This is institutional based data not trial based data and what we particularly wanted to look at was the diagnostic process in intracranial germ cell tumours within the limits of a retrospective study. So it will be well recognised in this audience that some germ cell tumours have a very indolent presentation. We’re dealing with a largely, but not entirely, highly curable group of tumours so this may obscure the effect of delayed diagnosis. The aim of pooling this data was to examine, or to attempt to examine, the relationship, if any, between time to diagnosis or symptom interval and site histology stage at diagnosis, possibly the healthcare system or population that these patients are diagnosed in, where the delay is coming in the pathway and, if any, the quality of survival or cost to the patient.

So the study population, and I said before this is retrospective with all the limitations of a retrospective and note space study, in four institutions, one Canada, two UK and one Germany. We looked at all CNS germ cell tumours diagnosed over a ten year period 2002 to December ’11; for three institutions that was all patients, for one institution, the German one, it was patients where there was complete enough information to contribute so that may slightly influence the information from that centre.

We looked at 68 patients from those four institutions, 25 from the UK institutions, 31 from Canada and 12 from Germany; 44 male, 24 female, not unexpected; age range 0.6 to 22.5 years with a median, again not unexpected, of 13 years. Two institutions only take patients, just because of referral patterns, up to about 16; two institutions, one UK and Germany, take patients up into young adulthood. 42 patients had germinoma, 24 non-germinoma and 2 teratoma, both immature teratoma; 18 patients suprasellar, 28 pineal, 18 bifocal and 4 other which were, I think, all basal ganglia. At diagnosis 11 were metastatic, 57 localised.

If we look at symptom interval first and we look at it by national group, or by the nation of the institutions, starting with the UK, just because I feel we should, the symptom interval is not one that we can be complacent about. It ranged from 1 to 6 to 9 months with a median of 5 but actually it’s much more relevant to look at this by site because we know, and I’ll come on to that, that that influences the duration of symptom interval. So for suprasellar tumours it ranged from 3 to 36 months, median 12; bifocal 5 to 69, median 10.5 and pineal was short in the UK. If you look at Canada overall the median is shorter than the UK. And as is true for both suprasellar and bifocal tumours in comparison to the UK, Germany the median for suprasellar tumours is a little bit longer. If you look at this statistically both for all patients between the three groups and for suprasellar bifocal only there is a clear difference in the symptom interval between the three national groups with the UK not needing to be complacent because we definitely have a longer symptom interval in our suprasellar and bifocal tumours. That’s not the case for pineal tumours, we’re all fairly good at recognising raised intracranial pressure which is how they generally present.

If we look specifically at patients with prolonged symptom intervals, and we have empirically defined that as a symptom interval of greater or equal to six months, that’s from first symptom reported by a patient and picked up in the medical notes to a diagnosis of an intracranial germ cell tumour, there were 23 patients in this cohort, that’s 34% of patients had a symptom interval of greater or equal to six months. If you look at it by national group 11 of the 25 UK patients fell into this, 8 of the 31 Canadian patients, 4 of the 12 German patients and, predictably really, 70% of patients who had a prolonged symptom interval had germinoma as the histological diagnosis. The symptom interval greater or equal to six months was more likely in patients with suprasellar bifocal tumours, that would be expected. In the group of patients with a prolonged symptom interval 82% had suprasellar bifocal tumours compared to 40% in the group with a shorter symptom interval.

What I hadn’t expected to find was that metastatic or dissemination was significantly associated with a prolonged symptom interval. In the group of patients with a prolonged symptom interval 39% were metastatic at diagnosis compared to 4% in the group with a short symptom interval. Of these, not surprisingly, 8 out of 11 were germinoma and 2 of the others were what I think we really would call an HCG secreting germinoma, it’s just they fall into non-germinoma by European definitions. 10 out of the 11 metastatic were suprasellar or bifocal primaries.

We struggled a bit to look at the pathway to diagnosis and have different amounts of information from the different national groups. We actually have most information from the UK two institutions. There were 11 patients with prolonged symptoms interval. Where is the problem? Well, 8 out of those 11 patients only took 0-2 months to seek medical attention for their symptoms. So actually that’s not where the problem is. There were two patients who took slightly longer and one where we don’t have the information. But from first medical contact to diagnosis there was a range of 1 to 69 months symptom interval with a median of 18 and quite a lot of that time, because of the UK health system where we have a non-specialist primary care system, was spent in non-specialist primary care.

For Germany there were 4 patients with a prolonged symptom interval and it seems that for those patients, and this is a small number, the problem is the reverse here, that actually from first medical contact to diagnosis the time was extremely short and for those patients actually the time was spent with the patient seeking medical attention. There were 8 patients from the Canadian group but I’m afraid just because of difficulties extracting this data from the notes we don’t have detailed information although Ute may be able to comment on this more after I finish.

What’s important is what is the consequence to patients of this. We can say this is not really a survival issue or doesn’t appear to be in the numbers we’ve got and that won’t surprise anyone. Of the 23 patients with prolonged symptom interval only one of them relapsed compared to eight relapses overall and that patient was salvaged. There’s an increased likelihood of metastatic disease unexpectedly and therefore there are consequences to the patient for the intensity of treatment. That’s currently a group that we give craniospinal irradiation to with its consequences. As far as we can access this information and what we got, in terms of diminished quality of survival between first symptom and diagnosis in the 23 patients, 14 had additional pituitary axes affected. Now I recognise those patients didn’t have formal pituitary testing at first symptom, they did at diagnosis, but from the history this is fairly convincing. More importantly, and David has already mentioned this, 11 out of the 23 had new or additional visual loss and we know that is not always fully recoverable. 6 out of the 23 developed raised intracranial pressure in that time with its consequences for possible cognition and 2 out of 23 had very definite recording of cognitive deterioration in that time, again not fully recoverable.

So where can we potentially modify this process? That’s difficult, these are very rare tumours as everyone will know. I think an important message, and JP has already referred to this, is the recognition and investigation of new central diabetes insipidus, which is badly done. 10 of the 23 with prolonged symptom interval in this group had DI as their first symptom. We need to encourage early imaging; it wasn’t getting to imaging, it was getting to imaging that was the problem here for new or progressive pituitary dysfunction, that’s where a lot of the indolent presentations are. That’s particularly true for patients over 8, there’s been a paper from the Italian group before showing that the incidence overall of new DI having an underlying tumour is 38% and that goes up if you concentrate on the 8 year olds.

And medical education. I think David would be able to talk better about the HeadSmart programme in the UK which is designed to try and improve the symptom interval for all brain tumours but this would particularly apply to germ cell tumours.

So, in conclusion, prolonged symptom interval is an issue in germ cell tumours. It does increase the likelihood of dissemination; it does have a long-term cost with irrecoverable visual, cognitive and endocrine losses and perhaps we need to be looking at a targeted intervention with our endocrine colleagues and with primary care in the UK. Thank you.