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Future Directions and Conclusion

M. Aapro (Switzerland)

SlotAE-6 Conclusion

Conclusion by Dr. Matti Aapro on new avenues under development to achieve Optimal Disease Control and maximize patient benefit

Transcription

Again, reminding you that you have the question cards, I already have one question, that has come, which is very important, and at any time you can scribble a question, raise your hand, and we will get it from you. 

Could I ask the speakers to join Mary O’Brien up on the podium, because what I will do is that I will go through some slides to comment and make some conclusions, and I will start by looking at some of the questions that we asked at the beginning and see how you are now reacting and, from there, I will ask the panel to make some comments. 

Full transcription

Full transcription

 

Again, reminding you that you have the question cards, I already have one question, that has come, which is very important, and at any time you can scribble a question, raise your hand, and we will get it from you. 

Could I ask the speakers to join Mary O’Brien up on the podium, because what I will do is that I will go through some slides to comment and make some conclusions, and I will start by looking at some of the questions that we asked at the beginning and see how you are now reacting and, from there, I will ask the panel to make some comments.

Changing a paradigm: More is Better?

What we tried to discuss with you here, thanks to the speakers that are there at the table, is that obviously we have this concept of disease control, in that at one point or another the tumour is going to win, but we can keep it under control for a certain while. 

As things have evolved in the cancer field, from maximal surgery to adapted surgery, from radiation to very focalised radiations, also in the setting of chemotherapies we have changed our opinions and our thoughts and have realised that the “as little as necessary and as long as possible”, which is wording that was introduced, as far as I know, by Michael Untch, is a way to go. 

One way to go is to use the metronomic approach, which was so elegantly presented to you by Gérard Milano so that we could understand what is behind the concept.  It is very important for us to realise that it is a concept which is not cytotoxic; it is about modulating the tumour environment. 

Maintenance of Chemotherapy

A long time ago, when we discussed this, people looked at it ‘Ooh, what is that,’ since then we have had other agents that have led to some excitement to begin with and then less after that and then, of course, I mention bevacizumab because a lot of the data with the metronomic treatment is very similar to some observations with this interesting, but relatively expensive, antibody. We do have different issues with maintenance of chemotherapy and this has put forward the idea of using oral approaches and also the metronomic approach. 

We know that we are limited for anthracyclines; there is a point in which you just simply cannot use anthracyclines anymore, even though there are some anthracyclines that are modified in their structure that might be useful even in those situations. 

We know that for our taxanes we do have some issues which can be very interesting, capillary leakage syndrome with docetaxel and also some neurotoxicity and, clearly, neurotoxicity with standard doses of paclitaxel. 

We know that we have to know how to modulate capecitabine in order to decrease the risk of the terrible hand-foot syndrome, which is extremely annoying to patients, albeit it will diminish after a certain time from first observation and sufferance for the patients.  Also there are some issues with diarrhoea. 

Main assets for metronomic CT

Finally, we do have some data to show to us that the approach with oral vinorelbine is quite acceptable, but as indicated by the speakers in the standard doses – and this was relevant in the speech of Dr Cazzaniga – it still has some modest hematotoxicity that we would like to avoid. 

Metronomic therapy is what we wanted to discuss with you, because of its potential activity in tumour models, of course, but now in the clinic, as you have seen from the data that has been shared with you, in slowing the tumour progression, because it does have some activity on the tumour cell itself, but especially it has activity on the tumour cell environment in the angiogenesis environment and then into immunological control that we can have on the disease. 

What is your favourite music style?

The question here is ‘How do we pursue this type of strategy?’ 

Before I go ahead, I thought that I might want to ask you the following question: What is your favourite music style?  Rock and Pop, Jazz and Soul, Samba and Bossa Nova, Classical Music, all of them or you are not a music amateur, can we have an opinion here, please?  I will give you 10 seconds, I can see quite a few of you have voted already. 

What is your favourite music style? (Voting Screen)

 [Brief pause for voting] Okay, Rock and Pop, all of them – I am so unhappy, Samba and Bossa Nova is not your favourite!  You know that I have a Finnish name, Matti Aapro, but I was actually born in Brazil, so I was born with Samba and Bossa Nova.  [Laughter]  I am happy to see that only 5% are not music amateurs. 

The word “Metronomic”

We can move on now with the slides.  Just the concept of metronomic, we could have started the session with this, it comes, of course, from Greek, as many say – including my wife, who has gone through Classical studies – everything which is good is Greek. 

