Interest of Dynamic Contrast-Enhanced US for the Early Evaluation of Anti-Angiogenesis Treatments - SD

Introduction

Good morning.

I am Dr. Lasso from France.

I am radiologist in the most important European oncology center.

My goal is develop a new technology, the dynamic contrast enhanced ultra ultrasonography in order to evaluate earlier patient treated with new angiogenic drugs.

In my work, I am both clinical in unit, and I am a horse researcher and I try to develop and to reinforce the new methodology.

I would like to explain the interest of dynamic contrast and harm ultrasonography for the early evaluation of anti androgenic treatments.

Introduction to Angiogenesis

Before, I would like to give you an introduction of angiogenesis.

Remember, we have a lot of angiogenic factors, more than 30, and the strategy is to block the development of neovascularization in order to stop the tumors.

Containing the major mediator of angiogenesis vascular on do growth factor, you could stop aim by different way using upstream activators or antibody has Avastin or with the strength pathway.

Remember, in oncology we have currently 200 approval drugs, but also more than 800 new drugs in A and d and all molecular targeted therapies are expected to experience positive compound annual growth rate between 2006 and 2016.

The matter point is, if you check this slide, all drugs targets the same receptor.

You can see here the receptor, and we don't know, and we don't have currently a biomarker in order to select the best drug for the patient.

And the majority example is the renal cell carcinoma.

Remember, we have five new drugs approval in three years, and we don't know which is the best drug for the patient.

If this is bevacizumab, the sorafenib, the sunitinib, and the inhibitor and probably the functional imaging could be a biomarker in order to select the best drug.

Need for Tumor Functional Evaluation

Finally, what do we need? Tumor functional evaluation.

Because treatments in oncology targeting angiogenesis and use the destruction of neovascularization and necrosis, often without tumor tumor volume changes.

And if you check these patients, or before 12 months and after nine months, according the criteria, we don't have the modification of the size, but you immediately understand that probably we have a necrosis.

And the goal of the functional imaging is to try to quantify this necrosis and to correlate this necrosis to the follow up of the patient, to the progression-free survival and to the overall survival.

Finally, two goals.

To save time for patients and also to save money for economical models.

And the challenge of this US are to select which is the most appropriate drug.

And we would like to give this answer earlier before the recess criteria.

Institutional Work and History

In my institution, when I start in 2000, it was only with a qualitative analysis at the beginning only with a doppler.

And we met the first phase one of sunitinib published in GCO.

And after we used a contrast Hagen in 2001, the vis and vu, the approval contrast Hagen Europe and we decide to start in different tumor.

For example, in sarcoma treated with tumor necrosis factor or in GT with glevec or in kidney cancer with the new drugs, the sorafenib.

And the goal was to confirm the oncology only with a qualitative analysis that probably we have a very sensitive tool in order to select immediately the best drug.

And on this slide, you have a patient on CT scan.

Before 12 months, it was a pelvic tumors.

And after one month, you don't have the modification of the size, but if you check the this US, you immediately understand that after one month you have a beginning of the necrosis of tumor.

And we also demonstrate that in metastatic R cell carcinoma on the left, it was bad responder.

Before treat months and after three weeks, we don't have the modification of the vascularization.

And if you compare with a good responder on the right, this is vascular isolation, you immediately check after three weeks the beginning of the necrosis more than 80%.

And when the oncologist received on the computer this kind of fifth match, he wanted finally to use this kind of methodology.

But we had to solve some problems with functional imaging.

And currently we don't have a consensus about the parameter, about the timing for the evaluation of these new drugs.

And this is the same problem with the CT perfusion, the CMRI and this s And the key point is the standardization.

In fact, you had to understand if you have a tumor, you could evaluate this tumor by using different way.

You could evaluate in red here the blood flow, which buffer the tumor.

You could also evaluate blood volume and often publication who had this parameters, the blood volume.

This is a percentage of the vessels in the total tumor.

This is has the MVD, the mara, the microvascular density had histological analysis, but with the functional criteria.

And we call also measure the main transit time.

But remember the difference between the dus and the CT perfusion.

And this CMRI have the size of microbials.

In fact, our microbials stay in the vessels, so we are not able to evaluate the permeability and the crons.

Methodology

The next point very important is the methodology.

And we published a paper with David Cosgrove from London and pno, which is an inventor of the Polestar player.

