Treating Bone and Soft Tissue Sarcomas

Jonathan C. Trent, MD, PhD

Breelyn A. Wilky, MD

Sylvester Comprehensive Cancer Center

University of Miami Miller School of Medicine

Miami, FL

Determining the best course of treatment for sarcomas of the bone and soft tissues is a complex process. Clinicians have identified more than 100 different types of sarcomas such as gastrointestinal stromal tumors (GISTs), as well as benign tumors such as desmoid fibromatosis, chordoma, giant cell tumors of bone, or pigmented villonodular synovitis. Because making an accurate diagnosis is essential to developing effective personalized treatment strategies, practice guidelines from the National Comprehensive Cancer Network call for patients with sarcoma to be evaluated at sarcoma centers with experienced, multidisciplinary teams.

The Patient’s Journey

Imaging and Biopsy

The Bone and Soft Tissue Sarcoma Program at the Sylvester Comprehensive Cancer Center— South Florida’s only Cancer Center of Excellence— provides an example of how this patient management approach can be put into practice, leading to better outcomes. Each year, our team sees more than 600 new pediatric, adolescent, and adult cases, serving as a vital resource for patients from throughout the United States, the Caribbean, and Latin America.A typical patient journey begins with a phone call from a patient or referring physician to the sarcoma nurse navigator, who gathers information and organizes the process.

The first step involves appropriate imaging. A musculoskeletal radiologist may identify unique imaging features on CT or MRI scans that suggest sarcoma. Together, the radiologist and orthopedic oncologists determine the best approach for a biopsy.

Molecular Analyses

IDH Mutations

An accurate biopsy is vital. A mistake in the biopsy approach can lead to contamination of surgical planes, necessitating a more extensive surgery or even higher risk for recurrent disease. Biopsy material and any archival tissue from outside institutions are then forwarded to our board-certified pathologist, Andrew E. Rosenberg, MD, chief of Anatomic Pathology, and director of the Bone and Soft Tissue Service. Dr Rosenberg has extensive experience in diagnosing musculoskeletal neoplasms and metabolic bone disease.At this juncture, additional molecular or immunohistochemical analysis is employed to make every effort to subtype the sarcoma. At Sylvester, the diagnostic process includes molecular analysis of tumor tissue for mutations, translocations, amplifications, or deletions. These additional analyses can drastically alter treatment plans.For example, Dr Rosenberg played a pivotal role in describing a gene mutation in the isocitrate dehydrogenases (IDH) enzyme and discovering that it expressed very frequently in chondrosarcoma.

KIT Mutations

With that finding, our researchers have been studying the mutation in chondrosarcoma cell lines in the lab and have partnered with industry to conduct the first clinical trials of IDH inhibitors. Now, all suspected chondrosarcomas are submitted for IDH testing up front so that patients with this mutation may be offered clinical trials of IDH inhibitors, if appropriate, for the current disease stage.Another example occurs in patients with GIST, the most common sarcoma of the GI tract. All patients are tested for the KIT gene mutation at diagnosis. If the mutation is in the exon 11 region of that gene, we treat it with 400 mg of imatinib aday. If the mutation lies in the exon 9 region, we treat the patient with 800 mg a day.

Determining Treatment

Additionally, other mutations have been identified that predict resistance to imatinib and support enrollment in other clinical trials, saving the patient from unnecessary and ineffective treatment. Ten years ago, medical oncologists did not have the capability to inhibit these gene mutations that are driving the cancers.Sylvester, which is part of UHealth—University of Miami Health System and the University of Miami Miller School of Medicine, can draw on the knowledge of professionals throughout the academic medical center in treating patients with sarcoma. Our core 15-person multidisciplinary team holds a sarcoma conference twice a week to evaluate the management of current patients and discuss optimal treatment strategies for new patients.