From “Μετρον” to “Tempo”

Μετρον – to measure, νόμοs – the rule and the law, an assessor of measures is metronomic.  This is, indeed, used in music, many of you know about the metronome that is used to have the rhythm in music, the tempo.

From “Μετρον” to “Tempo”

We now have a little bit of information for you, because, of course, the metronomic approach in medicine is one thing, but the metronomic approach in music is another one, and we will now share with you some knowledge. 

Adagio

Adagio, for those of you who do not know Italian, means relatively slow and this is a tempo in Mozart’s Piano Concerto No 23, so everyone knows – not really, here it is.  [Brief excerpt of music played]  We all agree, it is slow; okay, we are in Vienna, we had to start with Mozart. 

Andante

Next, Andante; Andante in Italian is ‘you are going’, so it is a tempo which is 84 to 90 BPM and an example is in Tchaikovsky’s The Nutcracker, do you remember The Nutcracker?  For those of you who like Classical Music, here we go.  [Brief excerpt of music played]

Moderato

Okay, we remain in Russia for the next example with the tempo Moderato, moderate, 96 to 108 BPM, from Sergei Rachmaninoff’s Piano Concerto No 2, one of my favourite concertos.  [Brief excerpt of music played]  But some people do not like Rachmaninoff’s Concerto No 2; I can tell you that at home I have to put my headphones on because my wife hates it!  [Laughter]  It is not Greek and she does not like it!  She is not a Greek, by the way, she is Italian. 

From “Μετρον” to “Tempo”

The tempo drives the way you play a piece of music.

From “Μετρον” to “Tempo”

The tempo is also part of our approach to cancer cells.  We know that cancer cells have different tempos, the progression of the disease is different in different patients, we do not use these wonderful words of music to define that, but we know that this happens and we know that our treatments are also tempo, and this is what metronomic treatment is all about.

 “Tempo” of schedules of chemotherapy

As illustrated earlier in the brilliant talk of Professor Milano, we have different types of approaches and we believe that metronomic is a way to deliver another approach with classic cytotoxic agents that does not use a cytotoxic approach and can maintain tumour, and actually, as you certainly have observed, obtain responses in quite a few tumour types in patients where you would believe that this would not happen. 

From “Μετρον” to “Tempo” 

So different tempos of administration and the favourite seems to be a continuous one, or an almost continuous one, as illustrated with oral vinorelbine at three times a week. 

Randomized phase II trial: Tempo-Breast 1

We do have studies ongoing; studies have started now randomizing patients between the metronomic schedule and the weekly schedule. 

Please observe here in Tempo-Breast 1 the schedule that has been chosen.  This answers the question that one of you put to us, which is ‘What is the recommended dose nowadays?’  This is the one that, after the extensive work of many investigators, everyone has concluded seems to be the best in the use of oral vinorelbine, 50mg total dose three times a week continuously until disease progression and for oral vinorelbine classic style in weekly 80mg/m2, starting the first cycle at 60mg/m2, until disease progression.  This study is ongoing.

Randomized phase II trial: Tempo-Lung 1

Another one in lung cancer, Tempo-Lung 1, is also going to address the same type of question.  Again, realise the dose is the same, 50mg three times a week until disease progression and the other is the classic approach with weekly oral vinorelbine, again with the first cycle at 60mg/m2

These studies should finally establish that, yes, along with the data presented, for example by Marina Cazzaniga and by Francesco Grossi, we do have a very well established and active regimen with this type of very easy to tolerate  approach. 

At this point, before we go to the questions that I would like to repeat, I would like to ask the panellists if they have any further comments they would like to share before we get your opinion, after you have heard all of this very exciting information about a new approach with the drug that we have had for such a long time already?  Are there any comments, any further ideas from the panellists?  [Brief pause, there were no comments]  No, you had the opportunity to prepare your presentations and your slides and you feel quite convinced that you have shared all the information needed. 

Again, if you have any questions you can either come to the microphone or wave your hand with the card and I will be more than happy to share the question with the faculty. 

How relevant is disease control to you when treating your metastatic breast cancer patients?

In the meanwhile, many of you have actually been reading and answering this first question, which is the question that I asked earlier: How relevant is disease control to you when treating metastatic breast cancer patients?  Let’s see if there is any change compared to the previous vote.  I will give you another 10 seconds to vote.  [Brief pause for voting]

How relevant is disease control to you when treating your metastatic breast cancer patients?

