European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Emerging strategies for the treatment of ovarian cancer

Professor Eric Pujade-Lauraine – Hopital Hotel-Dieu, Paris, France
Professor Jonathan Ledermann – UCL Cancer Institute, London, UK



JL:    We’re going to talk a bit about recurrent ovarian cancer because this is really quite a complex area of gynaecological oncology and there has been a lot that has changed in the last few years. Over the last twenty years or so, we’ve very much used the term platinum sensitivity in selecting patients, treatment for patients, with recurrent ovarian cancer. Do you think that’s still an important point in the decision making?

EPL:    I think it was one of the major progress advances in the last twenty years because it has allowed us to tailor the treatment of each patient according to a criteria which was platinum sensitivity. And what is the definition of platinum sensitivity? Well it has been, again, very well defined during the last Consensus Conference in Vancouver. It is the time between the last dose of platinum to the relapse defines what we call the therapy free interval or platinum free interval. And when the platinum free interval is over six months then we consider that the patient is again sensitive to platinum free treatment, that is platinum sensitive. And when the patient relapses within six months, then the patient is considered as resistant.

JL:    There have been a number of trials that have been done in the platinum sensitive population and I think over the years we would probably both agree that combination therapy on re-challenges is superior to singe agent therapy. But how do we make a decision about whether to combine carboplatin with paclitaxel, liposomal doxorubicin or gemcitabine, which are the three trials that have been done looking at combination therapy? How do we make those decisions? How do you make those decisions?

EPL:    A long marker trial has been the trial run by Jonathan Ledermann, which is called the ICON4 trial, which showed that carboplatin-paclitaxel was superior to carboplatin alone. And from this point, two other big trials have been run, one showing that carboplatin-gemcitabine was superior to carboplatin and obviously carbo-gem is now another option in platinum sensitive ovarian cancer, and the more recent trial called CALYPSO…

JL:    Your study.

EPL:    I was the PI, which showed that carboplatin and PLD was slightly superior in PFS compared to carboplatin and paclitaxel, not superior in overall survival, but with a toxicity profile which was in favour of the carboplatin PLD. So we have, I would say, these three combinations in our hand and it depends how the patients… the patient will accept, or not, to lose her hair, according to the neural toxicity and according to each preference. I don’t know what is your preference, Jonathan?

JL:    Well I think it actually is leading to an important change where we used to reserve liposomal doxorubicin for platinum resistant ovarian cancer late stage treatment where we really didn’t have very much else to offer them and it is a relatively low toxicity. But I think bringing in liposomal doxorubicin earlier also gives us the opportunity of using paclitaxel later and we now accept that paclitaxel is probably better delivered on a weekly schedule than on a three-weekly schedule. So now, I think, there’s a shift to using weekly paclitaxel in patients who have got platinum resistant ovarian cancer and bringing the liposomal doxorubicin further forward, partnering it with carboplatin in the platinum sensitive group. I was quite impressed by many things in the CALYPSO data but one that particularly stands out to me is the relatively low frequency of hypersensitivity to carboplatin when you use liposomal doxorubicin with carboplatin. Because this is a real problem in practice, if you re-treat patients with carboplatin or carboplatin and taxel, you often see platinum hypersensitivity and, although there are ways round it - desensitisation, switching to cisplatin, it’s quite a difficult thing to manage. Yet it was very low in the CALYPSO trial, do you have any reason why that might have been the case? Any hypotheses to put forward?

EPL:    Well we have looked very carefully to this point because it was very impressive how low the hypersensitivity to carboplatin was in the CALYPSO study and, as you mentioned, it is now with the ability to retreat patients several times with carboplatin combinations, it is now a real issue in treating patients. Obviously it was not a question Genex, we thought that perhaps that compared to the Princeps, Genex could have altered a little bit the drug. But we looked very deeply in this context and we didn’t find any difference between the Princeps and the Genex. So it seems, from the experimental point of view, directly linked to liposome and pegylation which may alter the reaction of the immune system. It’s still, of course, grounds for further research but it’s a very interesting field.

JL:    Good, good. Now partial platinum sensitivity, which the term has been around for some time, the progression or recurrence of disease more than six but less than twelve months after the last dose of platinum and, again, was endorsed through the consensus meeting, is a bit of a grey area in terms of decision making. Traditionally we have always used platinum in that period of treatment but there are other options now and I just would be interested to hear your views on the combination of trabectedin and liposomal doxorubicin in that partially platinum sensitive group of patients. Do you think that this is a treatment that we should be exploring more, that is a valuable treatment?

