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Leiomyosarcoma is an aggressive soft tissue sarcoma with complex molecular features, variable clinical presentations, and limited systemic treatment options. Despite advances in oncologic care, clinicians frequently encounter challenges in timely diagnosis, appropriate biopsy technique, staging, and treatment sequencing. This activity addresses the gap between current practice patterns and evidence-based standards for leiomyosarcoma management by providing a comprehensive review of pathophysiology, histologic classification, staging systems, and interdisciplinary treatment strategies. Participants will gain updated knowledge regarding surgical principles, perioperative radiotherapy, chemotherapy regimens, and emerging targeted therapies. The activity emphasizes the critical role of high-volume sarcoma centers, tumor board involvement, and clinical trial participation in optimizing patient outcomes. Clinicians will leave with actionable skills to improve diagnostic accuracy, refine treatment planning, and strengthen interdisciplinary collaboration in the care of patients with leiomyosarcoma. Objectives: Apply appropriate pathologic and radiologic diagnostic tests to identify and stage leiomyosarcoma. Determine the correct treatment algorithm for patients with localized and metastatic leiomyosarcoma. Determine the most appropriate medical treatment for patients with leiomyosarcoma. Implement effective collaboration, coordination, and communication strategies among interprofessional team members to improve patient outcomes. Access free multiple choice questions on this topic.

Leiomyosarcoma, a common subtype of soft tissue sarcoma (STS), accounts for up to 10% to 20% of all sarcomas.[1] Originating from either smooth muscle cells or their mesenchymal cell precursors, leiomyosarcoma primarily occurs in the retroperitoneum, uterus, and extremities, in descending order of frequency.[2] The genetic abnormalities in leiomyosarcoma are complex, and our current knowledge remains incomplete. The clinical presentation, signs, and symptoms vary depending on the site of origin. Prognosis is determined by the tumor's location, size, and grade, with tumor grade significantly affecting overall survival. With higher-grade lesions, the rate of distant metastasis increases. Treatment can be nuanced and often requires an interdisciplinary approach. The current standard of care involves upfront surgical procedure for resectable tumors, with chemotherapy and radiation typically serving as adjuncts.[3] Treatment at high-volume sarcoma centers is preferred and associated with improved patient outcomes.[4] Despite advances in cancer treatment overall, the overall survival of patients with leiomyosarcoma remains poor. Consequently, clinicians should strongly encourage patients with leiomyosarcoma to participate in clinical trials at any stage of diagnosis.

Leiomyosarcoma is a sporadic malignant neoplasm with no clear etiologic factors. History of radiation therapy, exposure to carcinogens like vinyl chloride, or exposure to Agent Orange, are associated with the development of soft tissue sarcoma, less commonly with leiomyosarcoma.[5][6] Patients with hereditary retinoblastoma (RB gene mutation) or Li-Fraumeni syndrome (TP53 mutation) are at an increased risk of developing leiomyosarcoma.[7][8] Evidence does not convincingly show that leiomyoma (uterine fibroids) predispose to the development of leiomyosarcoma, and such cases are considered de novo.[2]

Leiomyosarcoma accounts for 10% to 20% of all newly diagnosed STS.[9] In recent years, advancements in molecular diagnostics have improved diagnostic accuracy. Leiomyosarcoma most commonly occurs in the retroperitoneum, followed by the uterus, extremities, and trunk. Uterine sarcomas comprise about 3% to 7% of all uterine malignant neoplasms, with leiomyosarcoma being the most common subtype, accounting for nearly 80% of all uterine sarcomas.[10][11] The incidence of leiomyosarcoma increases with age, peaking in the seventh decade of life. The exception to this is uterine leiomyosarcoma, which occurs most commonly in women who are perimenopausal. Tumors associated with genetic syndromes occur earlier in life. Retroperitoneal leiomyosarcoma and tumors arising from visceral blood vessels are more common in women, whereas the disease at other sites is more common in men.[12]

Leiomyosarcoma is a genomically heterogeneous disease with no known activating mutation in the oncogenic genes. Molecular studies have consistently shown mutations in the TP53, RB1, and PTEN genes, which are recognized as the tumor suppressor genes.[13] Collectively, leiomyosarcomas are known to harbor an unstable karyotype with several genomic alterations, making it a complex and heterogeneous disease.[2] Three distinct subtypes have been identified: subtype I resembles smooth muscle differentiation and is associated with a favorable outcome, whereas subtype II resembles it less and is associated with a worse prognosis.[9] However, the clinical behaviour of leiomyosarcoma of the same origin can vary widely among patients, underscoring the disease's molecular heterogeneity and the unpredictability of clinical response. Leiomyosarcoma is a genomically heterogeneous disease with no known activating mutation in oncogenic genes. Molecular studies have consistently demonstrated mutations in the TP53, RB1, and Phosphatase and TENsin homolog (PTEN) genes, which are recognized as tumor suppressor genes.[13] Collectively, leiomyosarcomas are known to harbor an unstable karyotype with several genomic alterations, making leiomyosarcoma a complex and heterogeneous disease.[2] Three distinct subtypes have been identified: subtype I resembles smooth muscle differentiation and is associated with a favorable outcome, whereas subtype II resembles it less and is associated with a worse prognosis.[9] However, the clinical behavior of leiomyosarcoma of the same origin can vary widely among patients, underscoring the disease's molecular heterogeneity and the unpredictability of clinical response.

Histology Leiomyosarcomas originate from the smooth muscle cells or their mesenchymal precursors.[14] Grossly, they are typically solitary, well-circumscribed lesions that often have areas of cystic degeneration and necrosis. Classic leiomyosarcoma is characterized by spindle-shaped cells arranged in intersecting fascicles, similar to smooth muscle. The nuclei are typically elongated and hyperchromatic with abundant eosinophilic cytoplasm.[2] Varying degrees of pleomorphism can occur. When poorly differentiated, leiomyosarcoma can resemble any of the undifferentiated STS.[2] Other histologic variants include pleiomorphic, myxoid, and undifferentiated leiomyosarcoma. Uterine leiomyosarcomas are typically intramural and solitary and rarely arise from the cervix. Unlike leiomyomas, which have a well-defined, non-infiltrating border, leiomyosarcomas are often irregular and infiltrating. On gross inspection, most uterine leiomyosarcomas appear as large, solitary lesions with irregular and infiltrative borders.[15] On microscopy, the hallmarks of leiomyosarcoma include nuclear atypia, greater than 5 to 10 mitoses per high-power field (HPF), and tumor necrosis (see Image. Leiomyosarcoma of the Uterus).[16] Tumor necrosis is typically coagulative, with viable tumor cells sharply demarcated from the necrotic areas. The coagulative pattern contrasts with the infarct-like necrosis typically seen in benign tumors such as leiomyomas, where a regenerative zone surrounds the necrotic area. The pattern and type of necrosis can help differentiate benign from malignant lesions. Uterine leiomyosarcoma can further be divided into spindle cell (classic type), epithelioid (more than 50% epithelial cells), myxoid (hypocellular with basophilic stroma), and other rare types. Lesions arising from smooth muscle cells but lacking the definitive features of leiomyosarcoma are labeled smooth muscle tumors of uncertain malignant potential.[15] Immunohistochemistry

