Infantile Fibrosarcoma – Sarcoma Talk #10 with Daniel Orbach

In this edition of Sarcoma Talk on OncoDaily, Dr. Daniel Orbach, pediatric oncologist and head of the Department of Pediatric, Adolescent, and Young Adult Oncology at Institut Curie, joins host Shushan Hovsepyan. Dr. Orbach delves into infantile fibrosarcoma, discussing its rarity, unique characteristics, and challenges in treating infants. He highlights the transformative impact of NTRK inhibitors like larotrectinib and entrectinib, which offer rapid tumor reduction with minimal side effects.

Shushan Hovsepyan is the Editor in Chief of the OncoDaily Medical Journal, a pediatric oncologist and an adjunct assistant professor at the Yerevan State Medical University. Currently, she is the Editor-in-Chief of OncoDaily Medical Journal.

She completed her clinical fellowship at the National Institute of Cancer in Milan, Italy and at the St. Anna Children’s Research Hospital in Austria Furthermore, she held a research fellowship position at the European Organisation for Research and Treatment of Cancer in Brussels, Belgium. She is a former co-chair of the SIOP Global Health Network Education and Training Working Group.

Dr. Daniel Orbach is a pediatric oncologist and the head of the Department of Pediatric, Adolescent, and Young-Adult Oncology at Institut Curie. He is actively involved in both the French and European medical groups dedicated to childhood and adolescent soft tissue sarcoma, including the SFCE (French Society of Childhood and Adolescent Cancers and Leukemia) committee and the EpSSG. Dr. Orbach also coordinates the French “Fracture” group, which focuses on very rare childhood cancers, and is a founding member of the European Expert Group for pediatricians treating young patients with rare cancers. Additionally, he is part of the SFCE’s childhood malignant germ cell tumor (MGCT) committee.

Shushan Hovsepyan: Welcome back to our five-minute sarcoma talk sessions on OncoDaily TV and this is Shushan Hovsepyan, your host as always. I’m honored to have Dr. Daniel Orbach with us today, who is a pediatric oncologist and leads the Department of Pediatric Adolescent and Young Adult Oncology at the Institute of Curie in France. So Dr. Orbach, thank you very much for joining us today and for our listeners, we are going to discuss a very interesting topic and to start with the basics. What is infantile fibrosarcoma and what makes it different from other pediatric sarcomas?

Daniel Orbach: Thank you and to invite me to speak about this very intriguing tumor. Infantile fibrosarcoma is a quite rare sarcoma and we consider that this tumor occurs in one percent of all the soft tissue sarcoma in children, but even with this, it is the most frequent soft tissue sarcoma before the year of one. So it means that this tumor has a median age of two months, which corresponds to the fact that it could be diagnosed before birth, at birth, or during the months following the birth.

And this tumor is considered as an intermediate malignant disease, which means that it’s not, of course, a benign lesion. It’s not a highly aggressive sarcoma. It’s in between with a very low risk of metastasis that can occur in something like one to three percent of cases.

And what is always interesting is that as this tumor occurs in infants, we have to deal with all the therapy that we want to give in these very small children.

Shushan Hovsepyan: Thank you very much for sharing that. It’s very helpful. And to move forward to the treatment, how was infantile fibrosarcoma treated in pre-targeted therapy era and what challenges did oncologists face with these approaches?

Daniel Orbach: By the past, as we are treating sarcoma in very young children, the main treatment that we give is surgery. And if we have the chance, and it’s not always the case to have a very limited tumor localized, we propose conservative surgery. But most of the cases, this tumor was very huge and has an extension occurring in the limbs, which means that the conservative surgery was not possible.

It’s the reason why by the past we gave chemotherapy and we know that this tumor can be very chemosensitive. In Europe, we were used to give vincristine actinomycin D as a main regimen in such a disease. In US, it was vac chemotherapy, which means vincristine actinomycin and cyclophosphamide.

And of course, both of these regimens were efficient. But in Europe, we prefer to avoid to use cyclophosphamide, of course, due to the potential long-term side effect on gonadal function, of course, of mutagenesis possibility of this drug. With this, the aim of this neoadjuvant chemotherapy was to obtain a reduction, a tumor reduction, and to allow a delayed conservative surgery, which was sometime possible in most of the cases, but not always.

And in such a case, when we have no possibility to propose a conservative surgery, most of the time we needed to do a mutilating, which means amputation, because the main site of this tumor is arm and limbs, which means that we needed some time cases by the past to do mutilating surgery.

Shushan Hovsepyan: That must have been very difficult for families to accept that the treatment could be life-altering, but having that in our mind, now let’s speak about molecularly targeted therapies like N-drug inhibitors. If I’m not mistaken, there have been two studies back in 2015 where pediatric patients were included. So could you walk us through how these inhibitors work and why it’s been such a game changer for these patients?

