7[e]: Anti-Angiogenics
As tumours develop, they require a blood supply, The blood vessels that support them are very different from normal human blood vessels. There has for some years been the notion that tumour growth might be inhibited by inhibiting the growth of new blood vessels, but this form of treatment has only been taken up in recent years.
The development of new blood vessels is called angiogenesis. To oppose that is thus anti-angiogenesis.
At the core of the idea is the fact that tumours cannot grow beyond pinhead size without angiogenesis. So the interest is in anti-angiogenics.
Thalidomide
In western medicine there is one notorious anti-angiogenic drug, sauramide, sold as Thalidomide. Its anti-angiogenic properties were demonstrated in the late 1950s when, in Australia, Canada and the UK, but not in the US, Thalidomide was approved for sale as an anti-nausea drug, to be used in pregnancy. Foetuses must develop new blood vessels, of course. Many babies of mothers taking Thalidomide were born without limbs, because Thalidomide opposed the development of the necessary blood vessels at the critical time.
While Thalidomide has demonstrated considerable value in clinical trials in the US and at the Royal North Shore Hospital in Sydney, it is still a drug with a past, a prohibited substance, unsubsidised and with no drug company interested in the work needing to be done to secure its approval and marketing as a drug because it is out of patent, and thus not profitable.
In a presentation to the Sydney Neuro-Oncology Group's support group's first meeting in February 2001, Dr Helen Wheeler indicated that patients using a combination of Temodal and Thalidomide had done better than patients using either of these drugs alone.
The 5/28 schedule of Temodal is not designed thus for optimal tumour killing capability, it is designed with breaks between treatment rounds to allow the body, particularly the blood count, to recover. Tumours are often able to recover swiftly from the effects of the Temodal. The combination with Thalidomide can be seen as of especial value in minimising tumour growth between Temodal rounds. It remains the case that there is no Pharmaceutical Benefits Scheme subsidy to Thalidomide; the patient pays the full cost, which is considerable.
The dosages of Thalidomide used at RNSH are smaller than in the United States. The Australian trials and the US trials seem to have had comparable results; the therapeutic dose is not settled.
There are a number of new anti-angiogenic drugs being trialed in the United States; there is the prospect that some drug company will find a way to modify the Thalidomide molecule sufficiently to allow the new molecule to be patented under a new name, and thus profitable, while retaining the established anti-angiogenic property of Thalidomide.
Thalidomide side-effects
The lower Australian doses have advantages in reducing side effects. Side effects include:
• sedation — when the drug is commenced there is an immediate powerful sleeping effect, so it needs to be taken at bedtime. This sleep seems recuperative and relatively refreshing, rather than stupefying. This effect may reduce in a week or so, may recur with dosage increases.
• constipation — this is a persistent effect and there is a considerable combined effect during the period when Temodal and Zofran (both also constipating) are taken, so that there is a need for constant laxative doses and effort the clear the gut immediately before the Temodal round, to avoid the gut turning to concrete.
• peripheral nerve damage — Thalidomide is a neurotoxin and sustained larger doses are likely to produce tinglings in hands, feet, arms, etc. This may be reducible by reducing dose. Or it may require cessation.
Avastin
There are some in Australia advocating for early access by brain tumour patients to a next generation anti-angiogenic drug called Avastin. Regarding Avastin, these are my notes of what Dr Helen Wheeler had to say to patients and carers in October 2008:
Avastin is the new antiangiogenic drug after Thalidomide. In 2005
there were rumours of 70% response rate. Unfortunately the response is
quite temporary. The scan looks better. Avastin quickly changes what
the scan looks like. We still don't know how much to give the patient
or for how long. We don't know why tumours take off like wildfire when
you stop.We are holding our breath while we prescribe Avastin.
As yet, there has been no Phase III clinical trial. There is anecdotal evidence of devastating side effects in some patients using this drug for various cancers, as Avastin has serious effects on healing wounds and increases risk of blood clots and stroke. In a situation of 'no cure' some may take the risks, but do please inform yourself of risk clearly... you are going to the front line of knowledge, do the research, get the best advice. This is also a treatment for which there is no government subsidy.