EPL:    I think it’s a very nice area of discussion between us two. I’m still in favour of using a carboplatin combination in this small group of patients, relapsing between six and twelve months, partially sensitive group. I think one major advance of this trial comparing trabectedin PLD versus PLD was to show that combinations are superior in this subgroup which was not evident before the trial because single agent was an option. So now we must be sure of ourselves, we should offer a combination in this setting. Carboplatin based or non-carboplatin based, that’s still a matter of discussion because there is no direct comparison and we all feel that when the patients have been recently treated with carboplatin and paclitaxel we should offer the patients other options. Carboplatin Kinex PLD is an option, but it’s again with platinum, and why not trabectedin and PLD? But the control arm was only PLD and not carboplatin PLD. So I don’t know what is your view but this trial…

JL:    That’s a good point in the sense that is it just combination versus single agent therapy. The hypothesis that was generated from that trial was that delaying the reintroduction of platinum actually was the beneficial part as well, it wasn’t only the combination therapy. So I think the jury is still out on that but I think that the Innovation trial which is now starting throughout Europe will specifically examine whether the delay of platinum in these patients is leading to almost re-sensitisation, if you like, to platinum. That would be an important study but it will take us some time before we get the results of that.

    Now, we’re two medical oncologists but we work closely with surgeons and there’s a lot of discussion as to whether or not surgery has a role in the management of recurrent ovarian cancer, I’d just be interested to hear your views on it and I’ll tell you mine in a minute.

EPL:    There is a lot of discussion and the conviction of the importance of surgery in relapse is highly dependent on the team and more than on data. So my conviction would be that I think that it is something we should discuss every time the patient is in platinum sensitive relapse. But the number of patients who can benefit from this surgery might be very limited and what are the criteria? We have the AGO criteria which are those patients who had complete resection at initial surgery, no anxieties and good performance status, are they the right criteria? I don’t know. What is your own opinion about this?

JL:    I share your views and I really, really don’t know what the role is and I think it’s important that we try and answer that in the clinical trial. As you know, the DESKTOP III trial which is now being rolled out through Europe will address this question so patients where the disease is technically operable will be randomised to surgery followed by chemotherapy or chemotherapy. So we should try and see once and for all whether surgery has a role. I have another difficulty outside of the clinical trial with these patients in that if the disease has been resected, would you then give the patient chemotherapy or would you just wait until the next bit of disease appears? That’s another question that we don’t really know the answer to and is actually not going to be answered by that trial either. What’s your personal view about that?

EPL:    I’m as confused as you are on this situation and I agree that I’m not sure that I have always been rational in my decision in this situation. I know that I have some patients who had relapse only in the spleen, for instance, and who enjoyed a very long outcome without relapse with surgery alone. I would be more reluctant not to do chemotherapy in addition to surgery in patients with isolated peritoneal relapse but, of course, it’s very subjective.

JL:    Yes, I know. It’s one of those unanswered questions but I think let’s get the surgery question answered first and then think about the other one. Now of course, unfortunately, most patients, nearly all these patients who do relapse will eventually develop platinum resistant disease after several different courses of treatment. That’s really quite a challenge for us, isn’t it, to select the best treatment for those women with platinum resistant disease, so relapsing less than six months after their last platinum treatment. What are your therapeutic options there? What sort of treatments are you using at the moment for those patients?

EPL:    One of the chances of patients and medical oncologists in ovarian cancer is to have in our armamentarium a lot of drugs available for patients. The main drugs being, of course, weekly paclitaxel as you have mentioned, PLD, gemcitabine, topotecan. But we have also another long list of active agents, some of them have not been approved yet or won’t be approved but we know that they are active. If every one of us tried to propose very blindly one or the other according to the toxicity. I would like to know your opinion about personalised medicine – do you think it is time now to do a biopsy in patients with relapsing ovarian cancer to try to know more about their signalling pathway? What is your…?

JL:    That’s a very important point because we are almost randomly making decisions in this group of patients without any biological guidance. I think, yes, we need to personalise the medicine, not only actually for patients with resistant disease but also earlier on in the course of their disease. The difficulty that we have at the moment is we don’t know how to interpret the data that we have in terms of finding the right drugs to target. Having said that, there are a huge number of new agents coming through in clinical trials targeting a variety of molecular pathways and if we’re going to bring those drugs into treatment properly we must know which patients are going to benefit and not benefit. So, to answer your question, as we develop these new agents and do studies with these new agents, it’s vital that we do biopsy patients so that we can learn in a particular patient which pathways are activated or inhibited to make better use of these drugs. But at the moment, with the drugs that we have, there’s very little we can do at this phase of the illness. The other area that I think we do need to focus on more in patients with platinum resistant disease is how we evaluate the benefit of the drugs that we’re giving because we’ve tended to use response rate, progression free survival, which are very good parameters earlier on in the treatment but for patients who have unfortunately not got long to live and may well have multiple symptoms, we perhaps need to focus more on measurement of their symptoms and improvement of their symptoms rather than the traditional markers of response. I’m sure you are aware of the preliminary work that has been coming out of the Australian and New Zealand group looking at symptom benefit in ovarian cancer and they’re now launching an international trial through the Gynaecological Cancer Inter-Group called the Symptom Benefit Study that is going to evaluate, firstly, ways in which we can measure improvement in symptoms and, secondly, correlate that to outcome. So this could lead to a new means of us evaluating patients’ treatment, particularly in the late phase of their disease.

