Advances in soft tissue sarcoma from ESMO 2012
Professor Jean Yves Blay – Université Claude Bernard, France
Where are we today with current treatment strategies for soft tissue sarcoma?
Soft tissue sarcomas are a complex group of diseases and actually there are really two stages in the management of soft tissue sarcomas. The first one is the localised phase where basically we use surgery and radiotherapy combined to treat the most frequent high grade large tumours. Chemotherapy has little role here, adjuvant is not recommended as standard and few patients, probably less than 5% receive neoadjuvant treatment in very specific cases. So at this stage it’s clearly surgery and radiotherapy. Once the patient relapses, if the patient relapses, then cytotoxic treatment should be given. In this case the landscape has been very much moving in the last five years or so, so we are still in the first line in the strategy of giving first doxorubicin, an anthracycline-based regimen. It was debated to use it either alone or in combination with ifosfamide and this year in ESMO we are going to show a study which clearly shows that there is no survival advantage to using a combination over doxorubicin single agent. So doxorubicin single agent remains the standard treatment for this group of diseases and ifosfamide is useful but can be considered as second line or third line treatment. Now for third or fourth line treatment, or second line treatment, you have trabectedin, which has been registered in Europe and which is being used for those patients failing doxorubicin as well.
How does the phase II clinical trial of doxorubicin versus trabectedin plus doxo in first line treatment fit into the treatment landscape?
That is probably the most interesting study, trying to address a new strategy in first line because the last study with doxorubicin ifosfamide I mentioned did not demonstrate any improvement in overall survival. So trabectedin is a very active agent, it can be combined with doxorubicin, it has been shown in a phase I study, so testing doxorubicin, standard first line treatment, versus this combination is very next logical step. We definitely hope that it will be able to improve progression free survival, even more importantly, survival.
What implications do these data have on current clinical practice, if any?
At this stage we have to wait for the final results, in particular for overall survival. I would say that what is more important is survival which means that we have several drugs now which are active, some of these in specific subtypes, but still the standard remains on treatment which has been shown to improve survival, so doxorubicin is still the first, and ifosfamide and trabectedin are second line treatment. The study may change this landscape because in this case we would have a first line treatment with a combination.
In your opinion, what is the future of soft tissue sarcoma cancer treatment?
Clearly the concept of having a single study for all sarcoma is going to fade away. We clearly have a heterogeneous group of tumours here. Patients are being considered in different histological subtypes, different molecular subtypes and more than fifty different molecular subtypes, probably, across sarcoma. It’s clear that we will not be treating these patients the same way, these tumours the same way. So, in the future, we will probably observe a fragmentation of therapeutic strategy in advanced phase for all these different subsets, even though they are very rare. So what I expect is that, exactly like GIST and imatinib and tyrosine kinase inhibitors, which came out of the classical sarcoma field, completely different treatments now. We have started to see that with DFSP, another rare sarcoma, with giant-cell tumour of the bone, another rare sarcoma, with endometrial stromal sarcoma, hormonal treatment. This is going to happen in all sarcoma subsets. We do not yet have targeted treatment, all targeted treatment; we do not yet understand what are the relevant targets, but this is definitely the future.
What does this mean for clinical trial design?
That is going to be very challenging but actually the good news is that in this rare tumour field we have been able for years to gather the different clinical research groups around the world which means that even in very rare subtypes it’s feasible to do clinical trials, even randomised clinical trials, in the super rare subtypes. There are some examples of that, the best example again was GIST but there are now new examples on this strategy and I think that it comes to the question of having these patients being treated in reference centres and the reference centres being co-ordinated at worldwide level. We have this informal group, which is called World Sarcoma Network, which is trying to communicate between the different networks and putting trials together. It is very efficient actually.
What questions remain for the future of soft tissue sarcoma cancer treatment?
There are many questions but I think the most important question is probably what are the driving forces for all these subtypes. We know that we have different groups of sarcomas in terms of histologic molecular typing; understanding the real first molecular event is going to be the key to identifying a targeted treatment which is useful in this given subtype. So that’s a long work but we foresee it to be very long but actually will be surprised because the tools we have in terms of high throughput technology to get information on full genomic analysis and maybe epigenomic analysis are going to be available at reasonable prices very soon so that will be a question of bioinformatics finally, at the end and it may come earlier than we thought.
How will targeted therapy impact on treatment?
Yes, targeted therapy will take over. I still think that there is room for cytotoxic treatment and one thing which has been very much made of is these long term survivals, these patients who have been treated for years with these regimens. And in all series, including in the EORTC series of 3,000 patients, there are still 8 -10% of the patients long term survivors. Who are those patients, they can be found across all histological subtypes? Why are they surviving so long; why is their tumour cured? This is something on which we should get an insight and, of course, if we can identify them that would be the best treatment, to continue to give cytotoxic treatment for them. But we are not there yet.