CEUS: A New Approach to Tumor Response to Treatment - SD

Introduction

I am coming from Italy.

I'm working in medical director in ACO company.

And the purpose of the meeting of the presentation of today is to give you an overview of the use of contrast ultrasound in monitoring tumor response to new chemotherapy, especially to the angiogenesis drug.

Contrast Ultrasound Overview

Contrast ultrasound is a new imaging modality and is the result of a synergic integration between a contrast ultrasound agent and ultrasound system provided of contrast dedicated platform.

Contrast ultrasound characteristic is the real time evaluation of vascularization since ultrasound contrast agent once injected acts as red blood cell and remain in the vasculature.

Contrast ultrasound is a very sensitive modality, able to assess also the macrocirculation of organ tissue.

Example of Sensitivity

And I show here with an example.

This is a large chioma where biopsy has been performed.

And immediately after the injection of contrast, you may immediately see a bleeding.

And in the bleeding you can see almost see the single bubble entering in the large cyst.

And this can provide you with information of how sensitive is methodology.

You can see bubble running inside the tissue.

And since you are evaluating the macrocirculation, you can also explore the perfusion of organs and you may evaluate the normal part of the normal vascularization and also the abnormality of vascularization in this example of liver affected by large gastric cancer metastasis, where the two vascularization are clearly evident EV evidenced by the contrast agent and the possibility to explore a macrocirculation as pro as a caused of the development of large number of clinical studies in the area of especially in the area of cardiovascular area and inflammation and transplantation.

Applications in Oncology

And moreover in oncology and to our day a lot of clinical site are working in Europe and Asia in trying to use contrast ultrasound in monitoring chemotherapies, especially in a special type of chemotherapy, which is the anti-angiogenesis neurogenesis drugs.

Importance of Monitoring Anti-Angiogenesis Therapy

Why this is so important, what this the the the introduction of anti-angiogenesis drug as a data in required the introduction of a new of of a new modality of follow.

The the patient, first of all.

One point is that anti-angiogenesis therapy is characterized by by the fact that this therapy become a chronic therapy, the patient receive in most of the case, tablets for a longer period of their life.

And also that this therapy is a very expensive treatment, therefore, there is a need of early a continuous risk benefit assessment of this treatment.

The there are two main question that the monitoring of tumor response have to provide.

The first one is to guarantee that the the treatment is working in order to allow the oncologist to decide the right dose of a treatment or eventually to change the treatment.

And secondly, is to guarantee the patient that he's receiving adequate treatment and he is not suffering adverse events, which are less important than for the traditional therapy, but are still relevant even for this type of therapeutic approach.

And last but not least, also to avoid the unjustified cost.

If the treatment is not working, the patient continue to answer it.

If the patient continue to answer to the treatment, then we have the need to evaluate the the appearance of a secondary resistance and also the need to evaluate the compliance of a patient to the treatment.

Limitations of Traditional Imaging

The traditional imaging criteria to assess tumor response, the racist criteria are based on change of a dimension of a tumor.

And this treatment have been defined as unsuitable for a sensitive evaluation of the of um of the assessment of an angiogenesis treatment because in many in many cases, what's happened was that the treatment the the the tumor, the patient clinically improved after the assumption of this treatment.

But the the change the the dimension of the tumor didn't change and therefore the imaging was not able to support the oncologist in way seizure for the uh to to how to continue the management of this patient.

Role of Imaging Modalities

But are imaging modality useful to evaluate a tumor response?

The answer is probably is yes, because anti-angiogenic drug target neovascularization of the tumor and imaging modalities can detect the tumor perfusion and assess a change of perfusion.

There are different imaging modality, which can be uh suitable for this proposed contrast.

Enhanced MRI contrast enhanced spec, pet contrast announce ultrasound optical imaging, but uh which is the best modality, the best modality should be selected on the basis not only of efficacy, but also taking consideration the availability of the technique and the cost, because we are going to use this technology for a long time during a monitoring process.

And then we have also to consider if in the management of the patient, some of them can also be considered complementary in a different in order to assess different phase of a tumor response.

Validation Requirements

The first point that have to be uh underlined is that in order to uh start to use an imaging modality in to monitoring tumor response, the first thing is that the the value of change of perfusion as a a predictor of a tumor response of a of a tumor to the treatment has to be clinically validated.

