ASCO [2022] Sarcomas Cancer In-Depth Slides: MOASC

Warren Chow, MD, ASCO [2022] Sarcomas Cancer In-Depth Slides: MOASC Presentation


ASCO (American Society of Clinical Oncology) [2022] Sarcomas Cancer In-Depth Slides: MOASC


Dr. Warren Chow's MOASC Presentation on ASCO 2022 Sarcoma Cancer

So I also wanna thank Jason and the organizers of MOASC (ASCO 2022 sarcoma cancer (American Society of Clinical Oncology) update) for inviting me. I'm feeling my age because I see a lot of my former fellows in academia and pharma and in practice here. These funny stories are that when I was at city hope with Joe Chao, he used to be called young Chao, and I was called old Chow.


Now I'm very old chow. Today, I'll speak to you about sarcomas (clinical oncology) and my disclosures with that outline introduction to sarcomas. I'll talk about soft tissue sarcomas and then move to bone sarcomas as a finish-up. Sarcomas (cancers) are very rare tumors in clinical oncology. They rise from transformed connective tissues.

About Sarcoma In Clinical Oncology

There are a little over 13,000 estimated cases in 2022, a crude mortality rate of about 39% based on the number of deaths and in bone sarcomas (cancers) even rarer 3,900, and a crude mortality rate a little bit higher at 54%. So I always like to put a face to this disease by former president of Venezuela, Hugo Chavez.


He passed from Rhabdomyosarcoma. His famous quote was he followed President George W. Bush at the UN, and the quote

"The devil came here yesterday, and it smells of sulfur still today, this table that I am now standing in front of." President George W. Bush


I laugh at that quote. For those who are a little bit younger, Virgil Ablo is the artistic director of Louis Vuitton, and he founded the Off-White fashion house.


He recently passed from cardiac angiosarcoma. So sarcoma (patients) disproportionately affected younger individuals in the decade of the 90s. It counted for 11% of all cancers in children and adolescents. And it's the fourth most common cancer in young adults under 40.


The problem is that there are over 70 different types of soft tissue sarcomas (cancers) in clinical oncology. Most are located in the extremities. A third is located in the lower extremities, and the rest are distributed throughout the rest. Staging is based on size nodal status and the presence of metastasis.

French Cancer Centers Data

But in addition, it's also based on the grade of the tumor. So we have a grade 1 through grade 4, so T size is 5, 10, and anything over 15 as the cutoffs. The prognosis on the left is based.


This is from the French Cancer Centers. They showed that the prognosis of metastasis-free survival (median overall survival) is based on the grade.


So on the top is grade 1 on the bottom is grade 3. There is a grade 4, but that's strictly reserved for Ewing sarcoma (patients). And on the right, is sarcoma (cancers) was the first nomogram ever published.


Memorial Sloan Kettering Group Data

This is from the Memorial Sloan Kettering Group showing that points were awarded for various factors, including the size, the depth, the site, the subtype, and the median age. And they awarded given points for these various prognostic factors, and they predicted 12 years of sarcoma-specific death, not survival.


So you can see on a second to the bottom if you had a low-grade tumor and a high-grade tumor at the very bottom, so this was back in 2002. This is online now. So if you have a patient, you can go on the Memorial Sloan Kettering website and then download that, plug in the prognostic factors, and present them to your patient.


Here, I just want to emphasize that the treatment of softy sarcoma (patients) is surgery. Gotta get the patient to surgery. That's the only curative modality.


In other modalities, concurrent neoadjuvant radiation therapy (novel therapies) is a benefit, and I'll show you what the effects of chemotherapy (treatment) are in the second. Just to go way back here, just taking a holistic approach.

NCI Randomized Clinical Trial

This was the NCI randomized study data presented of radical, which was amputation radical surgery versus conservative or limb preservation surgery plus concurrent neoadjuvant radiation therapy (novel therapies). So it was a phase 2 randomized trial (outcomes), 2 to 1 to limb preservation versus amputation. So in the amputation arm, there were 16 subjects.