Uterine leiomyosarcomas are typically intramural and solitary and rarely arise from the cervix. Unlike leiomyomas, which have a well-defined, non-infiltrating border, leiomyosarcomas are often irregular and infiltrating. On gross inspection, most uterine leiomyosarcomas appear as large, solitary lesions with irregular and infiltrative borders.[15] On microscopy, the hallmarks of leiomyosarcoma include nuclear atypia, greater than 5 to 10 mitoses per high-power field (HPF), and tumor necrosis (see Image. Leiomyosarcoma of the Uterus).[16] Tumor necrosis is typically coagulative, with viable tumor cells sharply demarcated from the necrotic areas. The coagulative pattern contrasts with the infarct-like necrosis typically seen in benign tumors such as leiomyomas, where a regenerative zone surrounds the necrotic area. The pattern and type of necrosis can help differentiate benign from malignant lesions. Uterine leiomyosarcoma can further be divided into spindle cell (classic type), epithelioid (more than 50% epithelial cells), myxoid (hypocellular with basophilic stroma), and other rare types. Lesions arising from smooth muscle cells but lacking the definitive features of leiomyosarcoma are labeled smooth muscle tumors of uncertain malignant potential.[15] Immunohistochemistry Leiomyosarcoma demonstrates positive staining for smooth muscle–specific markers, including muscle-specific actin, desmin, and h-caldesmon. Immunohistochemical stains are typically used for confirmation or in undifferentiated tumors where the cell of origin is unclear. Subtypes of leiomyosarcoma may require additional stains. In particular, epithelioid leiomyosarcoma can be confused with carcinoma because it tends to stain for epithelial elements. In such cases, histone deacetylase-8 and myocardin are additional stains that can help confirm the diagnosis. Immunopositivity for p16 and p53, with a high Ki-67 proliferation index, has also demonstrated high sensitivity and specificity for differentiating leiomyosarcoma from leiomyoma. Compared to leiomyoma, leiomyosarcoma has lower estrogen receptor expression (40% in leiomyosarcoma versus 70% in leiomyoma) and lower progesterone receptor expression (38% in leiomyosarcoma versus 88% in leiomyoma).[17]

The clinical presentation of leiomyosarcoma depends on the location and is highly variable. Symptoms are often due to compression of surrounding organs. In locations such as the retroperitoneum, tumors can grow very large before becoming symptomatic. Uterine lesions are often diagnosed through pathological examination after a hysterectomy for a suspected leiomyoma.[10][12] Notably, morcellation of leiomyomas is discouraged to prevent the risk of missing an occult leiomyosarcoma.[18]

The appropriate workup of a suspected leiomyosarcoma should be decided by an interdisciplinary team. Initial cross-sectional imaging with CT or MRI helps identify the extent of the lesion, its relationship to surrounding structures, and potential biopsy targets. Although CT excels at assessing retroperitoneal and visceral lesions, MRI is effective for evaluating tumors originating in the extremities and head and neck.[19] Once a sarcoma is suspected, an image-guided core needle biopsy is required for diagnosis; fine-needle aspiration is insufficient for establishing a diagnosis.[20] For palpable lesions, image guidance improves the accuracy of core needle biopsies.[21] For abdominopelvic lesions, using a retroperitoneal approach is crucial to avoid peritoneal seeding. For superficial lesions, the biopsy must be performed with consideration of the potential surgical incision, ensuring that the biopsy tract is included in the surgical specimen. Incisional and excisional biopsies should be avoided, and with current techniques, an open surgical procedure should rarely be necessary. Referring suspected STS cases to a high-volume center is advisable because inappropriate diagnostic workups, particularly inappropriate surgical procedures, can lead to distortion of tissue planes, seeding of sarcomatous tissue, and alteration of the subsequent surgical approach. Chest and abdominopelvic CT imaging is necessary as part of the initial workup to rule out lung and liver metastasis. In cases of uterine leiomyosarcoma, an endometrial biopsy may yield a diagnosis; however, a negative biopsy result does not rule out leiomyosarcoma. Any leiomyoma that continues to grow beyond menopause should be evaluated to rule out leiomyosarcoma.[10][12]

The treatment of leiomyosarcoma depends on the site of the disease, tumor size, grade, and patient-related factors. Surgical resection, radiation therapy, and systemic agents (chemotherapy, targeted therapy, and immunotherapy) are the 3 critical components of leiomyosarcoma treatment. In general, sarcomas are rare malignant neoplasms, and an interdisciplinary approach at a high-volume sarcoma center is highly recommended to improve patient outcomes. For treatment purposes, sarcomas are classified as localized or metastatic disease. In patients with localized leiomyosarcoma, the primary treatment is surgical resection with the goal of achieving microscopic negative margins (R0 resection). An R0 resection is associated with the best local relapse-free survival.[12] Radiotherapy (RT) in STS has been shown to improve local control, preserve function, and reduce local recurrence, but does not improve overall survival or distant metastasis-free survival.[22]

The clinical presentation of a patient with STS is vague and nonspecific. The morphological diagnosis based on microscopic examination remains the gold standard. Ancillary testing, including immunohistochemistry, classic cytogenetics, and molecular testing, aids in diagnosis. The World Health Organization recognizes more than 70 different subtypes of sarcoma.[9] Diagnoses to consider due to similar presentation or histopathological similarity include meningioma, gastrointestinal stromal tumors, leiomyoma, dedifferentiated liposarcoma, endometrial stromal sarcoma, smooth muscle tumors of uncertain malignant potential, inflammatory myofibroblastic tumor, and perivascular epithelioid cell tumor.