EPL:    It’s a very important study; it’s an area where we have to make progress and particularly, of course, in resistant disease, as you said, because we expect only a very low response rate, not exceeding 15%, so of course control of symptoms seems the main aim in these patients. But also in first line because now we are using a maintenance trial and we have to evaluate how these long treatments are accepted by the patients and what are the benefits in terms of quality of life and symptom control. So it’s vital for us who are doing trials to improve our knowledge about symptom benefit.

JL:    Yes, I know.

EPL:    I fully agree with you.

JL:    But there are a lot of new agents, as we’ve just touched on earlier, that are coming into the treatment of ovarian cancer and perhaps we could just discuss a couple of those at the moment. One that I think we’ve seen a lot of in the last few years is bevacizumab, both in first line and now, more recently, in recurrent disease with the presentation of the OCEANS trial in combination with carboplatin and gemcitabine. And then there is your own trial in the platinum resistant population looking to see whether or not bevacizumab can make an impact in that late phase of treatment where the activity of chemotherapy is not so good. So what do you feel is likely to be the role of bevacizumab and, indeed, other antiangiogenic agents? There are a number of oral antiangiogenic agents under trial at the moment, what do you feel their role is likely to be in ovarian cancer treatment?

EPL:    My feeling is that bevacizumab, which is, as you said, the first leading antiangiogenic agent, is a real breakthrough in ovarian cancer treatment. The two trials in first line, in the US GOG218 and in Europe ICON7 led by your group, MRC, showed a delay in relapse, improvement in PFS. Perhaps a bit less than we could have expected initially but I think it is because these two trials have allowed us to learn a lot about the way to administer bevacizumab and perhaps it’s because we have not administered long enough bevacizumab, that the benefit was perhaps smaller than we could expect. But in fact it was very high in patients with poor prognosis where the bevacizumab was administered almost until progression in most of the patients. This was the case in relapse in the OCEANS study where the hazard ration was less than 0.5, which is just tremendous. So that’s my thinking but perhaps you would like to comment a little bit about this?

JL:    I agree with what you say and I think my own personal view is that there may be a better role for bevacizumab in recurrent disease than in first line disease but that might partly be because we’re treating the patients for longer in recurrent disease and the OCEANS trial treated the patients until progression whereas the first line trial, as you said, stopped early.

EPL:    Exactly.

JL:    So it’s difficult to know where the place is and we certainly need to see the full data, both from the first line studies, we haven’t got the survival data, and indeed from the OCEANS study itself. And then the additional study is your own study which will be available for presentation next year some time. So that, again, opens the opportunity of using bevacizumab at the late stage of treatment.

EPL:    And I fully agree with you. Once we will have all these data, the question will arise when to administer bevacizumab first line or relapse or perhaps both.

JL:    Yes, that’s right. There will be more work to do when it comes out to try and find that out.

EPL:    Yes, we will have to work a little bit to try to find out.

JL:    So just turning to one of the other new agents which is close to my own heart, as you know, and those are the PARP inhibitors in ovarian cancer.

EPL:    I think that you will be the best to speak about all of that because you have run the landmark study which opened a fantastic area of progress in ovarian cancer. So could you comment a little bit about the 19 study?

JL:    One of the pieces of encouragement to take away from PARP inhibitors is that they’re not only active in patients with BRCA mutations but what we showed very clearly in the study 19, which was in high grade serous cancer, that there are a population of patients with platinum sensitive high grade serous cancer who will benefit from maintenance therapy with a PARP inhibitor. That study which, at the moment, we’ve only reported the progression free survival, showed a highly significant improvement in disease control with a very good hazard ratio, 0.35 so we’re very pleased with that. But we need to see what the long term survival data are on these patients. But, again, it opens a similar sort of question to the ones with antiangiogenic therapies – where should we best use these drugs? Should they be used first line, should they be used in recurrence, should they be given with chemotherapy, as maintenance, for how long? So there are really a large number of questions and it’s a real challenge for us as clinical trialists, for industry who have to go through the processes of trialling these drugs, to try and find the best position of these drugs in the treatment of ovarian cancer.

EPL:    Many people talk about biomarkers, do you think that selecting patients should be high grade serous tumour for anti-PARP or do you think that other biomarkers could be found to target the right patients for anti-PARP?

JL:    At the moment I don’t think we have a particularly good biomarker, we’re just using a constellation of features, if you like, a phenotype – just the platinum sensitivity in high grade serous with or without the BRCA mutation. We need to find the molecular marker, you’re quite right, because these drugs and indeed the antiangiogenic drugs are very expensive drugs and we really have to target that population. So I think for the future, in addition to doing all these trials that we’ve talked about, the real area of work that needs to be done is to identify biomarkers that will allow us to select the appropriate treatment for the appropriate patients. Eric, thank you very much for talking to me.

EPL:    Thank you, Jonathan.