Welcome to the world of sarcoma with the fourth episode of ‘5 Min Sarcoma Talk’ on OncoDaily. In this episode, host Dr. Hovsepyan and esteemed sarcoma expert Prof. Leo Mascarenhas discuss the importance of the ageless Sarcoma Program, the history of sarcoma biology, Prof. Mascarenhas’ inspiring path to pediatric oncology, and more. Join us for an educational and inspiring journey into the sarcoma field.

Leo Mascarenhas

Professor Leo Mascarenhas, MD is renowned for his leadership in pediatric oncology and sarcoma research. He is the Director of Pediatric Hematology and Oncology at Cedars-Sinai Guerin Children’s and the Medical Director of the Sarcoma Program at Cedars-Sinai Cancer in Los Angeles California. Currently, he is the Principal Investigator for the National Cancer Institute-funded Children’s Oncology Group (COG) at Cedar-Sinai and also the Chair of the Voting Body of COG.

His research is focused on mainly solid tumors, particularly rare tumors.

Shushan Hovsepyan

Dr. Shushan Hovsepyan is a pediatric oncologist and adjunct assistant professor at the Yerevan State Medical University. Currently, she is the Editor-in-Chief of OncoDaily Medical Journal. She completed a clinical fellowship e pediatric oncology unit of the National Institute of Cancer in Milan, then 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. Dr. Hovsepyan also completed the Postgraduate Harvard Medical School ‘s Effective Writing for Healthcare program.

0:15 Introduction
1:18 What are the key goals and objectives of the Sarcoma Program at Cedars-Sinai Medical Center?
4:54 Challenges encountered during the implementation of innovative treatment strategies
8:39 Evolution of sarcoma biology in recent years
10:20 Key findings from Prof. Mascarenhas’s recent meta-analysis
14:27 Exploring the Professor’s personal journey

The Transcript of 5 min Sarcoma Talk with Shushan Hovsepyan and Leo Mascarenhas

Shushan Hovsepyan: So hello everyone and welcome back to another episode of five minutes sarcoma talk on OncoDaily. I’m your host Shushan Hovsepyan, a pediatric oncologist from Armenia. And today we are honored to have Professor Leo Mascarenhas join us to delve into the complex world of sarcoma.

Professor Mascarenhas is renowned for his leadership in pediatric oncology and sarcoma research. He serves as the director of pediatric hematology and oncology at Cedar Sinai’s Children’s and the medical director of the sarcoma program at Cedars- Sinai Cancer in Los Angeles, California. And his research focuses mainly on solid tumors, mostly soft tissue sarcomas.

So welcome Professor Mascarenhas and thank you for being with us today.

Leo Mascarenhas: Thank you for the kind invitation for me to speak to you, Dr. Hovsepyan. It’s really an honor. Thank you.

Shushan Hovsepyan: Thank you. The honor is all mine. So let’s get started. As you are leading the sarcoma program at Cedars- Sinai Cancer, what are the key goals and objectives of the program and what distinguishes it from other sarcoma programs, especially in terms of patient care and research initiatives?

Leo Mascarenhas: The major point of our program at Cedars-Sinai is that it encompasses the entire age range, with a dedicated team of specialists caring for patients. Sarcomas can occur at any age, from newborns to older adults, and care can vary across different institutions.

While many children’s hospitals have great expertise in treating pediatric sarcomas, and there are large medical centers with adult sarcoma programs, sarcomas are unique in that they span all age groups. This can lead to varying needs across different life stages.

A significant number of patients are adolescents and young adults, who may fall through the cracks when transitioning from pediatric to adult care. This age group often navigates the challenges of gaining independence, such as managing healthcare on their own, attending college, or starting a job.

At Cedars, we offer one program with unified leadership that spans all age groups. We have a multidisciplinary team that meets weekly to discuss all our sarcoma patients. This team includes expert surgeons, radiologists, pathologists, genomic medicine specialists, and medical and pediatric oncologists working together.

Our comprehensive program ensures that patients receive coordinated care throughout their entire sarcoma journey.

