Sarcoma treatments evolve as understanding of disease biology improves

NEW YORK — The treatment landscape in sarcoma is evolving rapidly as the research community recognizes the importance of matching therapies to specific molecularly defined histologies, according to a presenter at Chemotherapy Foundation Symposium.

“There actually is a lot going on in sarcoma right now, mainly because there are a lot of subtypes of sarcoma and we are trying to get better at specifically addressing each subtype,” Andrew J. Wagner, MD, PhD, medical director of ambulatory oncology and senior physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, said during a presentation.

An estimated 16,000 new cases of bone and soft tissue sarcomas are diagnosed in the United States each year, accounting for 1% of cancers among adults. However, misdiagnosis and misclassification leads to underreporting of the true incidence, Wagner said.

Sarcomas are a group of many different diseases. There are an estimated 50 to 100 subtypes, the most common of which are liposarcoma, leiomyosarcoma and unclassified pleomorphic sarcoma.

“Because they are rare, we tend to study them all together,” Wagner said. “But we all realize that is a mistake. As a comparison, we never would study ‘carcinomas’ as an entity. We would look at those as separate diseases, and we should get to a point where we can do that in sarcoma, as well. It’s just that the rarity of the tumors makes it more difficult to study each one individually.”

Pathology review is essential for patients with newly diagnosed localized sarcoma. In nearly one-quarter of cases, diagnoses change upon pathology review, considerably altering the prognosis or treatment approach.

“As with other cancers, we have to look at every patient as an individual, putting into context their comorbidities, the location of their tumor, the subtype and grade of the tumor, and the tumor’s growth pattern — meaning, does it have more indolent behavior or more aggressive behavior?” Wagner said. “We also recommend at least a consultation with a referral center, with care then shared with the local oncologist.”

Surgery with radiation therapy is standard for localized disease if it is in an extremity or the trunk. However, function of the limb must be factored into decisions about surgery. There is not yet a clear role for radiation for retroperitoneal or uterine sarcomas, and several studies showed no significant benefit to radiation for uterine sarcomas.

About half of patients diagnosed will develop metastatic disease. This raises questions about adjuvant therapy for high-grade tumors, as well as optimal treatment for metastatic disease, for which median OS is about 12 to 18 months.

There is a clear indication for adjuvant systemic therapy in select subtypes, Wagner said. These include vincristine, actinomycin-D and cyclophosphamide for embryonal rhabdomyosarcoma; vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide for Ewing sarcoma; methotrexate, doxorubicin and cisplatin for osteosarcoma; and imatinib for high-risk gastrointestinal stromal tumor.

Adjuvant therapy remains controversial for other subtypes, with opinions varying based on geographic region or practice preferences at individual centers.

“Some people feel very strongly that adjuvant chemotherapy should be used, others less so,” Wagner said. “It would be difficult to design a properly powered study that has acceptable chemotherapy arms that really addresses overall survival and targets specific histologies, so we probably are stuck with opinion and shared decision-making with patients.”

With rare exceptions, chemotherapy remains the mainstay of treatment for unresectable metastatic disease, with goals to extend survival and either palliate symptoms or prevent symptom onset. High-dose or combination chemotherapy regimens tend to be more toxic but are not clearly more effective, Wagner said.

“We still tend to use a one-size-fits-all approach for standard chemotherapy with anthracyclines with or without ifosfamide, or gemcitabine with docetaxel,” Wagner said.

The FDA has approved several other therapies, including doxorubicin in combination with the anti-platelet-derived growth factor receptor antibody olaratumab (Lartruvo, Eli Lilly) for soft tissue sarcoma, pazopanib (Votrient, Novartis) for soft tissue sarcoma; trabectedin (Yondelis; Janssen, PharmaMar) for leiomyosarcoma and liposarcoma; and eribulin (Halaven, Eisai) for liposarcoma.

Studies have shown no clear survival benefit from combination therapy, Wagner said.

“Single-agent doxorubicin is still our preferred and recommended agent for patients who don’t need symptom control,” he said. “Combination therapy may be valuable if tumor shrinkage is required for rapidly growing tumors or for symptom control, if preoperative tumor reduction would alter the surgical approach, or certainly if you are choosing to use it in the adjuvant setting.”

Research efforts also are intensifying to identify effective targeted therapies for appropriate histologies, as well as to determine the potential role of immunotherapy in sarcoma treatment. A couple small studies showed patients with certain subtypes, such as liposarcoma and unclassified pleomorphic sarcoma, responded to immunotherapy, but the modality remains unproven, Wagner said.

“Clearly we need more studies in this area, as there is plenty of room for improvement,” he said. – by Mark Leiser

For more information:

Wagner AJ. Key concepts in the diagnosis and treatment of soft-tissue sarcoma. Presented at: Chemotherapy Foundation Symposium; Nov. 7-9, 2018; New York.

Disclosure:

Wagner reports grant or research support from AADi, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Karyopharm, Novartis and Plexxikon. He also reports consultant roles with Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics and Novartis.