In that amputation arm, of course, there are no local recurrences. So when I say, of course, you have no extremity. You have no recurrence for those randomized to conservative surgery, there were 27 subjects, and 4 had a local recurrence. So the disease-free survival (median overall survival) was these disease-free recurrences was survival was 85%.


But those patients were salvaged with the amputation. Importantly, the last 2 points are metastasis-free survival between the 2 arms was no difference, so 5 years was 71% versus 78%. And overall also have the most important point is again no difference, 83% versus 88%.


So you can see on the curves on the right that disease-free survival because the local occurrences favored amputation, but you can see the overlapping curves for metastasis-free survival and overall survival.


So now, what is the role of adjuvant chemotherapy (treatment)? So up until 2012, sarcoma oncologists all believed that adjuvant chemotherapy (treatment) would be a benefit.

EORTC 629031 Cancer Clinical Trial Outcomes

And we relied finally on this very large European clinical trials, the EORTC 629031 of adjuvant chemotherapy (treatment) versus observation. So over 350 patients were randomized to 5 cycles of Filgrastim Ifosfamide's so-called AIM, an acronym for adriamycin, ifosfamide, and mesna, versus observation of the distribution of the types of sarcomas (cancers).


We're pretty what we would expect 15% Leiomyosarcoma. 13% liposarcomas, 11% malignant fibrous histiocytoma, which we now call ENT pleomorphic sarcomas, and 11% were synovial sarcomas.


So those synovial tend to happen in younger individuals. And they're the most, one of the most chemosensitive of our soft tissue sarcomas (cancers), the distribution, 2/3 of extremities.

Remainder tributed in the trunk in the pelvis 40% were larger than 10 centimeters, 73% of the patient randomized to chemotherapy (treatment) completed the prescribed 5 cycles of chemotherapy (treatment), and of that 63% without any dose reduction in July. Disappointingly the 5 years of recurrence-free survival was 53% for observation and 55% for chemotherapy (treatment).

And just as importantly overall survival, there was no difference. Here are the curves for this clinical trial, overall survival left recurrence for survival on the upper right and a local, regional recurrence on the lower. And the development of metastasis on the low. So curves are essentially super impossible.


Here's the forest plot looking if there was any subtype factor that might favor chemotherapy (treatment). The only one that looked had any potential difference was isolated limb perfusion.


That's where you isolate the vessels going in an extremity perfuse heated. Usually, maud land and Europe is TNF Alpha.


But TNF Alpha is unavailable here in the United States and may favor adjuvant chemotherapy (treatment). But again, that's primarily in Germany, what they do.


Given that statistics, what do we do for patients who develop metastasis? So again, as I said surgery, it's lung metastasectomy.


So the international registry of lung metastasis was reported.  back in 1997, they had over 2000 sarcoma (patients) cases and looked at those patients who underwent pulmonary metastasectomy (lung cancer), and they found a 5 years overall survival of 37% and  10 overall survival of 26%.


And when they looked at the risk factors for recurrence after pulmonary metastasectomy, the factors were found. The risk of recurrence was incomplete resection. Suppose you had a high number of metastasis, i.e., 4 plus, and the disease-free interval. Disease-free interval is a time from the original, the primary resection to the time of developmental pulmonary metastasis.

Thames Cancer Registry (TCR) On Pulmonary Sarcomas

An updated report was from the Thames Cancer Registry (TCR) in the UK. They had 1,357 pulmonary mastectomies over a 3 decades period. Up to 10 or more thoracotomies were performed, and the report the 5 years overall survivor for patients undergoing pulmonary metastasectomy for soft tissue sarcomas was 25% and 34% for bone SAR.


Whereas 50% of all primary sarcomas will be cared for with multimodality therapy. Unfortunately, the other half will eventually develop metastasis, and there's no curative treatment for patients with advanced sarcomas without surgery. What are the statistics for patients who cannot proceed to pulmonary metastasectomy?