And this means that the imaging measurement independently, if they come from MRI or CT or ultrasound, have to be validated against uh clinical endpoint like outcome or clinical surrogate, like progression-free survival, which are typical endpoint of the uh clinical development of uh tumoral and anti-cancer drugs.

And the imaging measurement can be compared versus the biomarkers in mono stone chemistry or other existing imaging method assessed in a later phase of the of a tumor treatment where it's clearly demonstrated with a traditional modality like um um racist criteria if the um the the the the tumor is responding or not to the treatment.

Last but not least, it's very important to demonstrate also the robustness and the reproducibility of the technology, which is under study.

Standard Protocol in Europe

This is the uh standard protocol that we are using in Europe to evaluate the tumor response we use in contrast ultrasound to uh anti-angiogenic treatment.

And uh let's say that the the primary objective that is used in this study is to come to evaluate if child is able to predict the tumor response at one, two week after the initiation of a treatment.

And to compare this results with uh racist criteria obtained on CT and MRI at two, six months from the beginning of a treatment.

Well, the second objective is uh also to evaluate if a contrast ultrasound is able to predict the clinical outcome.

And the last but not least, is also to detect the secondary resistance.

Study Design

The study design is very simple.

It is um it is designed in a way that the conscious ultrasound is performed just before the initiation of a treatment and repeated very frequently at, especially in the first four week of uh of treatment, and then can be repeatedly at um at the regular interval every month, every two month.

And then the results obtained at each visit have to be compared to the racist criteria obtained with A-C-T-M-R-I at the at the end of the first um important clinical cycle of treatment.

And this depends by and the inter, this interval depends by the type of tumor and by the type of treatment selected.

Observations from Imaging Studies

And this is what we are we are going to observe from imaging point of view.

These are two uh example uh one uh are two patient affected by renal cell carcinoma.

And these are two liver metastasis for the one patient is a bad responder and one is a good responder.

And you may see that uh at the beginning, at the baseline, the two lesion are very well perfused.

Every uh where you see uh green color, this means that is a perfusion.

But after 14 days, we see a very different uh aspect of the two lesion in uh the lesion of a patient or not.

Responders appear still very well perfused, very well green, very well colored, while the lesion of the patient responder is black.

So there there is a dramatic reduction of a perfusion, and this is a indicator that we are going to use for the further assessment.

Uh this data come from na, so who is one of a pioneer of this uh of a use of contrast ultrasound monitoring of tumor response.

And this slides show that the patient who had a good bad, who had not reduction in perfusion after two, four weeks of treatment had a progression free survival and an overall survival worse in respect to the one who had a reduction of perfusion.

And this is another study uh still again of na.

So with with another type of tumor.

In this case, we she's observed uh gist tumor and this patient were followed for six month and the six month on the basis of a racist criteria.

The patient were divided, the responder and not responder.

And if we go to look at the uh results of a of um of a person, of a percentage of perfuse tumor at the day plus seven and day 14 for the responder patient, we have a reduction, relevant reduction of perfusion respect to baseline.

While this does not happen for the non-responder um besides that uh besides the clinical validation, we have also to consider that uh we have to in order to select a method for monitoring tumor response, this method have to be reproducible.

Reproducibility and Standardization

And in the case of ultrasound, there are two strategy that have to be followed.

The first one is to standardize imaging acquisition, which means to select ultrasound equipment, appropriate ultrasound equipment to do the examination to to um to select the right setting, the right probe uh in order that the the quality of images remain constant in the time and reduce the variability link to the uh different uh uh organization of a machine contrast administration.

Also, it's a very important point because it's very important to define the strategy of administration of a of a contrast should be selected as uh we have to select the BS or infusion.

We have to select a dose, we have to select the speed of administration, the modality of examination.

Also, it's very important what uh ultrasound and our day is still working mainly in B mode.

So we are to select the lesion.

We have to be sure that we are going to evaluate the same lesion in the time and that we are exploring the same plane or during the all the the different visit we are uh using for monitoring the tumor response.

Preliminary Results

These are the results.

The preliminary results, again, from a multicenter study running in France where uh and is based on 470 patient and more, and on more of 1,600 the contrast ultrasound examination.

And after a standardization, they um the quality of the clips uh documenting of the examination arrived to the central lab.

They indicated that 85% of the of the of the clips arrived are perfectly uh are have a very good quality.

12% can be used, but are uh the full quality and only 3% cannot be used because they are definitely not of of quality.

Very very very bad.

