Osteosarcoma: Is big always worse?

The outcome for osteosarcoma has improved little over the last 25 years. As has happenedwithmost solid tumours in young people, attempts have been made to develop prognostic factors in order to refine treatments and hopefully improve the chances of survival, as well as, to minimise treatment for those with a good outlook. In osteosarcoma metastatic disease at diagnosis is probably themost important prognostic factor but after this themost consistent finding has been the histological appearance of the resected specimen, indicating the response of the tumour to preoperative chemotherapy, that is, an in vivo chemosensitivity test. Rosen was the first to recognise the adverse outcome of poorly responding tumours and he designed a treatment regime, which gave postoperative chemotherapy depending on the grade of histological response. He claimed that switching chemotherapy in this way, giving new drugs to the poor responders, could greatly improve the outcome in this group [1]. Unfortunately, others have not been able to convince themselves of the benefit of this approach.We are left, therefore, with the best prognostic factor being the only after initial available treatment; and there is notmuch possibility of successfully switching chemotherapy for poor responders. Whatwe clearly need is an upfront prognostic factor, so that chemotherapy treatment can be tailored to the initial characteristics of the tumour. The size of the tumourwould seem an obvious place to start and attempts have been made in the past to do this. However, results have been equivocal. It is likely that this is at least partly due to the difficulties of measuring tumour size in a standardised and reliable way. Even being certain on imaging of exactly what is tumour, what is reactive bone, and the consequent inflammation and oedema is controversial. Although, Bielack was able to show a correlation with size and outcome in a major review of 1,702 patients in the German COSS studies, he was only able to use a categorisation into very broad groups depending on how much of the bone was involved [2]. Another consideration is of course the biological behaviour of the particular tumour. It would seem common sense that the longer the tumour had been there, the bigger it would be and, therefore, more likely to have metastasised with a poor prognosis. In an important and often overlooked paper [3], Bacci and his colleagues at the Rizzoli Institute in Bologna looked at delay in diagnosis and outcome in osteosarcoma in 965 patients. They found no correlation between size of tumour and outcome. Those with a shorter history had a significantly poorer outcome suggesting an intrinsic biologic property of tumours. Those with a shorter history being more aggressive and more likely to metastasise early. The paper byKaste et al. in this issue ofPediatric Blood and Cancer is a review of size of osteosarcoma and outcome in a relatively small number of patients treated in a single institution on a single protocol. Of importance is that the MRI scans were looked at by a single paediatric radiologist. Although the numbers are small, there is a significant association between size and outcome and they advise larger confirmatory studies. Hopefully, the larger co-operative groups will be able to rapidly do this. However, it may not be so easy given all of the difficulties of central radiology review in multicentre/multinational studies. The organisation of large randomised trials is difficult. Central pathology and radiological review are one of the most challenging areas. There is little incentive for radiologists to have their films reviewed. They are reluctant to allow the original films to be sent away and copies are expensive.With the advent of digital technology, it was hoped that this would become much easier but so far this does not seem to be the case. If size is shown to be an important up-front prognostic factor, how are we going to use it? What could we do differently? Nothing much is unfortunately probably the answer at present. We already use all of the active chemotherapy agents in a variety of combinations and as can be seen from the lack of improvement in prognosis over 25 years, it does not really seem tomatter inwhat order the drugs are given. Immunotherapy in the form of interferon or MT-TPE, as used in the recently completed US study, shows promise. My own hunch is that size will not turn out to be as important as the so far undiscovered biological marker, which will allow us to develop targeted treatment. We must continue to undertake biological studies but in the mean time studies like that of Kaste are important.