The 2 years survival is less than 25%. And the 5 years survival is less than 10% for those patients who are ineligible for pulmonary metastasectomy or trying to get a pulmonary metastasectomy. We do offer chemotherapy (treatment).


EORTC-62012 Trial Outcomes

And so this is another very large EORTC-62012 trial (outcomes). Patients (in these clinical trials) were randomized to single-agent Doxorubicin. And the dose is 75 milligrams per square. And that's the standard dosing for soft sarcomas. Or they were randomized in combination chemotherapy (treatment) of Doxorubicin plus Ifosfamide (combination) again. Doxorubicin is 75 mixed per meter squared.


Ifosfamide was 10 grams per meter squared, the very dose-intensive chemotherapy (treatment). And you can see the (improve) outcomes on the right side for the Doxorubicin arm.


The objective response rate was 13.6% for the aim. Chemotherapy (treatment) is 26.5%. So doubling the response,  just below that, the median progression-free survival for Doxorubicin alone is 4.6 months.


And for the combination is 7.4 months. But note the bottom point overall survival Doxorubicin alone, 12.8 months combination 14.3 months. So that was not statistically least significant. Based upon this study, the standard of care for most patients with metastatic soft or com who require chemotherapy remains Doxorubicin.

GeDDiS Cancer Study

So you may have seen the use of Gemcitabine and Docetaxel. Usually, reserve that for the second line. So this, the GeDDiS study data presented is a UK study of moving Gemcitabine, Docetaxel (combination) front versus Doxorubicin. So the previous EORTC study was published first. So they're randomized to GEMTAX versus Doxorubicin.


The dosing you can see Doxorubicin is 75 Per meter squared GEMTAX 675 on day 1 and 8 Gemcitabine of Taxol 75 on day 8. And given every 3 weeks, you can see on the left, the median progression-free survival was essentially the same. Overall survival was essentially the same, but if you look at the curve at the bottom.


There is a bit of separation here after 36 weeks favoring Doxorubicin. Based upon this study, at least in the UK, the British steel field Doxorubicin is the first line of care, and Pazopanib, also known as Votrient, is FDA-approved for soft tissue sarcoma patients.

PALETTE Cancer Study

With the exception of liposarcoma (cancers), who've received at least 1 first frontline chemotherapy (treatment) or are chemotherapy ineligible. So in this study, the PALETTE study the data presented is a global phase 3 study for soft tissue sarcomas. Again, excluding liposarcomas because they are insensitive to this. They randomized in a 2-to-1 fashion to Pazopanib versus placebo.


You can see that the progression-free survival on the top favors Pazopanib versus placebo, 4.6 months versus 1.6 months. Overall survival was not statistically significant and based upon the PALETTE trial. This was FDA-approved back in 2000, Trabectedin is a drug that's HALAVEN is used for breast cancer care.


And the investigators looked at its use, particularly for liposarcomas (cancers) or leiomyosarcoma commerce. So you can see that the control arm is Dacarbazine, a very old drug with about a 5% response rate and is rarely used nowadays, but that was a control arm versus Trabectedin. You can see that progression-free survival is favored.


Trabectedin there was no difference in overall survival, but you can see that in the forest plot that when they looked at leiomyosarcoma (cancers) it did, I'm sorry, this is yes, Trabectedin not the Eribulin, Leiomyosarcoma (cancers), it favored Trabectedin it also favored liposarcomas.


But it was a particular type of liposarcoma(cancers), and the myxoid round cell that made up most of the liposarcomas that benefited from this response rate was about 10%, and PFS tripled from 1.5 months to 4.2 months. Here's Eribulin. I apologize again. This is a breast cancer drug. And this is again for patients with advanced liposarcomas or leiomyosarcoma.

What Were the Survival Outcomes?