Shushan Hovsepyan: It’s very encouraging to hear about programs setting new standards of excellence in the field of sarcoma, particularly in addressing the unique needs of adolescent and young adult (AYA) patients. It’s crucial to remember that a 40-year-old patient with rhabdomyosarcoma should be treated by a pediatric oncologist, not just a medical oncologist, highlighting the challenges faced worldwide.

Now, let’s focus on the challenges. As a leader in pediatric oncology, what challenges do you anticipate in implementing innovative treatment strategies for sarcoma patients? Additionally, how do you plan to address these challenges?

Leo Mascarenhas: That is indeed a challenge. Starting with sarcomas, broadly, they can be categorized into bone sarcomas and soft tissue sarcomas. Common types vary by age, with osteosarcoma and Ewing sarcoma being more prevalent in children and young adults, while chondrosarcomas and other rare sarcomas are more common in older adults.

Soft tissue sarcomas encompass over a hundred different types, all originating from the mesenchyme or mesoderm. Despite sharing a name, these sarcomas can vary significantly in biological features and prognoses. Some are indolent, causing little trouble even though they are malignant, while others are aggressive and require tailored treatment.

In the past, treatment approaches for sarcomas often started with surgery, followed by radiation therapy, and sometimes chemotherapy as an afterthought. However, over the last 50 years, we’ve learned that chemotherapy is crucial, particularly for high-grade lesions. Recent discoveries of specific oncogenic drivers have allowed us to target a few types of sarcomas, but more work remains to expand this approach.

One major challenge is moving away from lumping all sarcomas together and instead studying them in their purest form or as related groups. Genomic medicine can assist in this differentiation. Another challenge is that sarcomas are rare compared to other cancers, comprising only about 10% of cancers in children and 1% in adults.

Given their rarity, prioritizing sarcomas can be difficult, so advocacy is essential. Collaboration and broad clinical trials across multiple sites allow us to learn from these patients and make progress in sarcoma care. In this field, multidisciplinary care and collective efforts are key to making a meaningful impact.

Shushan Hovsepyan: Completely agree. Collaborative work in sarcomas is essential. So now that we’ve highlighted some of the challenges, let’s delve deep into the history a little bit. How has sarcoma biology evolved over the recent years, and what therapeutic implications does this have?

Leo Mascarenhas: Initially, sarcomas were all classified based on pathologists’ observations under a microscope, identifying the cells as resembling sarcoma. The next significant advance came with immunohistochemistry, allowing us to classify sarcomas more accurately by identifying the proteins produced by the cancer cells.

In the early 1990s, researchers began discovering specific genetic fusions in sarcomas, such as in rhabdomyosarcoma and Ewing sarcoma, which helped to differentiate these types more clearly. Over the years, we’ve improved our ability to diagnose conditions accurately, moving away from lumping them all together.

Now, with advancements in genomic medicine like Next Generation Sequencing and chromosomal microarray, we are gaining deeper insights into the different biological factors and their interactions. This knowledge provides valuable information on how patients may respond to treatment and helps us target these fusions more precisely for better patient outcomes.

Shushan Hovsepyan: That’s very helpful. Thank you for sharing that. I also wanted to discuss one of your recent articles, which I’m also interested in.

Could you please share with our listeners what were the key findings of your recent meta-analysis regarding the efficacy of vinorelbine in treating relapsed/refractory ALV and embryonal rhabdomyosarcoma?

Leo Mascarenhas: Using vinorelbine and cyclophosphamide in rhabdomyosarcoma at the time of relapse has proven to be a reasonable strategy. This approach builds on the work done in Italy by Dr. Casanova and colleagues, who observed that combining vinorelbine with oral cyclophosphamide may benefit patients with rhabdomyosarcoma.

Before that, the Children’s Oncology Group conducted a phase two trial with vinorelbine, which also showed positive responses in rhabdomyosarcoma compared to other tumors treated. I was fortunate to run a phase two clinical trial through the Children’s Oncology Group, which was a collaborative effort with the Soft Tissue Sarcoma Committee.