The general surgery principles applicable to any sarcoma also pertain to patients diagnosed with leiomyosarcoma. Leiomyosarcoma of the Extremity or Trunk The primary goal of the surgical procedure is to perform an R0 resection while making every attempt to preserve critical neurovascular structures. Historically, in patients with extremity leiomyosarcoma, amputation was performed to achieve a negative margin. However, this approach has been replaced by an extremity-salvage surgical procedure that combines surgical resection with perioperative RT.[23] Preoperative RT is preferred over postoperative RT due to fewer long-term complications.[24] Likewise, in patients with leiomyosarcoma of the trunk, surgical resection with perioperative RT is preferred over wide margins. In patients with a leiomyosarcoma smaller than 5 cm, perioperative RT can be omitted if the operating clinicians can safely achieve wide margins (see Image. Excision of Leiomyosarcoma of the Rectum). Leiomyosarcoma of Retroperitoneum Sarcomas of the retroperitoneum often present as large tumors and commonly arise from the smooth muscle lining of medium- to large-sized visceral veins, such as the inferior vena cava and the gonadal veins. The challenge in these cases is attaining a negative margin. An en bloc resection of the leiomyosarcoma along with any involved adjacent organs is associated with the best outcome for resectable tumors.[25] Because leiomyosarcomas are usually well-defined, compression of adjacent organs rather than invasion is a common intraoperative finding and sometimes allows preservation of surrounding organs. Tumor rupture and spillage are uniformly associated with poor outcomes and should be avoided.[26] Preoperative radiation for retroperitoneal leiomyosarcoma has largely been abandoned following the results of the European Organisation for Research and Treatment of Cancer (EORTC)-62092: Surgery with or without Radiotherapy in Retroperitoneal Sarcoma (STRASS) trial, which were negative.[27] (see Image. Excision of Leiomyosarcoma of the Rectum) Uterine Leiomyosarcoma

Sarcomas of the retroperitoneum often present as large tumors and commonly arise from the smooth muscle lining of medium- to large-sized visceral veins, such as the inferior vena cava and the gonadal veins. The challenge in these cases is attaining a negative margin. An en bloc resection of the leiomyosarcoma along with any involved adjacent organs is associated with the best outcome for resectable tumors.[25] Because leiomyosarcomas are usually well-defined, compression of adjacent organs rather than invasion is a common intraoperative finding and sometimes allows preservation of surrounding organs. Tumor rupture and spillage are uniformly associated with poor outcomes and should be avoided.[26] Preoperative radiation for retroperitoneal leiomyosarcoma has largely been abandoned following the results of the European Organisation for Research and Treatment of Cancer (EORTC)-62092: Surgery with or without Radiotherapy in Retroperitoneal Sarcoma (STRASS) trial, which were negative.[27] (see Image. Excision of Leiomyosarcoma of the Rectum) Uterine Leiomyosarcoma Hysterectomy and en bloc resection of the leiomyosarcoma are the surgical standards for uterine leiomyosarcoma. Bilateral oophorectomy is recommended for all patients; however, ovarian preservation may be considered in some women who are premenopausal.[28] Unlike carcinomas, the rate of lymph node involvement in leiomyosarcoma is low (5% to 11%), and lymph node dissection is unnecessary.[29] When the preoperative workup is concerning for a uterine leiomyosarcoma, every effort should be made to perform an en bloc resection without tumor spillage. Extrauterine disease, if resectable, should be completely excised. However, the diagnosis is often made on an incidental myomectomy or hysterectomy specimen, which may require a second-look operation for complete removal.[28]

The general principles of radiotherapy for any STS also apply to patients diagnosed with non–uterine leiomyosarcoma. Uterine leiomyosarcoma is a separate subgroup of patients diagnosed with leiomyosarcoma, covered in a separate section. Perioperative radiotherapy for STS is the gold standard treatment for localized disease in the extremities, trunk, and head and neck regions.[12] Results from 2 prospective randomized trials evaluating external-beam radiotherapy and postoperative brachytherapy demonstrated improved local control when adjuvant radiotherapy was added to surgery in patients with STS of the extremities and trunk.[22][30] Although the benefit of adjuvant radiotherapy is apparent in both high-grade and low-grade STS, high-grade tumors derive a greater benefit. Interstitial brachytherapy and intensity-modulated radiotherapy are 2 additional approaches for delivering radiotherapy to the extremity or trunk STS. These approaches have never been compared with external-beam radiotherapy in prospective trials for patients with STS.[31] The timing of radiotherapy (preoperative and postoperative) is a topic of debate. Preoperative radiotherapy has the benefit of delivering a lower total dose with a shorter course of treatment. The treatment field is smaller, which leads to less radiation toxicity and improved extremity function. Preoperative radiotherapy also offers potential downstaging of a borderline resectable sarcoma of an extremity with the possibility of salvaging the extremity. However, preoperative radiotherapy is associated with a higher rate of wound-healing complications (35% with preoperative radiotherapy versus 17% with postoperative radiotherapy). Conversely, postoperative radiotherapy allows for a definitive assessment of the tumor (including grade and margin status) and carries a lower rate of postoperative wound-healing complications. However, postoperative radiotherapy is associated with higher rates of fibrosis, edema, and joint stiffness.[32][33]

The timing of radiotherapy (preoperative and postoperative) is a topic of debate. Preoperative radiotherapy has the benefit of delivering a lower total dose with a shorter course of treatment. The treatment field is smaller, which leads to less radiation toxicity and improved extremity function. Preoperative radiotherapy also offers potential downstaging of a borderline resectable sarcoma of an extremity with the possibility of salvaging the extremity. However, preoperative radiotherapy is associated with a higher rate of wound-healing complications (35% with preoperative radiotherapy versus 17% with postoperative radiotherapy). Conversely, postoperative radiotherapy allows for a definitive assessment of the tumor (including grade and margin status) and carries a lower rate of postoperative wound-healing complications. However, postoperative radiotherapy is associated with higher rates of fibrosis, edema, and joint stiffness.[32][33] Patients with superficial or contained STS up to a size of 5 cm who undergo complete excision of the tumor with wide margins (more than 1 cm clean margin) can be monitored clinically without the need for postoperative radiotherapy. No evidence supports this approach; it is recommended that an interprofessional sarcoma group be involved before considering it.[33] Adding adjuvant radiotherapy is superior to the surgical procedure alone in patients with margin-positive resections.[34] Results from 2 prospective studies from Memorial Sloan Kettering and the National Cancer Institute demonstrated a low local recurrence rate when adjuvant radiotherapy was included in the treatment plan for patients with positive surgical margins.[22][30] Although adding perioperative radiotherapy improves local outcomes, perioperative radiotherapy has not shown any benefit for overall survival or distant recurrence-free survival.[33] Considerations in Retroperitoneal Sarcoma