Again the comparator was Dacarbazine, and you can see in blue that this is the overall survival (outcomes) favored Eribulin over Dacarbazine, and the progression-free survival was almost overlapping the PFS.


There was no difference, but the overall survival favored Eribulin by 2 months, and that was just as significant.


You look at that forest plot. It was only the liposarcoma subset that benefited leiomyosarcoma across unity. So based on this trial Eribulin is approved for patients with recurrent liposarcoma after frontline chemotherapy (treatment).


Chemotherapy (treatment) has modest benefits. What about immunotherapy? So this was addressed in the Sarcoma Alliance (SARC) through research, through collaboration. Our SARC 028 trial is an open-label phase 2 trial. They had several cohorts.


Soft tissue sarcomas included leiomyosarcoma and equals 10, UPS sarcomas (Undifferentiated pleomorphic sarcoma), liposarcomas, and synovial sarcomas that also did bone sarcomas, which were chondrosarcoma Ewing and osteosarcoma you could see the response rate.


For overall partial response rate for soft sarcomas with 15%, but it was primarily in the UPS sarcomas (Undifferentiated pleomorphic sarcoma) and the liposarcomas that benefited. There was one outta 10 synovial sarcomas that demonstrated a partial response for the bone sarcomas, 1 patient responded out of 5.


So accounting for a slightly higher response rate, we still don't feel it benefits patients with conjure sarcoma (cancers). They close that cohort early for 2 subtypes UPS sarcomas and degenerating liposarcomas. It may be a benefit.   Can we hone in on which of those subtypes might benefit the most?


This is a Nature Medicine paper that was just recently published in June. So this is from the European group, and they also looked at Pembrolizumab in soft tissue sarcomas regionally in their first attempt at using unselected patients with soft tissue sarcoma (patients) treated with Pembrolizumab. Their overall response was only 2.4%.


However, if you look for what are called tertiary lymphoid structures, the tertiary lymphoid structures look like lymph nodes within the soft tissue sarcoma (cancers). You can see the staining. It looks like a dermal follicular.


So if you have those in pathology in your tumor and you're treated then with Pembrolizumab, the response rate increased from 2.4% to 30% in patients with tertiary lymphoid structures. So this is the report. Potentially a marker for response to immunotherapy.

Why Is That Important (In These Clinical Trials)?

I'll move now on bone sarcomas. So we have 3 types of bone sarcomas. The first is chondrosarcoma conventional chondrosarcoma accounts for 90% of all chondrosarcoma.


Most are low grade, 1 or 2, 90%, with low metastatic potential. Up to 10% are grade 3 and do have high metastatic potential. Up to 86% of these cases have mutations in the isocitrate dehydrogenase gene, an oncometabolite gene.


Why is that important? Because IDH1 inhibitors Ivosidenib has been tested in this and showing, although there were no responses. This is from William Taft Memorial.


There was a prolonged disease free survival (outcomes) with Ivosidenib differentiated chondrosarcoma, our conventional sarcomas that have secondary dedifferentiation and look like osteosarcoma.


Because they're biomorphic now with either osteosarcoma or UPS features and chemotherapy (treatment) has been recommended by the NCCN Bone Cancers Committee, mesenchymal chondrosarcomas are rare. They're also biomorphic, but instead of the osteosarcoma or UPS, like feature.


They have small blue, round cells that look like an Ewing sarcoma. And it's an NCCN 2B recommendation to receive Ewing sarcoma-based chemotherapy (treatment).


Unfortunately, late recurrences are observed in this disease, and an 18-year-old patient recurred at (median) age 28. So 10 years later, he recurred pulmonary metastasis.


And clear cell (chondrosarcoma (CCC)) is another rare subtype moving on to osteosarcomas. The vast majority are conventional osteosarcomas. They are intramedullary, and all high-grade surface osteosarcomas are divided into a parosteal or low grade or parosteal, which are intramedullary grades. Chemotherapy (treatment) is recommended for these conventional, and it's arguable.