And four years ago, all companies provide us only the ification on the video screen.

So this ification was performed after the cosmetic log compression.

And finally it was a first quantification.

And the good news are now all companies, Toshiba Chi, CMS and Phillips provide this kind of data.

So you have access to the high dynamic range, about 1000, and you core perform through quantification.

The next point is the acquisition.

Remember with this techniques, you have the best temporal resolution.

You are able to record four frames per second.

So you stay on the same plan.

You inject the sun of you and you are able to record the washing and the wash out.

And during three minutes.

So we developed a methodology for deep lesion.

And for example, this is a metastatic in the pelvic area, a tumor measuring about six centimeters here.

This is very small metastasis from melanoma.

This is a tumor measuring only one centimeter.

And finally, if the patient had only one metastasis, very small, you are able to evaluate the treatments.

Next step was to develop the methodology in order to perform this care fitting very quickly, because it's important to save time for radiologist if you developed a methodology with the time consuming, the radiologist refuse to use this new technology.

So it was very important to work on the workflow and to perform a very quick acquisition and ification of these parameters.

So concerning the parameters, we're able to calculate seven parameters in green.

This is a parameters correlate to the blood volume.

This is the iron under the curve, under the washing, the wash out.

So this is the total integration under this curve.

And also the peak intensity are correlated to the blood volume in red, the time to peak and the slope are correlated to the blood flow, which es a tumor.

And the last parameters the maintenance time.

This is a peak, the health value of the peak intensity.

And you calculate the time of between these two points.

And this is a main transit time.

Remember, as there is no consensus, we decide to standardize the methodology and to calculate these seven parameters in our study.

So the study evaluating anti androgenic drugs as antibody with Avastin, with TKI are sorafenib and sunitinib and also with anti vascular drugs.

And we developed a workstation in order to calculate in few second seven parameters.

Because the goal remember, is to give very quickly all parameters to the oncologist in order to monitor the patient according the toxicity and the response.

Technical Aspects of Functional Imaging

The next points for concerning the functional imaging.

Remember, this is a motion and if you perform the this MRI and fusion, you know the problem of the motion.

Finally, our strategy was to learn to patient to have a slow respiration.

This is a very huge metastasis in the liver.

And if you check the very small vessels in blue and red, you understand that probably you stay on the same plan and after you are able to perform the tracking on this curve.

The last point for the technical aspect is the attenuation.

You know that this is an important on ultrasound, but we understand with pier PNO that and now we use these techniques.

If you put the focus chest in front of the middle of the tumor, you avoid and you decrease this.

In fact, if you perform a small quantification on the superficial error or on the deep or the total tumor, you understand that you have the same quantification.

So finally you decrease this phenomen.

Scientific Results

Now let's move to the scientific results on this slide.

You understand that we had this technology is phase one.

Remember the phase one? This is a new study when you start the first use of the drugs in the patients.

Remember currently the international role is only to use the resist criteria, but you understand that the company want to use the functional imaging in order to understand very quickly, which is the best drug for the best patient in order to push the drug in different tumor in very selected tumors or to stop the development of drug if we have no answer with the functional imaging.

And we also develop this methodology in phase two, phase three, and also in the routine, for example, in hepato cell carcinoma in GT or in melanoma and in colon cancer.

In breast cancer. Concerning the level of validation, we decide to evaluate four different drugs in four different tumors in order to understand if we have the same parameters and the same timing.

So we decide to evaluate the sorafenib.

So sunitinib, the Zain and bevacizumab, a four different tumors.

So phase one, this is a lot of different patients, but also in renal cell carcinoma in a chest and hepato cell carcinoma.

And concerning the results we understand we never had seven parameters, but three to five parameters.

And for the first time we're able to demonstrate the correlation with the progression-free survival and overall survival.

And remember, for the oncologist, this is the best endpoint in order to validate a new technology.

Patient Examples in Different Tumors

Now I would like to show you some example of patient in different tumors.

We're starting with the renal cell carcinoma.

It was a patient with a superficial lesion, you call check on the CT scan, and this is a bmo you recognize the lesion.

And so finally this is perfect target with automation.

We inject the sun of you and you are able to visualize a very vascular isolation with the washing and the wash shot.

So we follow the patient after two weeks.

Remember, according the recess criteria, we have no modification of the size, but check if we inject the sun of you.

We have only a very small vascularized.

