Friday, 6 June 2014

Osteosarcoma - A Proposal for Reducing the Relapse Rate



As has been mentioned on this site before, there has been little progress in the treatment osteosarcoma – the disease that killed my son,George – in the last twenty-five to thirty years. The actual figures vary by country, but generally the five year disease free survival is around 60% - 70%, though in the UK the last published figures were an absolutely appalling 43%. But these figures mask what’s really going – osteosarcoma of the extremities (the long bones in the arms and legs) has a much higher disease free survival rate than osteosarcoma at other sites. So the figures for England show that the rate is 48% for osteosarcoma of the extremities and only 16% for other sites. And, regardless of site, the prognosis for relapsed disease (whether it’s a local recurrence or a distant metastasis) is truly grim.

Looking at the patterns of relapse however shows us something really interesting and, hopefully, significant. The vast majority of relapses occur within 18 months of surgical resection (and in osteosarcoma the only way for definitive cure is to surgically remove the tumour). What is more, most of these relapses take the form of distant metastases, the majority appearing as new tumours in the lungs. This begs the question as to why this pattern? It suggests that there’s something systemic going on – and it’s a similar pattern to the relapse/recurrence of breast, lung, head and neck and other cancers. 

One possible mechanism involves the surgery itself. The body responds to the trauma of surgery by releasing different growth factors, cytokines and other inflammatory responses. This is necessary for wound healing, but it also creates an environment that is conducive to cancer growth – there are pro-angiogenic growth signals, immune suppression and so on. It all adds up to an environment that gives any microscopic pockets of cancer cells the chance to expand and grow into new tumours, particularly in the lungs.

In breast cancer there is evidence, in the work of PatriceForget and others, that some simple interventions during the period before and after surgery can drastically alter this pro-tumour inflammatory environment. Using the well-known, cheap and safe anti-inflammatory pain-killers ketorolacand diclofenac the breast cancer relapse rate dropped dramatically. That was based on a retrospective analysis of cases, there is now an on-going clinical trial in Belgium comparing surgery with and without ketorolac to see if the results still stand. And if it does, then this is a truly significant result that will save thousands of lives a year, and all for the cost of a few dollars per patient.

There is good reason to believe that the same thing applies to other cancers, including osteosarcoma. The trick now is to build the case so that this too can be testing in a clinical trial. It would be a phenomenal result to be able to reduce that risk of relapse, it will mean we can inch the survival rate in osteosarcoma up again after three years of it being stubbornly flat.

How can we do this? Unfortunately we don’t have the kind of retrospective data that Patrice Forget had for breast cancer. However, there may be one way in this. Osteosarcoma is also one of the most common cancers in dogs and cats – and it’s a killer there too. What’s more the disease in dogs very closely matches the disease in humans. It’s the best animal model of human osteosarcoma there is, better by far than any mouse or rat model. If we can trial the use of ketorolac in the surgical treatment of osteosarcoma in dogs we will have results back that are directly applicable to the human disease. So, if you know of any charity or foundation that is interested in human or canine osteosarcoma, then please bring this work to their attention.

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