Daniel Orbach: We knew for a lot of decades that this tumor, I speak only about infertile pleurosarcoma, harbor quite pathognomonic ETV6-NTRK3 fusion transcripts, and this fusion transcript was used to confirm the diagnosis, because at the beginning, when we had the tumor with spindle cells, aggressive tumor, we were discussing what type of tumor it is, and when we found this fusion transcript, we can confirm this diagnosis.

So it was used by the past only for the diagnosis. Nowadays, we have developed drugs that could block this NTRK3 fusion transcript, and that is very specific to the tumor who had such a N-DRK3 fusion transcript, and with a very, very important tumor rejection with efficacy, and we consider that this drug, I speak about larotrectinib, but we can tell that n-trectinib is another very efficient second drug that we can use in NTRK3 fusion tumors, are very efficient in such a disease

which means that we are expecting more than 90% of tumor control or tumor reduction with such a drug, and what is incredible is that these drugs are working very fast, which means that you can see some tumor reduction in the days, sometime following the initiation of the therapy

And of course, when you have a very large tumor that may have bleeding or that is in a life-threatening situation, we are very happy to have a very fast tumor reduction, and the other thing that is very nice in such a drug, larotrectinib or n-trectinib, is that the tolerance is very good.

Larotrectinib could be given as a solution, which means it’s a clear, without odor, very good, tasty solution. The side effects are very moderated. You can see an elevation of the hepatic liver enzyme or some quite reduction of the neutrophil count, but when you reduce the dosage of the larotrectinib, this side effect, in most of the cases, reduces and disappears.

So, the tolerance and the safety of this drug are very, very good. So, for us, it’s the ideal drug. It goes fast.
It’s easy to give because it’s an oral drug. It’s not like chemotherapy, which needs vincristine, actinomycin or cyclophosphamide weekly injection, central venous access. You may have VOD.
You may have some side effect, gastrointestinal side effect with conventional chemotherapy, which is a new drug, target therapy. It’s not the case.

Shushan Hovsepyan: Yeah, that’s really exciting. The idea of shrinking tumors without the harsh side effects and also very quick is incredible. And where do you see the treatment landscape for infantile fibrosarcoma going?
What areas of research and innovation do you think will further improve outcomes for these young patients?

Daniel Orbach: Today, as we have a very efficient drug, we are all switching to use this drug before conventional chemotherapy. Of course, there are some remaining questions. The first question is the duration of the treatment.

When you have the ability to have a tumor that reduces very nicely, and this is most of the case, the fact in infantile fibrosarcoma, if you are able to propose a conservative surgery, please do it. Because we know that in other entract tumors, the rate of relapse is possible, is important.

So not in infantile fibrosarcoma, which is very, very common sensitive to larotrectinoma and entractinoma, but we know that when the tumor reduces sufficiently to propose a conservative surgery, it’s the time to do it.
So the duration of the treatment is not really known. We give the drug up to the surgery, and if the surgery is complete, we call that pathology complete remission. We stop the drug and follow the patient.

When we have metastatic disease, which is not so common, 1 to 3% of all the cases, of course we give this drug, but we don’t know exactly the duration. Sometime two, three years, there is a study ongoing in US trying to validate the value of the long-term therapy, which means that they are giving this drug one year after the complete clearance of all the lung metastasis. The other question that we have now is the comparison between drugs.

We don’t know if it’s better to start with larotrectinib, which was the first drug used in this disease, so we have the most experience in this drug, or entractinib, and there is new drugs that are called second generation entract inhibitor, and we don’t know exactly the role and the place of all these drugs, but we will probably have the ability to propose comparative studies in the future.

Shushan Hovsepyan: Yeah, a lot of questions, and hopefully we will have the answers soon. And finally, on a more personal note, could you share what inspired you to become a pediatric oncologist, and in particular to work with sarcova patients?

Daniel Orbach: Thank you for this question. Of course, it’s always a difficult question. When I was a student, I went in some pediatric oncology department as, of course, a resident, and I was very impressed by the way we considered the contact, the relationship with families, with patients, pediatric patients, and I enjoyed it very much.

So for me, there were no doubt that I wanted to do such a therapy. Of course, pediatrician, because it was my wish before starting medicine, but when I see how we discuss with family, how we are treating patients, and in a holistic way, it was for me the specialty that I wanted to do it. And during the year, becoming a pediatric oncologist, I specialized in sarcoma because I, to be honest, I met a lot of persons who were very interesting.

There is, it’s a moving specialty, so we change our main way to think about some disease every year, so it’s always a modern way. And the last thing that I wanted to say is that I met so many people very nice as the editor-in-chief of this OncoDaily website.

Shushan Hovsepyan: Thank you very much for that. It’s really inspiring and motivational. And thank you so much, Dr. Orbach, for sharing your insights. It was very informative and helpful. And for our listeners, stay tuned for more 5 Minutes Sarcoma Talks on OncoDaily. Thanks a lot.

Daniel Orbach: Thank you very much to all of you. Bye.