Before it was 56% “Very relevant”, now it is 66% “Very relevant”, thank you very much, Mary, for having convinced some that this is “Very relevant”, not only “Relevant”.  Now from 6% who did not know, you have 3% who do not understand, so we still have a couple of you that should go and talk to Mary after the end of the session. 

How relevant is disease control to you when treating your metastatic NSCLC cancer patients?

How relevant is disease control to you when treating your metastatic non small cell lung cancer patients?  We had 100 and something answers previously, let’s try to get to similar numbers here, allowing you to push your buttons, I can see the numbers increasing and increasing quite quickly – slowing down, slowing down.  I will give you 10 seconds.  [Brief pause for voting

How relevant is disease control to you when treating your metastatic NSCLC cancer patients?

Let’s see; okay, once again, thank you, Mary, “Relevant”, “Very relevant”, very important.  Unfortunately, I see that we went from 5% to 9% “I am uncertain about what you mean” in non small cell lung cancer.  Mary, I am sorry, your dinner is going to be delayed, because many people will come to you and ask some questions again. 

In view of the presentations, which strategy do you envisage to use tomorrow to achieve optimal disease control in MBC, which is not hormone-responsive?

Okay, let’s move to the next question.  I asked before what do you do and you answered what you do.  Now, after this session when you leave this wonderful city of Vienna, unless some of you actually work in Vienna, you will go back to your clinics all over the world and you will take your decisions for your next patients, so after this meeting is this going to change or not, would you like to participate in some of these studies? 

The question here is:  In view of the presentations, which strategy do you envisage to use tomorrow to achieve optimal disease control in metastatic breast cancer, which is not hormone-responsive?  You know the questions,  they are the same as previously, quite a few have already answered, let’s try to get to more than 100 answers and see if there is a change, and then I will ask the faculty to make comments.  Okay, we are getting to above 100; I will give you 10 seconds.  [Brief pause for voting].

In view of the presentations, which strategy do you envisage to use tomorrow to achieve optimal disease control in MBC, which is not hormone-responsive?

Let’s see what has or has not changed.  I do see that many of you have carefully listened to the presentations and are really considering switching to a metronomic schedule of maintenance compared to what you were using until now. 

Could I have some comments here about this metastatic breast cancer change of approach?  Mary, I see we have some questions coming in.

Marina Cazzaniga:  Thank you.  I think that the switch maintenance is a key topic at this moment, in particular in some groups of patients when there is a strong clinical need to improve the disease control and typically, I think, in triple-negative breast cancer patients.  This is a particular group of patients, different strategies, new approaches in monotherapy, new targets, I think that perhaps in the future we will have results about these strategies, but now I think that we have an option for tomorrow’s daily practice. 

Matti Aapro:  Thank you, Marina, for your comments.  I see now questions are starting to pour in, we still have a few minutes, according to the agenda, and I am very happy; I have a couple of questions here for Dr Cazzaniga. 

Obviously, when you prescribe an oral medication to patients to take three times a week you want to know whether the patients have adhered to the treatment scheme.  What is your impression, is this an easy scheme for patients and they do adhere, they do comply, or do you sometimes have patients that are not complying?  What is your impression? 

Marina Cazzaniga:  My feeling is very good, because it is a very simple administration, capecitabine has to be taken three times a day, after breakfast, lunch and dinner, in the combination VICTOR-2 regimen, and vinorelbine, in this case, 40mg three times a week, on Monday, Wednesday, Friday, so it is very simple and in the VICTOR-2 we have evaluated the compliance by patients’ diaries too.

Matti Aapro:  Again, I have a question about the dose here, I showed the doses question coming before that, reminding again, single agent it is 50mg, combination is 40mg. 

A question here, when you have the combination and the patient has, nevertheless, a toxicity, it can happen sometimes, what do you do?

Marina Cazzaniga:  I continue. 

Matti Aapro:  Do you dose reduce?

Marina Cazzaniga:  No dose reduction.  We have the data of a small subgroup of patients who had a prolonged treatment for more than one and a half years without rest. 

Matti Aapro:  The last question for you, in the VICTOR studies was vinorelbine used first-line? 

Marina Cazzaniga:  The standard regimen is one possible option, for example in some patients.  In the VICTOR-1 the amount of patients treated in the first-line setting was very small, in the VICTOR-2 we had approximately one quarter of the patients treated as first-line.  No correlation with the performance status; it is not the regimen for frail patients. 