We tested vinorelbine, intravenous cyclophosphamide, and two molecularly targeted therapy agents. This was the first time in pediatric sarcoma where we combined chemotherapy with molecularly targeted therapy, and the trial turned out to be positive. Temsirolimus, in combination with vinorelbine and cyclophosphamide, showed an advantage over the other arm, which included vinorelbine, cyclophosphamide, and bismuth.

Looking at these studies, patients with alveolar histology seemed to have a higher response rate. However, alveolar histology, particularly when associated with a FOX01 fusion, is also linked to a higher risk of relapse. We needed to determine whether this effect was genuine or biased by a higher representation of patients with alveolar disease.

By collaborating with our statistical colleagues, we analyzed over 150 patients from five different trials and found that the chance of responding with alveolar histology was about 40% higher compared to embryonal histology. This does not mean that patients with embryonal histology do not benefit.

To assess the risk of progressive disease, we examined what happens to patients once they start treatment. There was no difference in risk between alveolar and embryonal histology. However, vinorelbine caused higher responses in alveolar histology, which was backed by strong pre-clinical data.

This data paved the way for the high-risk metastatic disease trial being conducted by the Gynecologic Oncology Group AR S2031, which randomizes patients to receive vinorelbine, actinomycin, and cyclophosphamide versus the traditional vincristine, actinomycin, and cyclophosphamide. We hope to have results from the study within the next one to two years.

Shushan Hovsepyan: So the results are actually very promising for vinorelbine, and I also personally think that vinorelbine has some role in embryonal patients and bringing it up front will answer a lot of questions.

So now that we have explored some research findings, let’s take a moment to learn about your personal journey and experiences that led you to pursue a career in medicine and particularly in the field of pediatric oncology.

Leo Mascarenhas: I’ve wanted to be a physician since I was five or six years old, and I maintained that passion throughout my life. I was fortunate to attend an outstanding medical school where I received personalized attention and had excellent growth opportunities. During my studies, I discovered my love for pathology, particularly the oncology aspect. However, I decided against becoming a pathologist and instead sought a clinical field where I could study oncology.

Initially, I considered becoming a surgical oncologist or a gynecological oncologist. However, during my rotations, I fell in love with pediatrics, which led me to specialize in pediatrics. I then completed a fellowship in pediatric hematology and oncology at Children’s Hospital Los Angeles, gaining valuable experience in the field.

During my pediatric rotations in medical school, I encountered a six-year-old girl diagnosed with rhabdomyosarcoma. At the time, we had nothing to offer her, so we sent her home on palliative care. That experience left a lasting impression on me, and years later, I found myself working with rhabdomyosarcoma patients.

One of my mentors advised me early on to tackle tough problems rather than easy ones, as those are the areas where significant efforts are needed. Metastatic sarcomas had a terrible prognosis during my training and still have a poor prognosis today, motivating me to focus on clinical trials and research in this challenging area.

I am grateful for the opportunities that have come my way and for the many colleagues and mentors who have helped me throughout my career. My work in pediatric solid tumors and sarcomas has been highly engaging and fulfilling. I hope to continue contributing to this field for many more years.

Shushan Hovsepyan: Yeah, that’s very much motivational. And, as you mentioned about your mentor, my mentor Professor Tamamyan is also saying that don’t take easy patients, always take the difficult patients because that is the way to learn and force yourself to find the solutions for even for impossible things.

Leo Mascarenhas: So, yeah, and that’s very, very good advice. Alright, I mean, we live in a field where we need hope. All of us need hope, including our patients, so that we could actually all do better, you know, to really, hopefully, make things better for all our patients and for science and for the world in general.

Shushan Hovsepyan: Yeah, exactly. And on this positive note I would like to thank you for accepting our invitation. It was an honor for me, and thank you for your dedication and commitment to making a difference in the lives of sarcoma patients.

Leo Mascarenhas: Thank you, Dr. Hovsepyan, and all the best to you and all your efforts too. And I’m sure we’ll meet each other at several different meetings around or, if not, virtually for sure. Thanks a lot. Bye-bye.

Shushan Hovsepyan: Bye.

Previous episodes of  5 min Sarcoma Talk with Shushan Hovsepyan

Episode 1: Leo Kager

Episode 2: Rajkumar Venkatramani

Episode 3: Aaron Weiss