Osteosarcoma - A Small Step Forward?

In the past I have written about Dr Stefano Fais in Italy and his work on the use of anti-acid drugs in relation to cancer, for example here and here.In particular his work using proton pump inhibitors (PPI), some of them over-the-counter drugs, to change the tumour micro-environment shows huge potential for therapeutic benefit to patients. One example of this was work done using lansoprazole and standard chemotherapy to treat pets afflicted with cancer, to quote from my previous article:

...this study uses a cheap and readily available drug that is widely used, thus short circuiting many years of safety testing. It is part of a welcome trend in using existing drugs for tackling cancer and cancer-related conditions – other notable examples include the anti-diabetic drug metformin, beta blockers, celecoxib and aspirin. Finally, as with many of the other off-label drugs listed, the target here isn't cancer cells directly, but the tumour microenvironment.  Without a supportive microenvironment, cancer cannot thrive and prosper, which is exactly what we want. In this case, by attacking the microenvironment it means that existing chemotherapy drugs can work more effectively and kill the cancer cells. The hope now is that these results can be replicated in a wide range of human cancers, making them susceptible again to the chemotherapy that all too often stops working.

In a new paper Dr Fais and colleagues report a small clinical trial that combined a PPI drug with the standard treatment for osteosarcoma (the bone cancer that killed my son, George). Now the standard treatment for osteosarcoma is multi-drug chemotherapy followed by surgical resection of the bone tumour. A key prognostic marker for this treatment is to look at the degree of cancer cell death in the tumour after it has been removed. A good response is normally when there is greater than 90% tumour necrosis, less than 90% is counted as a poor response to the chemotherapy. So, for this trial Dr Fais and colleagues added pre-treatment with the anti-acid drug Esomeprazole to the standard four drug chemotherapy treatment for osteosarcoma.

The results show that there was a higher rate of good responses in patients taking the esomeprazole prior to chemotherapy compared to historical controls. In the case of the chondroblastic subtype of osteosarcoma the difference in the number of good responders is truly striking. Overall though across all types of osteosarcomas the difference was 47% good responders in the control group versus 57% in the PPI group.

This was a small study, not randomised (due to the fact that osteosarcoma is a relatively rare cancer), and it was looking at response to chemotherapy and not overall survival, but with those caveats this is an important step forward. It adds significantly to the evidence that adding PPI to existing treatments can have positive effects. And, in terms of osteosarcoma, it shows that there is something that can be done to incrementally improve treatments for a disease that remains stubbornly hard to treat.

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.

Campaign For Earlier Bone Cancer Diagnosis

I have written before about the poor record we have in the UK regarding osteosarcoma, the disease that ultimately killed my son George. It  is a scandal that survival rates have not improved for more than 25 years in this country, and that the figures are lower than for comparable countries in Europe and North America, (see for example my article on dismal bone cancer statistics). Figures from Cancer Research UK suggest that survival for many common cancers has doubled in the last 40 years, but there has been no change in the 54% overall survival rates for bone cancers (osteosarcoma and Ewings sarcoma) in 25 years. I don't know about you, but I find that shocking.

In a bid to address this the Bone Cancer Research Trust, in alliance with the Royal College of GPs, has launched a new e-learning module to help doctors recognise and diagnose bone cancers earlier. The idea being that earlier disgnosis will lead to better outcomes as there is less disease and lower risk of metastates at diagnosis. I know from our own experience with George that it took many weeks of visits to a number of oncology departments before even the experts were able to diagnose osteosarcoma of the jaw. Admittedly this is a rare cancer, but too many doctors were not alerted to the possibility that a numbness of the lips is a warning of cancer in the jaw. Bone cancers are more common in the long bones of the arms and legs, but we know from other parents that we met that even in the more common cases there were long delays in their children being diagnosed.

While we should welcome the campaign to get earlier diagnosis and improve the recognition of the key symptoms, we also need to make sure we do more to research on new treatments. As with many cancers, it is often metastatic disease that kills, not the primary tumour. So it's with some interest that we note that one of the cancers that has a bimodal pattern of recurrence is osteosarcoma. As with breast cancer, there is a spike of metastases/recurrence in the first couple of years after surgical treatment. This is the trigger for the work of Dr Patrice Forget, who has found that treatment with the anti-inflammatory pain-killer ketorolac at the time of surgery massively reduces the rate of recurrence in breast cancer patients. Perhaps it's time we looked at osteosarcoma in the same way. Can the pattern of metastases/recurrence be massively reduced by the use of ketorolac (or other similar drugs) before and during surgery?