Our medical oncologists, pediatric oncologists, radiation oncologists, surgical oncologists, musculoskeletal radiologists, and pathologists may use chemotherapy, surgery, or radiation therapy, depending on the individual case. The prospective treatment options include:

• Preoperative chemotherapy, targeted therapy, or immunotherapy, which can dramatically improve surgical outcomes, guided by a sarcoma medical oncologist
• Preoperative radiation therapy by a sarcoma radiation oncologist
• Resection of primary and/or metastatic sarcoma by an orthopedic, surgical, head and neck, genitourinary, or gynecologic sarcoma oncology specialist
• Postoperative chemotherapy, targeted therapy, or immunotherapy to decrease the risk of recurrent disease, by a sarcoma medical oncologist
• Follow-up visits with a sarcoma medical oncologist

In developing a treatment plan, it is also important to consider the psychosocial issues facing an individual patient. For example, adolescents and young adults with sarcomas are likely to have deep concerns about their fertility, education, and careers. Having a social worker and health system navigator on the sarcoma team can provide both patients and family members with needed support.

Clinical Trials

Additionally, Sylvester has an accomplished psychiatry/psychology division through the Courtelis Center, specifically focused on treatment of mental illness and adjustment problems that are common in patients undergoing cancer therapy.At Sylvester, well-designed, patient-relevant research studies are incorporated into our discussion of treatment options, including clinical trials for newly diagnosed cases as well as for metastatic or recurrent sarcomas.

Our portfolio includes cooperative group studies, industry-sponsored studies, and investigatorinitiated studies. Additionally, as members of the Sarcoma Alliance for Research through Collaboration (SARC), our oncologists can serve as a liaison for patients to clinical trial opportunities elsewhere in the international sarcoma community.

Figure. MRI Images of a 48-year-old Firefighter With High-Grade Pleomorphic Myxofibrosarcoma

The tumor dramatically decreased in size and enhancement after six cycles of preoperative doxorubicin/ifosfamide chemotherapy and preoperative radiation, permitting a complete resection and removal of 100% necrotic tumor without damage to neurovascular structures.

Research Directions

Currently, there are nearly 20 clinical trials available for sarcoma patients at Sylvester, including two trials for patients with the IDH gene mutation, who currently have no other treatment options. Sylvester has two of the few patients with chondrosarcoma in the world enrolled on IDH inhibitor studies.Drawing on the “bench-to-bedside” treatment concept, Sylvester’s researchers are focusing on genetics, stem cells, immunotherapy, and other strategies. Whereas immunotherapy has only recently made national headlines, we have been enrolling patients with sarcoma on a highly innovative vaccine protocol for more than a year. After patients undergo surgery, their dendritic cells are harvested and incubated in the lab with protein lysates isolated from the patient’s own tumor to make personalized vaccines. The “educated” dendritic cells and additional tumor protein “boosters” are then administered over the next several months.

Additional trials involving immunotherapy are in the planning stages and will be available in the coming months for patients with sarcoma. Along with investing in sarcoma research, we are building a comprehensive sarcoma patient registry and tissue bank, with the ultimate goal of analyzing the molecular biology of sarcoma cancer cells and using that knowledge to design new treatments.

In the near future, consenting sarcoma patients can have their tumor tissue submitted for sequencing, to detect the “mistakes” in the genetic code driving the tumor growth. Any identified mistakes may be used to direct patients to clinical trials specific for those abnormalities. Additionally, these data will be collected and maintained in the sarcoma databases for future analysis.

About the Authors

Jonathan C. Trent, MD, PhD, is co-director of the Musculoskeletal Center, Sarcoma Medical Research Program at the Sylvester Comprehensive Cancer Center, and professor of Medicine, University of Miami Miller School of Medicine. He serves as editor of The GIST Cancer Journal.

Breelyn A. Wilky, MD, is an oncologist in the Sarcoma Program at the Sylvester Comprehensive Cancer Center, and assistant professor of Medicine, University of Miami Miller School of Medicine.