EURAMOS-1 Cancer Trial

But most people will give for periosteal osteosarcoma chemotherapy (treatment) should not be given for periosteal osteosarcoma. The EURAMOS-1 is a European, American osteosarcoma trial, all patients who were 30 years of age or who presented with osteosarcoma localized received 2 cycles of MAP chemotherapy, which is high dose Methotrexate, Adriamycin, and Platinum, and then PA patients.


We all know that when you resect the tumor after neoadjuvant chemotherapy (treatment), you look, the pathologist looks at the percent necrosis. Your aim is to have more than 90% necrosis of the tumor.


If patients in this trial did not if they did not reach 90% necrosis, they were randomized to continue the same chemotherapy (treatment) MAP chemotherapy or add a phosphide atopic side to the MAP chemotherapy (treatment) postoperatively.


You can see the 3 years of event-free (improved overall) survival were no different. PCOS .80 and 3 years overall survival (outcomes) was, again, no different. And based upon this changing chemotherapy (treatment), postoperatively added, 2 other agents do not benefit patients with osteosarcoma with less than adequate necrosis.


Ewing sarcoma is the second most common sarcoma in the bone in children and adolescent young adults. Typically, diaphysis versus metaphysis for osteosarcoma is again characterized by reciprocal chromosome translocation creating a novel fusion gene, the EWS-FLI-1 chimera, and 10 to  20% of cases are extraskeletal. This is a patient of mine.


She was diagnosed with Ewing sarcoma. When she presented at 34 weeks of intrauterine pregnancy, she delivered, and then we treated her afterward, and she did very well.

AEWS1031 Trial Outcomes

How do we treat Ewing sarcoma? It's 5 drugs. I've been Vincristine, Doxorubicin, and Cyclophosphamide, alternating with Ifosfamide and Etoposide. So this is a Children's Oncology Group (COG a clinical oncology group) AEWS1031 trial reported in 2012. Patients with localized Ewing sarcoma were randomized to the standard arm and treated every 3 weeks for 2 cycles.


Local control and additional adjuvant chemotherapy or the same number of overall chemotherapies treated every 2 weeks. So basically, dose compression regimen B. Again, the total number of chemotherapy (treatment) cycles was exactly the same, based on dose compress.


The 5 years event for survival improved (improve outcomes) from 65% with a standard arm to 73% with a dose compression arm, also improving overall survival (outcomes) again. It's barely significant (in cancer care).


So for patients with localized Ewing sarcoma, we always try to do dose-dense chemotherapy every 2 weeks. Usually, towards the end, because it's 14 cycles overall of chemotherapy, your bone marrow poops out here. And usually end up doing it every 3 weeks for the last few cycles.


And that's a quick tour de force of sarcomas (in clinical oncology), again, a very rare cancer, and I'm happy to answer any questions you might have.


Warren Chow, MD - ASCO 2022 Sarcoma Cancer Cancer Question & Answer

Warren Chow, MD - About The Author, Credentials, and Affiliations
Dr. Warren A. Chow is a oncologist at UCI Health who is board-certified and specializes in treating patients who have melanoma and sarcoma. At the Chao Family Comprehensive Cancer Center at the University of California, Irvine, he will be working as the associate director for cancer clinical (0ncology) sciences.


He attended Chicago Medical School, which is now part of Rosalind Franklin University of Medicine and Science and is located in North Chicago, Illinois. This is where he earned his medical degree.


At the Cedars-Sinai Medical Center in Los Angeles, where he also served as a resident, he finished his internship and residency in internal medicine. After that, he went on to receive fellowship training in medical (clinical) oncology, hematology, and bone marrow transplantation at the City of Hope in Duarte, California.


There, he worked for nearly 30 years as a clinician and research conducting bench-to-bedside research in both bone and soft-tissue sarcomas. During this time, he also served as a faculty member.