Epithelioid Sarcoma: Clinical Insights on Diagnosis and Treatment
by Dr. Joseph Barone, BCOP
Background
Sarcomas include a heterogeneous group of rare solid tumor malignancies that arise from mesenchymal cell origin and have distinct clinical and pathologic features. Sarcomas account for about 1% of all adult cancers and 15% of all pediatric cancers. Sarcomas are typically divided into two main categories; soft tissue sarcomas (STS) and sarcomas of the bone.1
The broad categorization of STS includes tumors of the muscles, fat, nerves, nerve sheaths, blood vessels, and other connective tissues. Over 50 histologic subtypes of STS have been identified. Typical STS locations include the extremities, trunk, retroperitoneum, and head and neck. It is estimated that 13,040 people have been diagnosed with STS in the United States, with a corresponding 5,150 deaths.2
Epithelioid sarcoma (ES) is a rare, slow-growing subtype of STS that accounts for approximately 1% of all STS cases annually. ES is categorized, in more than 90% of cases, by a genetic mutation referred to as inactivation, deletion, or loss of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1 or INI-1). Loss of this tumor-suppressor gene can result in oncogenic transformation and thus the development of ES. Initially, ES forms as a hard lump in the soft tissue under the skin. There are two forms of ES; distal-type and proximal-type. Distal-type ES (also referred to as Classic ES) is the more common subtype, typically affects teenagers and young adults, is associated with favorable survival rates, and usually occurs in the hands, forearms, feet, or ankles. Proximal-type ES is a rarer variant of ES that typically affects older adults, is associated with less favorable survival rates, and usually occurs in the pelvic area or abdomen.3 The five-year overall survival (OS) for ES varies from 25-78% depending on staging at the time of initial diagnosis.
Diagnosis/Staging
Initial evaluation for a patient suspected of having ES or another histologic subtype of STS should include a pre-treatment biopsy performed by a surgeon or radiologist. The goals of a pre-treatment biopsy are to establish whether the tumor is benign or malignant, to obtain a definite diagnosis, and to obtain the grade of the tumor. Different methods of biopsy include core needle biopsy (preferred), open incisional biopsy, and fine-needle aspiration (FNA).
A pathologist will review the biopsy specimen and determine the primary diagnosis based on the World Health Organization’s (WHO’s) standardized nomenclature for STS, organ/site of sarcoma, tumor depth, tumor size, the histologic grade of the tumor, presence or absence of necrosis, mitotic rate, presence or absence of vascular invasion, the status of excision margins and lymph nodes, and tumor stage. Additionally, molecular genetic testing via conventional cytogenetic analysis, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) may be helpful in terms of survival prognostication and treatment planning.
Staging of STS is defined based on the American Joint Committee on Cancer (AJCC) Staging System for Soft Tissue Sarcomas of the Trunk, Extremities, Abdomen, and Thoracic Visceral Organs (8th edition; 2017). This system may also be referred to as the “TNM” system with T representing the size of the primary tumor, N representing regional lymph node involvement, and M representing distant metastatic disease. Collectively, the TNM system allows an oncologist to categorize an STS patient as Stage I, II, III, or IV.
Treatment of Resectable Epithelioid Sarcoma Involving Extremities, Trunk, Head, and Neck
The treatment of early-stage resectable ES involving the extremities, trunk, head, and neck would mimic that of other subtypes of STS.
Stage IA or IB (low grade) tumors are treated with surgical wide resection. For patients with appropriate surgical margins, no further therapy is required. For patients with positive surgical margins, observation, re-resection, or radiation therapy would be considered appropriate treatment options. Post-treatment follow-up would include evaluation for occupational or physical therapy, physical exams every three to six months for two to three years followed annually thereafter, and consideration of periodic imaging of the primary tumor location based on risk of recurrence.
Stage II tumors may be treated with surgical resection alone, surgical resection followed by adjuvant radiation therapy, or with preoperative radiation therapy followed by surgical resection. For patients with positive surgical margins, observation, re-resection, or radiation therapy would be considered appropriate treatment options. Post-treatment follow-up would include evaluation for occupational or physical therapy, physical exams every three to six months for two to three years followed by annually thereafter, and consideration of periodic imaging of the primary tumor location based on the risk of recurrence.
Stage IIIA or IIIB tumors may be treated with surgical resection followed by adjuvant radiation therapy or adjuvant radiation therapy and chemotherapy, preoperative radiation therapy followed by surgical resection followed by adjuvant chemotherapy, preoperative chemoradiation followed by surgical resection followed by adjuvant chemotherapy or preoperative chemotherapy followed by surgical resection followed by adjuvant radiation therapy or adjuvant radiation therapy and chemotherapy. Systemic chemotherapy regimens utilized in this scenario would include regimens such as single-agent Doxorubicin, Doxorubicin + Ifosfamide + Mesna (AIM regime), or Gemcitabine + Docetaxel. Post-treatment follow-up would include evaluation for occupational or physical therapy, physical exams every three to six months for two to three years followed annually thereafter, and consideration of periodic imaging of the primary tumor location based on the risk of recurrence.
Treatment of Resectable Retroperitoneal or Intra-Abdominal Epithelioid Sarcoma
The treatment of early-stage resectable retroperitoneal or intra-abdominal ES would mimic that of other subtypes of STS.
