Initial Guideline Development Showcases Future Directions in Ultra-Rare Sarcoma Subtype

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As part of a global consensus meeting, experts from several disciplines convened to define evidence-based guidelines for the treatment of patients with primary and metastatic epithelioid hemangioendothelioma with locoregional and systemic therapies, as well as palliative care.

William D. Tap, MD

William D. Tap, MD

As part of a global consensus meeting, experts from several disciplines convened to define evidence-based guidelines for the treatment of patients with primary and metastatic epithelioid hemangioendothelioma (EHE) with locoregional and systemic therapies, as well as palliative care, according to the resultant consensus paper published in ESMO Open Cancer Horizons.1

“The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients,” lead study author Silvia Stacchiotti, MD, a medical oncologist in the Adult Mesenchymal Tumor and Rare Cancer Unit of the Cancer Medicine Department at the Fondazione IRCCS Istituto Nazionale Tumori in Milan, Italy, and coauthors wrote.

EHE is an ultra-rare subtype of translocated, vascular sarcoma that can present as a low- or high-grade malignancy anywhere in the body. The disease is characterized by an epithelioid endothelial cell population located in a distinctive myxohyaline stroma that harbors WWTR1-CAMTA1 or YAP1-TFE3 gene fusions. Currently, no systemic therapies are approved for specific use in EHE, but patients with EHE are often refractory to traditional sarcoma therapies.

“EHE is a very complicated disease,” study author William D. Tap, MD, a medical oncologist and chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center said.2 “Some people can have very slow-growing disease and can go for long periods without treatment. Or they may do very well with surgery to remove the tumor and nothing else. But for others, it can be very aggressive and dangerous.”

Because of its rarity and lack of available therapies, establishing clinical guidelines for the management of EHE has been challenging and therapeutic approaches to treating patients with this disease vary globally.

Notably, no randomized phase 2 or 3 studies have ever been conducted in EHE. Data from 2 phase 2 studies are available, but the quality of evidence is lacking compared with that in common cancer types. Moreover, most clinical decisions in EHE are based on retrospective findings or case studies.

The global consensus meeting, which was organized in December 2020 under the European Society for Medical Oncology, brought together over 80 experts from Europe, North America, and Asia, as well as a patient representative from the EHE Group and Sarcoma Patient EuroNet.

Regarding treatment, complete resection remains the main goal for patients with confirmed unifocal EHE of the soft tissue. Surgery with microscopic negative margins yields an expected cure rate of up to 80%, but individual progression is difficult to predict. Additionally, specific surgical considerations are needed for patients with EHE of the soft tissue or bone, liver, and thorax. Patients with asymptomatic locoregional or systemic metastases and those who are not fit for surgery should be considered for active surveillance.

Although there are limited data evaluating the role of radiation therapy alone in EHE, EHE is thought to be a radiosensitive disease and radiation can often be combined with surgery based on individual patient considerations, such as tumor resectability and risk of recurrence.

Other locoregional therapies, such as percutaneous ablation, transarterial chemoembolization, radioembolization, and intensed pulsed light therapy are potential options, but only retrospective data exist on their use as an alternative to surgery and/or radiotherapy.

Regarding systemic treatment, no data have suggested utility with neoadjuvant or adjuvant therapy for patients with localized, resectable EHE. Up-front surveillance is indicated for patients with asymptomatic metastatic disease. However, patients with serosal effusion and/or marked systemic systems, who tend to have rapidly progressive disease, could be considered for early systemic therapy.

In the metastatic setting, patients with evident disease progression, worsening symptoms, and/or organ dysfunction should be considered for systemic treatment, but no standard approach is established. EHE does not appear to be sensitive to conventional chemotherapy, but antitumor activity has been observed retrospectively with treatments including interferon, thalidomide (Thalomid), TKIs, and mTOR inhibitors.

Personalized palliative care, including clinical and psychosocial support, should be considered a critical step in the treatment of patients with EHE, particularly those with symptomatic disease or serosal effusion. Palliative care should be multidisciplinary in nature and involve all relevant specialties to the individual case.

Ultimately, participation in clinical trials is recommended whenever possible, the study authors wrote.

“Clinical trials allow us to offer people with EHE cutting-edge therapies that are aligned with the biology and nuances of their disease,” Tap said. “They also allow us to collect prospective data about EHE and the best ways to treat people who have it.”

Currently, 2 clinical trials (NCT03331250; NCT03148275) are ongoing in EHE evaluating eribulin mesylate (Halaven) and trametinib (Mekinist).

Additionally, because clinical trials are likely to be uncontrolled based on the rarity of EHE, patient registries could yield important insight into external controls for these trials.

“Global collaboration will be critical to advance our knowledge, including [having] a better definition of [quality of life] for patients [with EHE], [collecting] prospective data, and understanding the role of [liver transplant] in isolated multifocal liver EHE,” concluded Stacchiotti and coauthors.


  1. Stacchiotti S, Miah AB, Frezza AM, et al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts. ESMO Open. 2021;6(3):100170. doi:10.1016/j.esmoop.2021.100170
  2. MSK experts develop new guidelines to treat rare form of sarcoma: epithelioid hemangioendothelioma. News release. Memorial Sloan Kettering Cancer Center. July 21, 2021. Accessed September 1, 2021.
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