So it's amazing to demonstrate that only after two weeks.

And this techniques is also very useful currently for the second cell biopsy, for the genomic analysis.

In fact, if you use a morphologic analysis, I could perform the biopsy in different area.

And remember, if you don't have more than 30% of variable cells, you could delete your and your biopsy.

But finally, if you use sono, you are immediately target this area in order to have a very high quality of the tissue.

And in fact, this patient had a very nice answer because he had partial response after three months and six months.

And remember, only 15 to 20% had partial response.

If you check on this graph, the ification you call say, so before 12 months in blue, the ification the time intensity chart, and after you perform the ification after two weeks, cycle four, cycle six, and cycle eight.

Another example, a patient who with a very small metastasis in the neck, you could check on the CT scan, you use a superficial probe.

So this is a lymph node, the tumor and you inject.

This is a very vascularized lesion.

And in fact, after two weeks we have a strong traumatic decrease of this vascularization only with this very small vascularized area.

And after we follow the patient after three months, you could check the lesion on the neck, on the CT scan.

On the B mode, it's impossible to understand if you have a necrotic area or not.

You inject and in fact, you have only a very small vascularized area and we continue to follow the patient after six months on B mod and after injection.

And this is a quantification.

Now explain the gist tumor.

In this very interesting study, we compare our results to the pet city and this is a patient with pelvic tumor.

Before 12 months, after one week, we have the beginning of the necrosis and after two weeks you can see a dramatic decrease of the vascularization and of the size.

And after one month, and this is a CT scan and a very important point for this patient.

When we perform the pet, the pet was normalized.

And why, because remember the resolution of the pet is about three millimeters and this techniques is not able to detect this vascularized world in the tumor probably measuring three millimeters.

So finally the ultrasound is more sensitive than the pet.

And this is a quantification curve.

We're moving to the hepato cell carcinoma.

It was a study with patient with it with visine.

So we follow the lesion in the segment four.

This is this lesion on in BMO at baseline and after one week and after four months.

And this is a CT scan after two months and after four months and the time intensity curve.

The rare tumors, I would like to show you a good responder and a bad responder and you could check it.

Now it's very easy to understand the patient is responder on non-responder.

It was a patient who is very rare tumor, the hepatic metastasis from the GIO recit.

So this is the lesion before 12 months and after one week and after three weeks.

So a very strong necrosis.

And we confirm this necrotic area after cycle 18.

And it's very rare to have a long follow up.

Remember the PFS for the phase one patient is only three months, but we are able finally after three weeks to demonstrate that probably this drug is very useful for this patient and compare a bad responder immediately.

You understand before 12 months and after one week we have no modification and we know that probably this patient will be in progressive disease after two months.

Concerning the comparison, so we compare the four study including more than 100 patient and more than 800 examination.

And we understand that only two parameters, remember I under the curve the total curve and IA under the wash out.

This is the parameters correlate to blood volume.

This is a percentage of the vessels of the tumor.

And these two parameters are always correlated to the response.

So probably it was the most robust parameters.

And for these parameters we demonstrate when we performed the this US three days after the beginning of the treatments, we have a collection with the overall survival for the eye under the curve and for the eye under the workshop.

But you have to understand if you want to validate techniques, if you want to improve the evidence base medicine, you had to validate your new methodology in multicentric study.

Multicentric Study

So we have a huge support of the Ministry of Health Health in France and from Toshiba and Bracco in order to diffuse this technique using the rolling data in 20 hospital in order to determine remember which is the best parameter, which is the best timing, and also to assess the economic impact because currently we have no reimbursement in France for this technique.

So we decide to include a 20 center and probably you recognize some city ion marsai and of course Bordeaux.

We include 11 comprehensive cancer centers and I'm teaching hospitals and we decide to teach 65 radiologists from student to the professor.

So very different population of radiologists.

We decide to include all patient treated with this new anti drugs.

For example, this is patient with metastasis from breast cancer treated with Avastin and chemotherapy.

This is melanoma treated with sorafenib colon cancer tweeted with Avastin and chemotherapy chest tweeted with sunitinib and glevec renal cell carcinoma with five approval drugs that we explained at the beginning of this talk and the HC with their nava.

And we standardize the methodology.

All patient had baseline and examination after one week, two weeks, one month, two months, and we perform a CT scan at baseline.

And every two months we standardize.