Patients with superficial or contained STS up to a size of 5 cm who undergo complete excision of the tumor with wide margins (more than 1 cm clean margin) can be monitored clinically without the need for postoperative radiotherapy. No evidence supports this approach; it is recommended that an interprofessional sarcoma group be involved before considering it.[33] Adding adjuvant radiotherapy is superior to the surgical procedure alone in patients with margin-positive resections.[34] Results from 2 prospective studies from Memorial Sloan Kettering and the National Cancer Institute demonstrated a low local recurrence rate when adjuvant radiotherapy was included in the treatment plan for patients with positive surgical margins.[22][30] Although adding perioperative radiotherapy improves local outcomes, perioperative radiotherapy has not shown any benefit for overall survival or distant recurrence-free survival.[33] Considerations in Retroperitoneal Sarcoma Preoperative radiotherapy for patients with retroperitoneal leiomyosarcoma has been abandoned since the results of the European Organisation for Research and Treatment of Cancer (EORTC)-62092: Surgery with or without Radiotherapy in Retroperitoneal Sarcoma (STRASS) trial were negative.[27] In this phase 3 randomized controlled trial, treatment-naive patients with any retroperitoneal sarcoma were randomized to receive either preoperative RT (50 Gy in 28 fractions) followed by surgical procedure or surgical resection alone. Unfortunately, the trial did not meet its primary endpoint of abdominal recurrence-free survival. The median abdominal radiation-free survival was 4.5 years in the radiotherapy plus surgical procedure group and 5.0 years in the surgical procedure only group (hazard ratio [HR] 1.01, 95% CI, 0.71 to 1.44; P = .95). The STRASS trial was the first international, randomized controlled trial in patients with retroperitoneal sarcoma providing high-quality evidence against preoperative RT in such patients. Considerations in Uterine Leiomyosarcoma

Preoperative radiotherapy for patients with retroperitoneal leiomyosarcoma has been abandoned since the results of the European Organisation for Research and Treatment of Cancer (EORTC)-62092: Surgery with or without Radiotherapy in Retroperitoneal Sarcoma (STRASS) trial were negative.[27] In this phase 3 randomized controlled trial, treatment-naive patients with any retroperitoneal sarcoma were randomized to receive either preoperative RT (50 Gy in 28 fractions) followed by surgical procedure or surgical resection alone. Unfortunately, the trial did not meet its primary endpoint of abdominal recurrence-free survival. The median abdominal radiation-free survival was 4.5 years in the radiotherapy plus surgical procedure group and 5.0 years in the surgical procedure only group (hazard ratio [HR] 1.01, 95% CI, 0.71 to 1.44; P = .95). The STRASS trial was the first international, randomized controlled trial in patients with retroperitoneal sarcoma providing high-quality evidence against preoperative RT in such patients. Considerations in Uterine Leiomyosarcoma The role of radiotherapy in uterine leiomyosarcoma is different from that in extrauterine leiomyosarcoma. A phase 3 trial conducted by the EORTC (protocol 55874) evaluated the role of adjuvant external beam radiotherapy in patients with stage I and II uterine leiomyosarcoma. Results showed no significant difference between the 2 groups in local or distant recurrence rates or overall survival. Although the results did not achieve statistical significance, researchers observed a trend toward inferior overall survival in the radiotherapy arm.[35] The French Sarcoma Group Study (SARCGYN) evaluated the combination of chemotherapy with radiotherapy versus radiotherapy alone. Of the 81 patients, 53 had leiomyosarcoma. The chemotherapy included a combination of doxorubicin, cisplatin, and ifosfamide (4 cycles to be given after radiotherapy). Results from the SARCGYN trial demonstrated a 3-year disease-free survival benefit in the combination arm, but no overall survival benefit at the 3-year or 5-year benchmarks.[36] Adjuvant radiotherapy is not recommended in an optimally resected uterine leiomyosarcoma due to the lack of obvious benefit. In the advanced stage, incompletely resected, or metastatic disease, the use of radiotherapy is exploratory.[10] Neoadjuvant Chemoradiation for Extremity or Trunk Soft Tissue Sarcoma

The role of radiotherapy in uterine leiomyosarcoma is different from that in extrauterine leiomyosarcoma. A phase 3 trial conducted by the EORTC (protocol 55874) evaluated the role of adjuvant external beam radiotherapy in patients with stage I and II uterine leiomyosarcoma. Results showed no significant difference between the 2 groups in local or distant recurrence rates or overall survival. Although the results did not achieve statistical significance, researchers observed a trend toward inferior overall survival in the radiotherapy arm.[35] The French Sarcoma Group Study (SARCGYN) evaluated the combination of chemotherapy with radiotherapy versus radiotherapy alone. Of the 81 patients, 53 had leiomyosarcoma. The chemotherapy included a combination of doxorubicin, cisplatin, and ifosfamide (4 cycles to be given after radiotherapy). Results from the SARCGYN trial demonstrated a 3-year disease-free survival benefit in the combination arm, but no overall survival benefit at the 3-year or 5-year benchmarks.[36] Adjuvant radiotherapy is not recommended in an optimally resected uterine leiomyosarcoma due to the lack of obvious benefit. In the advanced stage, incompletely resected, or metastatic disease, the use of radiotherapy is exploratory.[10] Neoadjuvant Chemoradiation for Extremity or Trunk Soft Tissue Sarcoma Although perioperative radiotherapy is the standard of care for STS of the extremity or trunk, the combination of chemotherapy with radiotherapy is still a topic of debate. The experience from nonsarcoma tumors has shown the positive radiosensitizing effect of combining chemotherapy with radiotherapy. The Radiation Therapy Oncology Group (RTOG) 9154 conducted a prospective phase 2 trial to evaluate the benefit of combining chemotherapy with radiotherapy in patients with extremity and trunk STS. Although grade 3 toxicity was relatively high in these patients, 5-year distant disease-free survival and overall survival were 64% and 71%, respectively.[37] Many other chemotherapy regimens have undergone testing since then. Among all regimens, ifosfamide is the most effective drug. Patients who developed tumor necrosis on ifosfamide had the lowest local recurrence rates. Similarly, patients with STS of the extremity or trunk received an increasing dose of gemcitabine and ifosfamide concurrently with preoperative radiotherapy (50 Gy). This approach resulted in 5-year local control, distant metastasis-free, and overall survival rates of 85%, 80%, and 86%, respectively.[38] Despite encouraging results, neoadjuvant chemoradiation for STS or leiomyosarcoma remains experimental.