Matti Aapro:  Okay, so I have here a question that is addressed to me, but I am addressing it to the expert sitting at the table, Professor Gérard Milano.  Is there anything that we could measure in the patients’ blood or in the tumours that would predict for a response to the metronomic chemotherapy?

Gérard Milano:  A good point.  I talked a little bit about that and I feel it is absolutely necessary to combine translational studies, like markers of of angiogenesis, like I spoke about thrombospondin 1, VEGF and so on and so on, that could be a good candidate.  We do not have, as you know, candidates for conventional treatment, anti-angiogenic treatments and predictors, so it will be difficult to identify a single predictor, but we have to at least enter data and we are eagerly missing such data.  

Matti Aapro:  Another question for you, Gérard, is there data to show the activity of a metronomic approach also on circulating endothelial cells?

Gérard Milano:  That is a good point.  The only data we have in our hands concerning the impact of this kind of treatment on the endothelial cells is very conventional pre-clinical studies using umbilical vein  cells and tube formation, this is not very relevant for the clinical setting and such data could be incorporated in the prospective studies.  We have a way to determine, as you know, the level of circulating endothelial cells and this is very relevant to consider this point, yes.

Matti Aapro:  Okay, thank you very much.

Which strategy do you envisage to use for achieving optimal disease control in NSCLC, when only chemo is an option?

Now we turn to the question in non small cell lung cancer, again, the same question that you were asked earlier, what do you do?  Do you maintain with the same standard chemotherapy, you will switch to metronomic, you will start with metronomic, what do you do?  Let’s see now in non small cell lung cancer what is your approach?  [Brief pause for voting]  It is going slowly, there are less non small cell lung cancer experts in the room than breast experts, but we are getting somewhere.  I will give you another 10 seconds to make up your minds.  [Brief pause for voting]

Which strategy do you envisage to use for achieving optimal disease control in NSCLC, when only chemo is an option?

Okay, let’s see.  We can see that also in this study in non small cell lung cancer you are seriously considering that this is a very, very interesting approach. 

Francesco, do you have any comment you would like to make here?  I have a question for you, but perhaps you want to make a comment. 

Francesco Grossi:  Yes, because switch maintenance is the way now, after the second voting, but I agree that we can consider metronomic because it is easy, especially oral vinorelbine we can use easily as the maintenance treatment.  Probably we need the results of the MA.NI.LA., because in this trial we randomized patients to metronomic oral vinorelbine versus observation, but I agree that it could be a very interesting approach for maintenance treatment. 

Matti Aapro:  I do have a question from one of our colleagues in the room, sometimes we observe that by RECIST criteria the patient is not responding, but the clinical observations say that the patient is doing better, the hemoptysis has disappeared, the breathing is much easier, the patient has actually gained weight, what do you do then?  By some protocols you should stop, but what do you do?

Francesco Grossi:  It is a very difficult question, because if a biological probably I would continue with the same treatment, but if I have a clear progression probably I need to change the treatment, also if I have a bad clinical benefit. 

Matti Aapro:  The question was no response, not progression?

Francesco Grossi:  No response, no, no response, this is stabilisation, it is okay, I can continue, sure. 

Matti Aapro:  Absolutely.

Francesco Grossi:  Especially if it is - 

Matti Aapro:  Especially if it is a metronomic schedule which is so well tolerated.

Francesco Grossi:  Yes.

Matti Aapro:  Thank you very much. 

We can now move to the next slide.

Take Home Messages

Dinner time, my last words and take home messages.  You voted that disease control is relevant, very relevant, thank you very much.  You also shared with us the idea that it is important to consider a metronomic maintenance treatment for your patients and that this is something that you might want to start applying in your centres, hopefully within a protocol, as of next week.  Also, of course, this amount of data that we shared with you was concentrated on oral vinorelbine, which is one choice in metronomic approaches, but certainly an extremely well documented choice by many investigators, some of you here in the room. 

With this, I would like to remind you that the voting pads there, they don’t help you at home, it will not work on your TV, just leave them on the seats, you do not need to give them to the hostesses, just leave them on the seats. 

For those of you that would like to see these presentations again and see the slides again, we are delighted to say that thanks to this meeting and to Elsevier  and this website, actually you do not need to jot it down, just keep this with you.  If you are very modern and you know how to do it, you go with your QR at the back here, put it on your mobile device and by the end of October you will have all of this available to you. 

I would like to thank Pierre Fabre for having convened all this, thank you all for not being at the museum and thanks especially to the faculty for a fantastic job.  Thank you very much and enjoy Vienna.  [Applause]