sort of cut-off in terms of how much proton beam can be used?

Answer
We’re hoping that it might be possible to dose escalate to a degree with similar dose to normal tissues to what we currently get with conventional radiotherapy. It is likely that would give us some better tumour control, it might cure a few more. The natural history of these is that they can spread very insidiously across the skull base, it’s always difficult to know that you’ve encompassed everything and whether we can get to high enough doses with acceptable toxicity to prevent recurrence, I’m not sure. But I think we should be able to improve outcomes.

Question 3
Do you think proton beam should be preceded by surgery? And for some of these difficult ones, do you feel that reducing the tumour load is really relevant if the proton is going to treat all of the tissue field anyhow?

Answer
The proton dose is not going to be that different to the tumour to the conventional radiotherapy dose. I think certainly for the higher grades -Grade IIs and IIIs- if you can get to total or near total resection of the gross disease, that does result in better long-term local control.