Leiomyosarcoma is a tumor with complex, unbalanced karyotypes and severe genomic instability, leading to multiple genetic aberrations. As a result, leiomyosarcoma is considered moderately sensitive to chemotherapy.[39] Adjuvant Chemotherapy after Surgery After a surgical procedure, adjuvant chemotherapy for a patient diagnosed with STS has primarily been tested in patients with extremity and truncal STS.[40] Although adjuvant therapy has proven to benefit the pediatric age group, the same has been controversial for adult STS. The Sarcoma Meta-Analysis Collaboration published its first meta-analysis in 1997, which included 14 trials investigating the role of adjuvant chemotherapy in STS. Notably, the chemotherapy offered in these trials had doxorubicin as the only active component when combined with another drug. Results from the analysis showed statistically significant improvements in both local and distant recurrence-free survival, but the benefit in overall survival did not reach statistical significance. Despite this, the analysis demonstrated a 6% absolute benefit over 10 years.[41] The Sarcoma Meta-Analysis Collaboration published an updated meta-analysis in 2008, including 4 additional trials of patients treated with the combination of ifosfamide and doxorubicin. Results from this analysis again showed the same benefit in local recurrence-free survival, distant recurrence-free survival, and overall recurrence-free survival. However, this analysis showed a statistically significant overall survival benefit (odds ratio for death 0.56; 95% CI, 0.36-0.85). Subgroup analysis of patients receiving the combination of doxorubicin and ifosfamide showed an absolute risk reduction of 11%, which was not observed in the doxorubicin-only group.[42]

After a surgical procedure, adjuvant chemotherapy for a patient diagnosed with STS has primarily been tested in patients with extremity and truncal STS.[40] Although adjuvant therapy has proven to benefit the pediatric age group, the same has been controversial for adult STS. The Sarcoma Meta-Analysis Collaboration published its first meta-analysis in 1997, which included 14 trials investigating the role of adjuvant chemotherapy in STS. Notably, the chemotherapy offered in these trials had doxorubicin as the only active component when combined with another drug. Results from the analysis showed statistically significant improvements in both local and distant recurrence-free survival, but the benefit in overall survival did not reach statistical significance. Despite this, the analysis demonstrated a 6% absolute benefit over 10 years.[41] The Sarcoma Meta-Analysis Collaboration published an updated meta-analysis in 2008, including 4 additional trials of patients treated with the combination of ifosfamide and doxorubicin. Results from this analysis again showed the same benefit in local recurrence-free survival, distant recurrence-free survival, and overall recurrence-free survival. However, this analysis showed a statistically significant overall survival benefit (odds ratio for death 0.56; 95% CI, 0.36-0.85). Subgroup analysis of patients receiving the combination of doxorubicin and ifosfamide showed an absolute risk reduction of 11%, which was not observed in the doxorubicin-only group.[42] The Italian Sarcoma Group conducted a randomized trial to assess the role of adjuvant chemotherapy in high-risk patients with spindle cell STS of extremities or pelvis. The group receiving adjuvant chemotherapy (epirubicin or ifosfamide with mesna) had a lower distant metastasis recurrence rate (45% versus 28%) and better overall survival at 4 years (69% versus 50%). However, at a 7-year follow-up, statistical significance was lost, and the local and distant relapse rates were similar (44% versus 45%).[43] The European Organisation for Research and Treatment of Cancer conducted a randomized trial (EORTC 62931) to investigate the role of adjuvant doxorubicin and ifosfamide in localized STS. All patients with positive margins also underwent adjuvant radiotherapy. Results from this study did not report any difference in the recurrence-free survival or overall survival between the 2 groups.[44] Current guidelines suggest that in patients with high-grade or intermediate-grade STS measuring more than 5 cm, doxorubicin-based chemotherapy can be considered a viable option in the adjuvant setting.[NCCN. NCCN Guidelines]

The Italian Sarcoma Group conducted a randomized trial to assess the role of adjuvant chemotherapy in high-risk patients with spindle cell STS of extremities or pelvis. The group receiving adjuvant chemotherapy (epirubicin or ifosfamide with mesna) had a lower distant metastasis recurrence rate (45% versus 28%) and better overall survival at 4 years (69% versus 50%). However, at a 7-year follow-up, statistical significance was lost, and the local and distant relapse rates were similar (44% versus 45%).[43] The European Organisation for Research and Treatment of Cancer conducted a randomized trial (EORTC 62931) to investigate the role of adjuvant doxorubicin and ifosfamide in localized STS. All patients with positive margins also underwent adjuvant radiotherapy. Results from this study did not report any difference in the recurrence-free survival or overall survival between the 2 groups.[44] Current guidelines suggest that in patients with high-grade or intermediate-grade STS measuring more than 5 cm, doxorubicin-based chemotherapy can be considered a viable option in the adjuvant setting.[NCCN. NCCN Guidelines] Neoadjuvant Chemotherapy