Remember the functional imaging, the key point is a standardization.

So we fixed the sitting and when the radiologist start the acquisition, it push on the button and in had to wait three minutes, he had to select only one target.

We inject the total al and we record three minutes of the raw data and all examination when sent using a network by internet in my institution in the huge database in order to perform in blind by the engineer the quantification.

So we finished the inclusion in LA in last March, 2010.

More than 500 patients.

And we present in the arrest in 2009 in Chicago.

The preliminary results including the economic results, it's very important currently the teaching results, how we are able to teach 65 radiologists and also the scientific results Concerning the population.

So we follow all patient during one year.

And it's not surprising that we have a lot of renal cell carcinoma, more than 150 patients because all oncologists understand that we had to use functional imaging.

We also have more than one or odd hepato cell carcinoma.

And finally, homogenous population more than 50 colon cancer, breast cancer, melanoma and gst.

And remember the star of treatments are sorafenib, bevacizumab, sunitinib and imatinib.

Concerning the localization of target lesion.

We are, we have health in the liver and this is a approval topic for the so of you, but we also decide to include patient with superficial lesions and in lymph node, for example, peritoneal area and pelvic tumor.

So the results, we perform about 2000 this OS and more than 1000 CT scan with a blind review.

And finally, we lose only 9% of the quantification because for example, the radiologist lose to push the examination or we have some technical problems concerning the response and for the first time.

But remember, this is only preliminary results, we are able to determine a cutoff comparing the responder and the non-responder.

And we have the same parameter.

Remember high under the curve, high under the wash out.

And if you perform an examination after one month, if you have a dramatic decrease of these parameters more than 70%, you are able to predict the response of the patient after 10 months.

Some example, the renal cell carcinoma, this is a patient with a huge pelvic tumor on CT scan.

And when you inject the contrast agent, so the patient had the treatment during 10 months and you can check after one week after two weeks, and after one month on BM mode after injection and on CT scan.

Another example, very interesting, this is a new combination of the mTOR inhibitor in Avastin.

So this is a lesion in the segment six in BM o we take the contrast, hun, this is very vascular isolation.

And after one week we have the beginning of the necrosis.

Remember if you had to perform the biopsy, probably you go directly in this area in order to have the high quality.

And if you check the bmo, it was impossible to understand the area with vascularization or necrotic area.

And it was the correlation before treatment and after two months on the CT scan and the time and on CT curve.

A very interesting patient story of the patient, remember now, and we're very happy for the patient.

We're able to include the patient in first line, second line, third line, and in renal SAR carcinoma.

For the patient, it was amazing story. He had six line.

And remember, if you had to follow this patient on CT scan, the dose of radiation will be so much because if you perform every two months a CT scan from June total, 2004, the dose of the radiation probably could be a problem.

So finally, this a s will be very important to follow this kind of patient.

The story of this patient, he had metastatic renal cell carcinoma.

So we start at the beginning with interleukin two.

He had the wraps, we moved to the interferon, he had the wraps, we moved to the Suan after the next, ever after the Tory cell.

And finally we start with a new drug from Novartis.

This is a multi tyrosine kinase inhibitor.

And we start in February, 2009.

The patient had metastasis in the liver in BM o, the vascular isolation.

And after one week we're able to demonstrate the necrotic area in more than 50% in the lesion.

And this patient had the treatment during 14 months.

It was amazing because normally the PFS in the first line is only 10 months and after the sixth line we're able to demonstrate that probably this is very, very efficient new drugs.

Now we're moving to the colon cancer.

The patient with metastatic in the liver in boid before treat months after one week, after two weeks, you can say a strong necrotic area confirm after one month.

And in fact we follow this patient this lesion before treat month after two months.

And this is a time intensity curve.

We're moving to the gist.

This is a patient with metastatic in the liver.

Before 12 months, two weeks, one month and three months.

And the quantification another very interesting patient.

This is a comparison between the frank criteria, the famous CHO criteria from the MD Anderson and in at Houston.

If you follow this lesion, the useful units is 47 at the beginning and after two months, this is 32.

So this is as a good response according to shell criteria.

But when you come back after four months, we increase to 45 and half, we decrease to 30 four.

So finally it's difficult using the shock criteria to evaluate this patient.

But if you use a contrast heent, this is at baseline.

After two weeks, after two months and six months, you are able to evaluate very high efficiency.

