An Overview of Epithelioid Sarcoma

Sarcomas are a heterogeneous group of rare solid tumor malignancies which arise from mesenchymal cell origin; they 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 2 main categories: soft tissue sarcoma (STS) and sarcoma of the bone.¹

The broad categorization of STS includes tumors of the muscles, fat, nerves, nerve sheaths, blood vessels, and other connective tissues. More than 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 individuals received a diagnosis of STS in the United States in 2018 with a corresponding 5150 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 marked, 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).3 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 2 forms of ES: distal-type and proximal-type. Distal-type ES (also referred to as classic ES) is the more common, typically affecting teenagers and young adults. Usually occurring in the hands, forearms, feet, or ankles, it is associated with favorable survival rates. Proximal-type ES, the rarer variant, typically affects older adults and is associated with less favorable survival rates; it usually occurs in the pelvic area or abdomen.3 The 5-year overall survival for ES varies from 25% to 78%, dependent upon 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 pretreatment biopsy performed by a surgeon or radiologist. The goals of a pretreatment 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.

A pathologist will review the biopsy specimen and determine the primary diagnosis based upon the World Health Organization standardized nomenclature for STS, organ/site of sarcoma, tumor depth, tumor size, histologic grade of the tumor, presence or absence of necrosis, mitotic rate, presence or absence of vascular invasion, status of excision margins and lymph nodes, and tumor stage. Additionally, molecular genetic testing via conventional cytogenetic analysis, fluorescence in situ hybridization, and polymerase chain reaction may be helpful in terms of survival prognostication and treatment planning.

Staging of STS is based upon the American Joint Committee on Cancer “TNM” staging system, with T representing 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 ES Involving Extremities, Trunk, Head, and Neck

The treatment of early-stage resectable ES involving the extremities, trunk, head, or 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 (negative) 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. Posttreatment follow-up would include evaluation for occupational or physical therapy; physical exams every 3 to 6 months for 2 to 3 years, followed by annually thereafter; and consideration of periodic imaging of the primary tumor location based upon 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. Posttreatment follow-up would include evaluation for occupational or physical therapy; physical exams every 3 to 6 months for 2 to 3 years, followed by annually thereafter; and consideration of periodic imaging of the primary tumor location based upon risk of recurrence.

The options for treating stage IIIA or IIIB tumors include the following:

• Surgical resection followed by adjuvant radiation therapy or adjuvant radiation therapy plus chemotherapy
• Preoperative radiation therapy followed by surgical resection followed by adjuvant chemotherapy
• Preoperative chemoradiation followed by surgical resection followed by adjuvant chemotherapy
• Preoperative chemotherapy followed by surgical resection followed by adjuvant radiation therapy or adjuvant radiation therapy plus chemotherapy.

Options for systemic chemotherapy regimens in this scenario would include single-agent doxorubicin, doxorubicin plus ifosfamide plus mesna, or gemcitabine plus docetaxel. Posttreatment follow-up would include evaluation for occupational or physical therapy; physical exams every 3 to 6 months for 2 to 3 years, followed by annually thereafter; and consideration of periodic imaging of the primary tumor location based upon 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, appropriate treatment options would include surgical resection to obtain appropriate margins, with or without intraoperative radiation therapy; or preoperative radiation therapy or chemotherapy, followed by surgical resection to obtain appropriate margins. Depending on postsurgical outcome (ie, R0, R1, or R2 resections), postoperative radiation therapy or consideration of re-resection would be considered appropriate. Posttreatment follow-up would include physical exam with diagnostic imaging surveillance every 3 to 6 months for 2 to 3 years, followed by every 6 months for the next 2 years, followed by annually thereafter.

Treatment of Unresectable Epithelioid Sarcoma Involving Extremities, Trunk, Head, and Neck

Treatment for nonmetastatic, 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 nonmetastatic, unresectable ES (stage II or III) in this setting would include radiation therapy, chemoradiation, systemic chemotherapy (with the regimens described earlier), 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 tazemetostat (Tazverik; Epizyme), which will be described in a subsequent section. Posttreatment follow-up would include physical exam with diagnostic imaging surveillance every 3 to 6 months for 2 to 3 years, then every 6 months for the next 2 years, followed by annually thereafter.

Treatment of Unresectable Retroperitoneal or Intra-abdominal Epithelioid Sarcoma

Treatment for nonmetastatic, 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 (with the regimens described earlier), chemoradiation, or radiation therapy. If down-staging treatment renders the tumor surgically resectable, appropriate options would be surgical resection (with or without intraoperative radiation therapy), to obtain appropriate margins; or preoperative therapy with radiation therapy or systemic chemotherapy, followed by surgical resection to obtain appropriate margins. 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 tazemetostat. Posttreatment follow-up would include physical exam with diagnostic imaging surveillance every 3 to 6 months for 2 to 3 years, then every 6 months for the next 2 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 (with the regimens described earlier), radiation therapy, surgery, or ablation or embolization procedures.

Tazemetostat was approved by the FDA on January 23, 2020, for the treatment of adult and pediatric patients 16 years and older with metastatic or locally advanced ES that is not eligible for complete resection.3 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 the phase 2 EZH-202 clinical trial (NCT02601950), which demonstrated a 15% overall response rate in a cohort of 62 patients with unresectable, locally advanced or metastatic ES who were either previously treated (ie, with surgery, radiation, or chemotherapy) or previously untreated. Mechanistically, tazemetostat is a potent and selective inhibitor of histone methyltransferase EZH2 (enhancer of zeste homologue 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 upon tazemetostat’s prescribing information, the medication has no contraindications for use. The drug’s prescribing information contains warnings and precautions for the development of secondary malignancies, such as myelodysplastic syndrome, and acute myeloid leukemia, as well as warnings and precautions for embryo-fetal toxicity (ie, skeletal developmental abnormalities).4 The following adverse drug reactions occurred in more than 10% of patients who received tazemetostat 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 tazemetostat due to adverse drug reactions.

The FDA-approved initial dosing for tazemetostat is 800 mg orally twice daily with or without food until disease progression or unacceptable toxicity.3 Tazemetostat 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 (ie, moderate or strong CYP3A inhibitors). Tazemetostat is available as 200-mg tablets in a 240-count pill bottle and should be stored at room temperature, up to 86 o F.⁴

Joseph Barone, PharmD, BCOP is senior director, Clinical Oncology Services, Onco360 Oncology Pharmacy of Louisville, Kentucky.

REFERENCES

• NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 6.2019. Accessed April 7, 2020. https://www.nccn.org/professionals/physician_gls/pdf...
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi:10.3322/caac.21442
• Tazverik (tazemetostat). Prescribing information. Epizyme; 2020. Accessed June 23, 2020. href="https://www.tazverik.com/prescribing-information.pdf">https://www.tazverik.com/prescribing-information.pdf
• Epizyme announces U.S. FDA accelerated approval of Tazverik (tazemetostat) for the treatment of patients with epithelioid sarcoma. News release. Epizyme; January 23, 2020. Accessed June 23, 2020. href="https://www.businesswire.com/news/home/20200123005858/en/4697851/Epizyme-Announces-U.S.-FDA-Accelerated-Approval-TAZVERIK%E2%84%A2">https://www.businesswire.com/news/home/20200123005858/en/4697851/Epizyme-Announces-U.S.-FDA-Accelerated-Approval-TAZVERIK%E2%84%A2