The Italian Sarcoma Group conducted a randomized trial to assess the role of adjuvant chemotherapy in high-risk patients with spindle cell STS of extremities or pelvis. The group receiving adjuvant chemotherapy (epirubicin or ifosfamide with mesna) had a lower distant metastasis recurrence rate (45% versus 28%) and better overall survival at 4 years (69% versus 50%). However, at a 7-year follow-up, statistical significance was lost, and the local and distant relapse rates were similar (44% versus 45%).[43] The European Organisation for Research and Treatment of Cancer conducted a randomized trial (EORTC 62931) to investigate the role of adjuvant doxorubicin and ifosfamide in localized STS. All patients with positive margins also underwent adjuvant radiotherapy. Results from this study did not report any difference in the recurrence-free survival or overall survival between the 2 groups.[44] Current guidelines suggest that in patients with high-grade or intermediate-grade STS measuring more than 5 cm, doxorubicin-based chemotherapy can be considered a viable option in the adjuvant setting.[NCCN. NCCN Guidelines] Neoadjuvant Chemotherapy In theory, neoadjuvant chemotherapy can help shrink the tumor, thereby improving resectability, achieving negative margins, and enabling earlier control of microscopic disease, both local and distant. In addition, neoadjuvant chemotherapy can provide an essential clue about the tumor's responsiveness to chemotherapy. In a retrospective study examining STS and bone sarcoma, neoadjuvant chemotherapy was not associated with worse outcomes.[45] One of the early intergroup phase 3 trials evaluating the role of neoadjuvant chemotherapy (mesna, adriamycin [doxorubicin], ifosfamide, and dacarbazine [MAID] regimen) in patients with large high-grade extremity STS and bone sarcomas reported a complete response and partial response rate of 32%. Results from this study demonstrated a benefit in high-grade, borderline resectable lesions, particularly in younger patients, and in tumors with pulmonary metastases.[46] A European phase 2 and 3 trial in patients with extremity or trunk STS reported no difference in disease-free survival (56% versus 52%) between surgical procedures with or without neoadjuvant chemotherapy. The trial's limitations include the use of a lower dose of chemotherapy and an inconsistent definition of high-risk sarcomas, where low-grade tumors larger than 8 cm are categorized as high-risk sarcomas.[47]

In theory, neoadjuvant chemotherapy can help shrink the tumor, thereby improving resectability, achieving negative margins, and enabling earlier control of microscopic disease, both local and distant. In addition, neoadjuvant chemotherapy can provide an essential clue about the tumor's responsiveness to chemotherapy. In a retrospective study examining STS and bone sarcoma, neoadjuvant chemotherapy was not associated with worse outcomes.[45] One of the early intergroup phase 3 trials evaluating the role of neoadjuvant chemotherapy (mesna, adriamycin [doxorubicin], ifosfamide, and dacarbazine [MAID] regimen) in patients with large high-grade extremity STS and bone sarcomas reported a complete response and partial response rate of 32%. Results from this study demonstrated a benefit in high-grade, borderline resectable lesions, particularly in younger patients, and in tumors with pulmonary metastases.[46] A European phase 2 and 3 trial in patients with extremity or trunk STS reported no difference in disease-free survival (56% versus 52%) between surgical procedures with or without neoadjuvant chemotherapy. The trial's limitations include the use of a lower dose of chemotherapy and an inconsistent definition of high-risk sarcomas, where low-grade tumors larger than 8 cm are categorized as high-risk sarcomas.[47] Results from the Italian Study Group trial, which enrolled 252 patients to receive neoadjuvant chemotherapy followed by surgical procedure, and then randomized patients to receive 2 additional postoperative cycles (epirubicin and ifosfamide), showed that patients with positive or negative surgical margins had similar overall survival. Patients who had a positive surgical margin and received adjuvant radiotherapy along with neoadjuvant chemotherapy had a cumulative local recurrence rate of zero. Results from this study concluded that neoadjuvant chemotherapy could offset the negative impact of positive margins upon surgical resection and improve local control and survival.[48]

Results from the Italian Study Group trial, which enrolled 252 patients to receive neoadjuvant chemotherapy followed by surgical procedure, and then randomized patients to receive 2 additional postoperative cycles (epirubicin and ifosfamide), showed that patients with positive or negative surgical margins had similar overall survival. Patients who had a positive surgical margin and received adjuvant radiotherapy along with neoadjuvant chemotherapy had a cumulative local recurrence rate of zero. Results from this study concluded that neoadjuvant chemotherapy could offset the negative impact of positive margins upon surgical resection and improve local control and survival.[48] A histology-tailored approach was evaluated in a multicenter study, including the Italian, Spanish, French, and Polish sarcoma groups. The standard regimen of epirubicin and ifosfamide was compared to histology-tailored neoadjuvant treatment. The trial was stopped early due to overwhelming evidence in favor of standard chemotherapy with epirubicin and ifosfamide. The disease-free survival (62% versus 38%) and overall survival (89% versus 64%) favored the standard chemotherapy. Except for the myxoid liposarcoma subgroup, in which trabectedin was as effective as standard chemotherapy, all other disease subgroups showed poor outcomes with histology-tailored therapy.[49] For patients with high-risk leiomyosarcoma of the extremity, an anthracycline-based regimen is preferred in the neoadjuvant setting. A phase 3 randomized controlled trial is underway to test the utility of neoadjuvant chemotherapy (a combination of doxorubicin and ifosfamide) in patients with retroperitoneal soft tissue sarcoma.[50] Chemotherapy in Metastatic or Unresectable Soft Tissue Sarcoma Anthracycline-based regimens:

A histology-tailored approach was evaluated in a multicenter study, including the Italian, Spanish, French, and Polish sarcoma groups. The standard regimen of epirubicin and ifosfamide was compared to histology-tailored neoadjuvant treatment. The trial was stopped early due to overwhelming evidence in favor of standard chemotherapy with epirubicin and ifosfamide. The disease-free survival (62% versus 38%) and overall survival (89% versus 64%) favored the standard chemotherapy. Except for the myxoid liposarcoma subgroup, in which trabectedin was as effective as standard chemotherapy, all other disease subgroups showed poor outcomes with histology-tailored therapy.[49] For patients with high-risk leiomyosarcoma of the extremity, an anthracycline-based regimen is preferred in the neoadjuvant setting. A phase 3 randomized controlled trial is underway to test the utility of neoadjuvant chemotherapy (a combination of doxorubicin and ifosfamide) in patients with retroperitoneal soft tissue sarcoma.[50] Chemotherapy in Metastatic or Unresectable Soft Tissue Sarcoma Anthracycline-based regimens: Anthracyclines are usually the first choice of treatment for patients with metastatic STS. A response rate of 12% to 24% has been reported in the literature, although the risk of cardiotoxicity limits the use of doxorubicin.[51] Over many years, various chemotherapeutic agents have been combined with anthracyclines (doxorubicin or epirubicin) to improve outcomes. Although none of the regimens have ever demonstrated an improved overall survival, the combination arms have improved progression-free survival and response rates. The phase 3 trial EORTC Soft Tissue and Bone Sarcoma Group (STBSG) 62012 was pivotal, comparing single-agent doxorubicin with a combination of doxorubicin and ifosfamide. Although the response rate with combination therapy doubled (26.5% versus 13.6%), and progression-free survival improved (7.4 months versus 4.6 months), the overall survival benefit at 1 year (60% versus 51% patients; P = .76 and median survival of 14.3 months versus 12.8 months in the single-agent arm) did not reach statistical significance. Although this was a trial with negative results, the combination of doxorubicin and ifosfamide is still considered for patients requiring tumor shrinkage before a surgical procedure or when the tumor is close to a critical structure.[51]