If a sarcoma is identified on biopsy, surgical resection to obtain appropriate margins with or without intra-operative radiation therapy or preoperative radiation therapy or chemotherapy followed by surgical resection to obtain appropriate margins would be considered appropriate treatment options. Depending on post-surgical outcomes (i.e. R0, R1, or R2 resections), postoperative radiation therapy or consideration of re-resection would be considered appropriate. Post-treatment follow-up would include physical exam with diagnostic imaging surveillance every three to six months for two to three years followed by every six months for the next two years followed by annually thereafter.
Treatment of Unresectable Epithelioid Sarcoma Involving Extremities, Trunk, Head, and Neck
Treatment for non-metastatic, unresectable ES (Stage II or III) involving the extremities, trunk, head, and neck would mimic the treatment of other subtypes of STS.
Primary treatment of non-metastatic, unresectable ES (Stage II or III) in this setting would include radiation therapy, chemoradiation, systemic chemotherapy (regimens listed in a previous section), regional limb therapy, or amputation. If the tumor becomes resectable with acceptable functional outcomes following primary therapy, surgical resection followed by adjuvant radiation therapy or chemotherapy would be considered appropriate. If the tumor becomes resectable with adverse functional outcomes following primary therapy, amputation or definitive radiation therapy should be considered. If the tumor remains unresectable following primary treatment, radiation therapy (if not previously done) or chemotherapy would be considered appropriate. Consideration may be given to treatment with Tazverik®, which will be described in a subsequent section. Post-treatment follow-up would include physical exam with diagnostic imaging surveillance every three to six months for two to three years then every six months for the next two years followed by annually thereafter.
Treatment of Unresectable Retroperitoneal or Intra-Abdominal Epithelioid Sarcoma
Treatment for non-metastatic, unresectable retroperitoneal or intra-abdominal ES would mimic the treatment of other subtypes of STS.
Consideration may be given to attempt tumor down-staging with either systemic chemotherapy (regimens listed in a previous section), chemoradiation, or radiation therapy. If down-staging treatment renders the tumor surgically-resectable, surgical resection (with or without intra-operative radiation therapy) to obtain appropriate margins or pre-operative therapy with radiation therapy or systemic chemotherapy followed by surgical resection to obtain appropriate margins would be considered appropriate. If down-staging is not performed or results in the tumor remaining unresectable, systemic chemotherapy or radiation therapy may be considered. Consideration may be given to treatment with Tazverik®, which will be described in a subsequent section. Post-treatment follow-up would include physical exam with diagnostic imaging surveillance every three to six months for two to three years then every six months for the next two years followed by annually thereafter.
Treatment of Metastatic Epithelioid Sarcoma
The treatment of Stage IV ES generally follows the same treatment algorithm as that of other subtypes of STS. Palliative treatment options for Stage IV tumors include systemic chemotherapy (regimens mentioned in a previous section), radiation therapy, surgery, ablation procedures, or embolization procedures.
Tazemetostat (Tazverik®) was approved by the United States Food and Drug Administration (US FDA) on January 23, 2020, for the treatment of adult and pediatric patients, aged 16 years and older, with metastatic or locally advanced ES that is not eligible for complete resection.4 Prior to this pivotal approval, there were no medications with specific FDA-approved indications for use in the treatment of ES. Tazverik was approved as a result of Phase II EZH-202 clinical trial (NCT02601950), which demonstrated a 15% overall response rate (ORR) in a cohort of 62 patients with unresectable, locally advanced or metastatic ES who were either previously treated (i.e. surgery, radiation, or chemotherapy) or previously untreated.
Mechanistically, Tazverik is a potent and selective inhibitor of histone methyltransferase EZH2 (enhancer of zeste homolog 2). EZH2 becomes overexpressed in certain cancers, such as ES, that are characterized by loss of function of the INI-1 gene. Overexpression of EZH2 results in oncogenic transformation.
Based on Tazverik’s prescribing information, the medication has no contraindications for use. Tazverik’s prescribing information contains warnings and precautions for the development of secondary malignancies (i.e. myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) in 0.6% of patients, as well as warnings and precautions for embryo-fetal toxicity (i.e. skeletal developmental abnormalities). The following adverse drug reactions occurred in greater than 10% of patients who received Tazverik as part of the EZH-202 clinical trial: pain (52%), fatigue (47%), nausea (36%), decreased appetite (26%), vomiting (24%), constipation (21%), cough (18%), hemorrhage (18%), headache (18%), diarrhea (16%), dyspnea (16%), anemia (16%), weight loss (16%), abdominal pain (13%). As part of the EZH-202 clinical trial, only 2% of patients discontinued Tazverik due to adverse drug reactions.
The FDA-approved initial dosing for Tazverik is 800 mg orally twice daily with or without food until disease progression or unacceptable toxicity. Tazverik tablets should be swallowed whole. In the event of a missed dose or vomiting after a dose, patients should not take an additional dose but continue with the next scheduled dose. Dose reductions may be required if certain adverse drug reactions occur or if certain drug-drug interactions are present (i.e. moderate or strong CYP3A inhibitors). Tazverik is available as 200 mg tablets in a 240-count pill bottle (NDC 72607-100-00) and should be stored at room temperature (up to 86 degrees Fahrenheit).
1 National Comprehensive Cancer Network Soft Tissue Sarcoma Guidelines Version 6.2019
2 Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA Cancer J Clin 2018; 68:7-30
4 Tazverik Prescribing Information https://www.tazverik.com/prescribing-information.pdf