The last the last the second strategy that have to be followed uh in um in order to uh create a a contrast ultrasound um very reproducible, is to use a quantification analysis.

Quantification Analysis

All of the the evaluation that we have seen before were performed using a qualitative evaluation of the of of images, of evaluation of a perfusion.

It's very important to try to uh transform the the quality uh the difference of perfusion in mathematical parameters in order to have a more objective data and the different software are available.

And under evaluation for this proposed, this is an example of quantification.

The one one method, one possibility is to uh design a region of interest around the wall tumor and then evaluate the uh washing, wash out curve of the announcement in inside the this lesion at the different time uh time point.

And you may see in this case um the at the the the minus one, we had the the blue curve describe the behavior of a was shot uh at before the initiation of a treatment.

And all the other curve describe the behavior of a curve later on.

And you may see that the progressively we have a reduction of a peak announcement and of the value of the p ment of the the curve demonstrating a a let's say, more quantitative approach of the uh of uh evaluation of a of a tumor response.

And uh in this scheme, you have a representation of a time intensity curve uh describing the kin behavior of a contrast agent in lesion.

This curve can be described with different mathematical parameters, which can be correlated to the blood volume or blood flow inside the tumor.

And uh uh many clinical project are ongoing to identify the most relevant uh contrast ultrasound quantitative parameters.

And there are, these are just free example of free large multicenter trial ongoing in Europe.

But other study are uh are also going to try to define this approach.

And this is uh the results of uh one another study of Natalie.

So in uh which has been recently published on clinical cancer research, where uh she was able to d uh divide the patient with um renal cell carcinoma into population responder or responders of the basis of racist criteria at the third month, and said that she was able to demonstrate that the patient responders had a significant different value of five quantitative parameters respect to the non-responder patient um in in fact epic intensity, slope of machine area under the curve time uh and um uh area under the coral washin and area under the curve of wash out were all significant different between the two population and also the peak intensity and the washing slope correlated also to the to the um to the overall survival, to the progression-free survival.

Parametric Imaging

This parametric imaging is another ality to represent the quantification is very simple.

The H pixel uh uh um can be uh at at the level of each pixel.

We may have a time intensity curve, and therefore, with parametric imaging, we depict in the tumor using a color map, the parametric value specific for each pixel.

In this in the first example, we have a pick of announcement and we have a representation of um of high level in red and low level in blue, clearly immediately demonstrating the the uh let's say the uh non homogeneous distribution of a vascularization inside this tumor.

Then we have a relative perfuse area, which is another parameters to study uh uh is the the number of pixel who have an peak of intensity superior to the 50% of a maximum peak intensity found.

It's a different way to represent the perfused area using these parameters.

Uh Dr. Tran was able to clearly demonstrate already at the 15 day inpatient with liver column metastasis treated with Avastin.

Um dramatic difference between responders and our responder very well evident by the this the value of these two parameters, but which were not clearly.

Um but if we want, we went to look at the volume of a tumor at 15 days of the two population are uh practically superimposed.

So this parameter is able to demonstrate in advance respect to volume, the the tumor response to treatment.

Future Developments: Targeted Agents

And now few, just three slides to speak about the very far future.

Uh we are started to develop a new agent, a new target agent targeted to V-V-A-G-F-R two, and this bubble agent are able to link through a peptide uh to uh to this uh receptor, which is expressed on the endothelium of a new angiogenesis.

And uh this is just an imaging example of the how the the the the contrast behave in uh in a RTA model.

And uh we have the first part, we have a perfusion part, which is very similar to what we obtain with with some of you and uh with uh with a known target agent as and here.

Uh but at the end we have the uh link, we have the evidence of the bubble link to the to the to the tumor, which for sure, which provide more important information than infusion.

And this is an example in a pet dog where a carcinoma was detected using uh this approach.

And on the basis of this results, we are going to to have a first uh dosing in men of this uh of this compound in the next month.

And we hope that if this approach will be positive to open the new the new era of target imaging.

Conclusion

In conclusion, contrast ultrasound is a very sensitive imaging modality, able to evaluate a microcirculation perfusion in real time racist criteria are in a to evaluate tumor response.

There is a need for an accurate, friendly monitoring activities.

Perfusion imaging is a possible tool for treatment follow up validation is ongoing for the different imaging modality.

Contrast ultrasound is a very promising approach, and the clinical validation of quantitative contrast ultrasound is ongoing.

Target imaging can be the future, who knows.

Thank you very much.