Anthracyclines are usually the first choice of treatment for patients with metastatic STS. A response rate of 12% to 24% has been reported in the literature, although the risk of cardiotoxicity limits the use of doxorubicin.[51] Over many years, various chemotherapeutic agents have been combined with anthracyclines (doxorubicin or epirubicin) to improve outcomes. Although none of the regimens have ever demonstrated an improved overall survival, the combination arms have improved progression-free survival and response rates. The phase 3 trial EORTC Soft Tissue and Bone Sarcoma Group (STBSG) 62012 was pivotal, comparing single-agent doxorubicin with a combination of doxorubicin and ifosfamide. Although the response rate with combination therapy doubled (26.5% versus 13.6%), and progression-free survival improved (7.4 months versus 4.6 months), the overall survival benefit at 1 year (60% versus 51% patients; P = .76 and median survival of 14.3 months versus 12.8 months in the single-agent arm) did not reach statistical significance. Although this was a trial with negative results, the combination of doxorubicin and ifosfamide is still considered for patients requiring tumor shrinkage before a surgical procedure or when the tumor is close to a critical structure.[51] More recently, the combination of doxorubicin and trabectedin was evaluated in patients with metastatic or unresectable leiomyosarcoma, compared with doxorubicin monotherapy.[52] Patients in the experimental arm were to receive doxorubicin 60 mg/m² and trabectedin 1.1 mg/m² on day 1 of a 21-day cycle for 6 cycles, followed by trabectedin maintenance for 1 year. Patients in the control arm received doxorubicin monotherapy at 75 mg/m² on day 1 of a 21-day cycle for 6 cycles. The median progression-free survival was reported to favor the doxorubicin-trabectedin group (12 months versus 6 months; hazard ratio [HR], 0.37; 95% CI, 0.26-0.53). The 2-year progression-free survival also favored the doxorubicin-trabectedin group (30% versus 3% in the doxorubicin group). The median overall survival also favored the doxorubicin-trabectedin group (33 months versus 24 months; HR, 0.65; 95% CI, 0.44-0.95). The combination of doxorubicin and trabectedin is favored in patients with leiomyosarcoma due to its ease of administration and apparent survival benefit (secondary analysis). Gemcitabine-based regimens:

More recently, the combination of doxorubicin and trabectedin was evaluated in patients with metastatic or unresectable leiomyosarcoma, compared with doxorubicin monotherapy.[52] Patients in the experimental arm were to receive doxorubicin 60 mg/m² and trabectedin 1.1 mg/m² on day 1 of a 21-day cycle for 6 cycles, followed by trabectedin maintenance for 1 year. Patients in the control arm received doxorubicin monotherapy at 75 mg/m² on day 1 of a 21-day cycle for 6 cycles. The median progression-free survival was reported to favor the doxorubicin-trabectedin group (12 months versus 6 months; hazard ratio [HR], 0.37; 95% CI, 0.26-0.53). The 2-year progression-free survival also favored the doxorubicin-trabectedin group (30% versus 3% in the doxorubicin group). The median overall survival also favored the doxorubicin-trabectedin group (33 months versus 24 months; HR, 0.65; 95% CI, 0.44-0.95). The combination of doxorubicin and trabectedin is favored in patients with leiomyosarcoma due to its ease of administration and apparent survival benefit (secondary analysis). Gemcitabine-based regimens: Gemcitabine has shown activity in STS as a single agent and in combination with other chemotherapy agents. The infusion rate, fixed at 10 mg/m2/min, is superior to the 30-minute infusion, which is more common.[53] The phase 2 study, Comparison of Gemcitabine Versus Gemcitabine Plus Docetaxel in Unresectable Soft Tissue Sarcoma (SARC002), showed improved objective response rates, progression-free survival, and overall survival with gemcitabine plus docetaxel compared to gemcitabine alone in advanced, previously treated STS.[54] The subsets of both uterine leiomyosarcoma and extrauterine leiomyosarcoma were sensitive to the combination of gemcitabine and docetaxel. Following the success of this study, the combination of gemcitabine and docetaxel was compared with single-agent doxorubicin in the phase 3 Gemcitabine and Docetaxel Versus Doxorubicin as First-Line Treatment in Previously Untreated Advanced Unresectable or Metastatic Soft-Tissue Sarcomas (UK-GeDDiS) trial. No statistical difference was found between the 2 groups receiving doxorubicin and gemcitabine, or docetaxel, in the proportion of patients alive at 24 weeks. The median progression-free survival also did not differ between the 2 groups.[55] Notably, this trial used a lower dose of gemcitabine (675 mg/m2) and a standard dose of docetaxel (75 mg/m2), which may have contributed to lower efficacy and higher toxicity, respectively. The trial also recommends using doxorubicin-based regimens as the first line of treatment in patients with metastatic STS.[55]

Gemcitabine has shown activity in STS as a single agent and in combination with other chemotherapy agents. The infusion rate, fixed at 10 mg/m2/min, is superior to the 30-minute infusion, which is more common.[53] The phase 2 study, Comparison of Gemcitabine Versus Gemcitabine Plus Docetaxel in Unresectable Soft Tissue Sarcoma (SARC002), showed improved objective response rates, progression-free survival, and overall survival with gemcitabine plus docetaxel compared to gemcitabine alone in advanced, previously treated STS.[54] The subsets of both uterine leiomyosarcoma and extrauterine leiomyosarcoma were sensitive to the combination of gemcitabine and docetaxel. Following the success of this study, the combination of gemcitabine and docetaxel was compared with single-agent doxorubicin in the phase 3 Gemcitabine and Docetaxel Versus Doxorubicin as First-Line Treatment in Previously Untreated Advanced Unresectable or Metastatic Soft-Tissue Sarcomas (UK-GeDDiS) trial. No statistical difference was found between the 2 groups receiving doxorubicin and gemcitabine, or docetaxel, in the proportion of patients alive at 24 weeks. The median progression-free survival also did not differ between the 2 groups.[55] Notably, this trial used a lower dose of gemcitabine (675 mg/m2) and a standard dose of docetaxel (75 mg/m2), which may have contributed to lower efficacy and higher toxicity, respectively. The trial also recommends using doxorubicin-based regimens as the first line of treatment in patients with metastatic STS.[55] Ifosfamide monotherapy: Ifosfamide monotherapy is also active in patients with metastatic STS, resulting in a response rate of 25% and a median overall survival of 1 year. The drug exhibits a dose-response relationship, where higher doses yield a higher response rate, albeit at the cost of greater toxicity. However, higher doses have never translated into improved survival rates. Ifosfamide should be given at 9 to 10 g/m² with each cycle, repeated every 3 weeks. A dose beyond 12 g/m² saturates the enzymes and only adds to toxicity. Hemorrhagic cystitis, myelotoxicity, nephrotoxicity, and neurotoxicity are the limiting toxicities of ifosfamide.[56]