These treatments we're moving to the breast cancer also.

This is a patient woman with metastatic in the liver before treatments in BIM o using contrast hun.

And it was DYS lesion on CT scan.

And this patient had Avastin during 14 months.

So this is more than the progression for survival that they published in the huge publication.

And we followed the patient after one week.

You can see the beginning and after two months in necrotic area.

And this is a CT scan and the quantification curve.

The last example is amazing story because it was a phase one and this is a new combination.

This is a new drug. Currently this is a confidential drugs combining with radiotherapy.

Remember currently we have new approval drug in melanoma.

It was a patient with a huge lymph node in the axillary area and it was a lesion.

And this drug when we start was not antigenic drugs, but we decide to use the te these techniques in all phase one, we check the patient only after one week.

Without contrast, hun, it was impossible to understand the answer at the beginning of this evaluation.

But when we inject the contrast hedge, we have a dramatic decrease.

It was amazing answer.

We never had this kind of answer in melanoma.

And finally, the company decide to push.

Now a lot of patient with melanoma, we don't understand the mechanism of this drug, but we understand probably for the melanoma it'll be very nice.

And we confirm the answer of this patient.

You could check the CT scan.

This is has a show answer or you could say a necrotic area.

And when we inject, we have a only a small contrast uptake surrounding the tumor.

Quality Evaluation in the National Study

Now concerning the national study, we try to evaluate the quality because it's also very important in United States.

So you are starting this new methodology now and how we evaluate the quality of the acquisition.

So we decide to give a score between zero to five, and finally we only delete the number zero.

So this is only 3% of the acquisition Concerning the score of the radiologist.

And you had to remember if we perform Less than 10 examination, this is only for training.

But finally, if you perform more than 50, examination is not so much.

This is only during two months, you are able to have a very high quality for the tech for the acquisition.

So finally, it's very easy to learn and to teach this new technology contain the very important parameters.

Remember, the number of examination is better to have more than 50 exams.

And also, and I saw that you understand in different example that I saw you, if you choose a metastasis without motion, the quality is better.

So if the patient have metastasis in the liver and metastasis in peritoneal area on the neck, it's better to choose immediately the lesion without motion concerning the cost.

It's very important in United States, but also in Europe.

The time for the radiologist is only 23 minutes and we understand that in 20% of the cases we inject tris v at baseline it's very important to have a very nice acquisition at baseline.

And the cost including the staff, the contrast hedge and the equipment, the quantification is $273.

So it's not so much for the functional imaging and it's 182 euro.

Building Networks and Teaching

Now our goal is to build a European and international network.

So we try to start, we start collaboration with the Harvard team in Boston when with Annie Van and Donald de Salvos.

And now they are the same machines, the same methodology.

We also diffuse the techniques in Wild Mar in London and also in Tu tumor in Melano.

I am a new chairman of the European organization of oncology in order to push this technology in functional study.

And we are starting in an cell carcinoma with Pfizer.

And we also start with a phase one study with companies for example with ti but also we teach the Korean center in Seoul, in Hassan Medical Center, the Samsung Center and University of Seoul.

So currently we create this network and we hope that we reinforce this network with the United States because now they're starting the study with vu.

The last point, teaching in the world and to provide guidelines.

Teaching the world in the European Congress, we try to perform the workshop combining MRI, this MRI with Ani c perfusion and the so us, I am a chair in European Society of Oncology and we try to push our imaging session in oncology.

We organize international course for training and we also teach in China, Korea, Thailand, and Austria.

Concerning the guidelines, it's very important point.

This year the European and world guidelines will be provided in now August in Vienna.

And this methodology will be include in the guidelines with a level LA of validation.

Conclusion

To conclude, remember this new technology is a dynamic contrast and contrast sonography using the role linear data and the bolus injection allow us to calculate different functional parameters.

Remember the determination of threshold of quality.

If you perform more than 50 examination, this is excellent quality.

And finally, probably the eye under the curve and the wash out are predictive for tumor response and overall survival.

And this parameters could be a potential surrogate markers of the efficacy of antigenic agents.

And in fact, the next step, the future and the challenge will be the for the acquisi in raw data in order to avoid the operator dependence of the ultrasound.

And we hope that all companies develop a very new probe able to perform this 3D acquisition during three minute.

I hope you enjoy this talk and I hope you to meet you in order to create the network.

Thank you.