17th International Meeting of the European Society of Gynaecological Oncology (ESGO 2011) 11—14 September 2011, Milan, Italy

Early treatment in ovarian cancer relapses

Dr Gordon Rustin – Mount Vernon Cancer Centre, Hertfordshire, UK

We presented at ASCO two years ago, which was the number one plenary session, and the data was published last year in The Lancet, of a large trial, the AVEO5 MRC trial 55955 with the EORTC, which showed basically that early treatment of relapsed ovarian cancer was no better than delaying until patients had symptoms. This is very important and it’s becoming increasingly important as ovarian cancer becomes a chronic disease. It’s really important that patients are not over-treated but I’m worried that even though people accept the data showing that… this was all based on a rise in CA 125, that patients were randomised either to start treatment straight away once their CA 125 started rising or waiting until they developed symptoms. And there was a 5.5 month difference between the early and the delayed group but despite that there was absolutely no difference in survival.

We know that those patients who were treated earlier, on the early arm, received their next line of treatment earlier. So almost certainly patients who are treated early once will be treated early again and will end up getting more chemotherapy in their life which is unpleasant and toxic. So we’ve got to delay treatment until patients actually need it. And I’m trying to work out why there’s such a huge difference in practice around the world. Doctors who I speak to say, ‘Oh my patients demand to know their CA 125,’ but why do they demand to know it? And I’m beginning to realise that there is one probable fundamental difference between doctors. When I finish first line treatment for ovarian cancer I discuss with patients what the future holds; I tell them that their first line treatment, that’s the surgery and the chemotherapy, is basically their one chance of being cured. If the cancer comes back, you can treat it but you can’t cure it. By cure, and this again I think is a problem around the world, because I think cure to somebody who lives close to the Mediterranean probably is very different to my patients. My patients consider cure as the cancer is gone forever; a lot of patients think cure is the same as remission and that is completely different. Now I tell my patients that if the cancer comes back again, they will almost certainly die of that ovarian cancer, even though I might be able to keep them alive for many years, and therefore making sure their quality of life during those years is good is essential. Now if you don’t tell those patients that information, that you cannot cure a relapse, if somebody imagines that due to follow-up, earlier treatment will lead them to be cured, they’ll obviously want the relapse to be picked up as quickly as possible. I suspect that many doctors are not absolutely clear and frank with their patients and that is why the patients want to have regular CA 125 measurements. If the patients knew that doing regular CA 125s was likely to lead them to have far more treatment in their life, was not going to actually help them at all, then they would probably accept not to do it.

Now there’s another side to this because I give my patients, obviously, a choice. I say you can have the CA 125 measured or I recommend you don’t if you’re well. Now if the patients start having their CA 125 measured and the level starts going up, it’s then quite difficult not to treat them because they get so anxious because their CA 125 is going up. I know various colleagues of mine around the world now put those patients on drugs, which is tamoxifen, as almost like a placebo. It actually does help as well, tamoxifen but I personally think it’s far better to educate patients not to have the CA 125 if they’re well and then you don’t get into this very difficult discussion.

Is there any danger of over-treating patients in these cases?

That is obviously possible because we know that there are always deaths from chemotherapy, hopefully very few. But it’s really the quality of life that I’m talking about because if you speak to any ovarian cancer patient they all say that life off chemotherapy is far better than life on chemotherapy. This whole thing is slightly becoming more complicated, however, because maintenance therapy is now coming in. We’ve got bevacizumab and also olaparib, the data that Jonathon Meadowman presented this morning showed that probably the best hazard ratio we’ve ever seen in ovarian cancer of 0.34 in favour of olaparib for delaying progression. That’s not licensed and it won’t be licensed for some years but we’re very lucky that we’ve potentially got two drugs that could delay relapse. Now the big question is when do you give those drugs. To my way of thinking, I’ve always been in favour that probably these drugs should be given in patients who have relapsed rather than as maintenance for first line treatment. My reasons for that are that many patients who receive first line chemotherapy have remissions lasting years before they relapse, particularly if you fit into a good prognostic group. Now it would be awful if those patients and the cured patients had the toxicity from maintenance therapy for years. What’s really exciting is that the OCEANS data that was presented this morning showed that bevacizumab seems to work just as well, perhaps even better, in the relapsed situation than it did in the first line situation. So I’m far happier to give these treatments in relapse.

Now, if you start giving them first line, then you’ve got the issue of what do you do about CA 125, what do you do about scans? And my belief is that probably outside a clinical trial you’re probably better off not doing the CA 125, even if you’re on these maintenance treatments, because if these maintenance treatments are working, they will be slowing the rate of growth of the cancer. They won’t be probably getting rid of it but if they’re slowing the growth of the cancer we’re getting into this ridiculous situation, for example the definition for regression of ovarian cancer based on CA 125 is the level has gone more than 50% above the nadir. So what I keep on asking people, if the CA 125 has only gone up 49%, does that mean it’s still working? But once it gets to 51% it’s not working. It seems a nonsense that you should be stopping the drug just at that point. So we’ve got to do a lot more work on this but if somebody is well and you think you have a drug that is actually slowing the tumour growth rate then it makes a lot of sense not to be doing all these tests because you might well be stopping these drugs prematurely and harming the patients.