Improving the evidence base for symptom control

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Published: 23 Nov 2016
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Prof David Currow - Flinders University, Adelaide, Australia

Prof Currow speaks with ecancertv at NCRI 2016 about improving symptom control among patients with advanced cancer.

He describes trials finding limited-to-no benefit of treatments and treatment-associated medications compared to placebo.

Prof Currow also considers novel treatments for cancer cachexia, aiming to improve muscle recovery and reconsider the staging of cachexia as its own disease, rather than only an associated symptom

There’s great opportunity for us to improve symptom control for people who have cancer and, indeed, advanced cancer. These people deserve the same level of evidence that underpins everything else that we do in oncology and at the moment we know that we’re underestimating the impact of those symptoms, we’re underestimating their prevalence and we’re underestimating the impact that that has on the rest of their cancer treatment.

I think the important message is that we can do high quality phase III clinical trials, randomised controlled trials for improving symptom control in this patient population. Those studies are not only feasible, they’re ethically defensible. And what we find as we do those studies is, firstly, we can improve the care that we offer. Secondly, we have a huge burden of symptoms as people enter those studies, not just the symptom of interest that is being studied but other symptoms as well. And, thirdly, that we probably underestimate the toxicity, the harms, of some of our interventions at the moment which are not underpinned with high quality evidence.

Some of the examples that my group have studied include the use of octreotide, a somatostatin analogue, for the treatment of malignant bowel obstruction, bowel obstruction secondary to cancer or its treatments. When we looked at that we saw it was actually no better than placebo at actually reducing vomiting by 72 hours. Importantly, in the active arm however, there was more colicky pain. When we go back to the original registration studies we can see that that actually makes good sense, that increasing peristalsis, particularly in the small bowel, may well lead to greater symptoms in someone with multi-level bowel obstruction.

We studied ketamine which is widely used as a dissociative anaesthetic around the world and at sub-anaesthetic doses for neuropathic pain. Although there’s Cochrane evidence for excellent benefit in people in the acute post-operative setting, in the setting of complex cancer pain the studies really had not been done with a comparator arm. When we compare to placebo what we see is that actually, we have got a huge amount of toxicity due to dissociation from ketamine that is not seen in the placebo arm, and yet no benefit in pain over placebo. So, it is a challenge to us all that we need to seriously consider doing high quality studies to improve the treatment and care that is offered alongside disease modifying therapies.

Could you tell us about novel therapies for cancer cachexia?

At the NCRI conference this year there will be a presentation on cachexia. Cachexia is the final common pathway for more than 70% of people who have advanced cancer and go on to death. We underestimate its impact on patients, on their families and on their ability to tolerate therapy. We’ve largely ignored it because until now, although we have been able to do something to improve the symptom of poor appetite, actually getting muscle back without being able to treat the underlying disease has been a dream.

There are now several phase III studies that have looked at novel agents for cachexia and what we are seeing is a pattern that is allowing the body to actually regenerate lean body mass, that is muscle, to regenerate fat mass and in some cases also to improve the symptom of anorexia at the same time. This is a significant shift in how we think about this debilitating problem.

I hope that this is going to generate a conversation about how best to use these medications. There’s been an interesting natural experiment with one of those particular medications where the two randomised control trials are in slightly different populations, one with earlier stage disease and one with slightly later stage disease and it’s clear that those with an earlier stage disease are likely to do a little better, as one would expect. This work builds on important work led by Ken Fearon in an international consensus statement on understanding cachexia. Thinking about cachexia as a pre-cachexic state, as cachexia and indeed as refractory cachexia. The new agents that are becoming available are going to sit with pre-cachexia and cachexia at this stage that refractory cachexia is, by definition, refractory and a very big challenge to us as we move forward.

What agents are being looked at?

The agents include selective androgen receptor modulators, and ghrelin agonists. So two classes of drugs where phase III studies have been done where there are very promising signals that we are about to see a new approach to cachexia for the first time ever.