Ifosfamide monotherapy is also active in patients with metastatic STS, resulting in a response rate of 25% and a median overall survival of 1 year. The drug exhibits a dose-response relationship, where higher doses yield a higher response rate, albeit at the cost of greater toxicity. However, higher doses have never translated into improved survival rates. Ifosfamide should be given at 9 to 10 g/m² with each cycle, repeated every 3 weeks. A dose beyond 12 g/m² saturates the enzymes and only adds to toxicity. Hemorrhagic cystitis, myelotoxicity, nephrotoxicity, and neurotoxicity are the limiting toxicities of ifosfamide.[56] Results from a phase 3 randomized trial evaluating the effectiveness of high-dose ifosfamide with stem cell rescue in patients with STS demonstrated no overall survival benefit.[57] Results from an older meta-analysis of 1337 patients enrolled in EORTC-STBSG trials, evaluating the role of ifosfamide in the first-line setting, reported lower drug activity in patients with non–uterine leiomyosarcoma.[58] Hence, adding ifosfamide to doxorubicin is not routinely recommended in patients with non–uterine leiomyosarcoma unless the tumor is close to a critical organ or vessel. Second-line treatment: Multiple drugs have been evaluated as second-line treatment for STS or leiomyosarcoma. A gemcitabine-based regimen or an anthracycline-based regimen is an option in the second line, depending on the agents used in the first-line treatment. However, new targeted agents have provided many options. Monotherapy with trabectedin is the most promising of these and has been approved by the Food and Drug Administration (FDA) for patients with leiomyosarcoma and liposarcoma. Pazopanib, eribulin, liposomal doxorubicin, dacarbazine, and hormonal therapy (only for uterine leiomyosarcoma) are also active in leiomyosarcoma. Trabectedin (ET-743)

Multiple drugs have been evaluated as second-line treatment for STS or leiomyosarcoma. A gemcitabine-based regimen or an anthracycline-based regimen is an option in the second line, depending on the agents used in the first-line treatment. However, new targeted agents have provided many options. Monotherapy with trabectedin is the most promising of these and has been approved by the Food and Drug Administration (FDA) for patients with leiomyosarcoma and liposarcoma. Pazopanib, eribulin, liposomal doxorubicin, dacarbazine, and hormonal therapy (only for uterine leiomyosarcoma) are also active in leiomyosarcoma. Trabectedin (ET-743) Trabectedin is approved in the United States and European Union to treat patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have progressed after receiving a first-line anthracycline-based regimen or were ineligible for such a regimen. The approval basis was the progression-free survival benefit (4.2 months versus 1.5 months; CI, 0.44-0.70; P < .01) demonstrated in the phase 3 trial, where trabectedin was compared with dacarbazine. Although no overall survival benefit was observed in the trial, patients in the trabectedin arm had stable disease for a significantly longer time (6.01 months versus 4.17 months; P < .001) and had a higher clinical benefit ratio (34% versus 19%; HR, 2.3; CI, 1.45-3.7; P < .001) compared to those in the dacarbazine arm. The adverse effect profile is quite manageable with myelosuppression. Hepatic toxicity was reported as the most common grade 3 and 4 toxicity in the phase 3 trial.[59] Results from a recently concluded phase 2 trial by the French Sarcoma Group evaluated whether trabectedin can be discontinued after 6 cycles. After 6 cycles, patients who discontinued therapy experienced a rapid progression of the disease and a significantly reduced progression-free survival.[60] Currently, trabectedin is being tested in combination with immunotherapy and chemotherapy to improve treatment efficacy. Pazopanib

Trabectedin is approved in the United States and European Union to treat patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have progressed after receiving a first-line anthracycline-based regimen or were ineligible for such a regimen. The approval basis was the progression-free survival benefit (4.2 months versus 1.5 months; CI, 0.44-0.70; P < .01) demonstrated in the phase 3 trial, where trabectedin was compared with dacarbazine. Although no overall survival benefit was observed in the trial, patients in the trabectedin arm had stable disease for a significantly longer time (6.01 months versus 4.17 months; P < .001) and had a higher clinical benefit ratio (34% versus 19%; HR, 2.3; CI, 1.45-3.7; P < .001) compared to those in the dacarbazine arm. The adverse effect profile is quite manageable with myelosuppression. Hepatic toxicity was reported as the most common grade 3 and 4 toxicity in the phase 3 trial.[59] Results from a recently concluded phase 2 trial by the French Sarcoma Group evaluated whether trabectedin can be discontinued after 6 cycles. After 6 cycles, patients who discontinued therapy experienced a rapid progression of the disease and a significantly reduced progression-free survival.[60] Currently, trabectedin is being tested in combination with immunotherapy and chemotherapy to improve treatment efficacy. Pazopanib Multiple antiangiogenic agents, such as bevacizumab, sorafenib, sunitinib, pazopanib, vandetanib, DC-101, and TNP-470, have shown antisarcoma activity in mouse models. Few of these drugs showed clinical activity in phase 1 trials; however, the success of most could not be replicated in phase 2 trials.[61]  Pazopanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of advanced STS, regardless of histology, in patients who have previously received chemotherapy. Pazopanib is administered orally at a daily dose of 800 mg. Pazopanib is an inhibitor of vascular endothelial growth factor receptor–mediated angiogenesis and blocks the growth-promoting receptor tyrosine kinases, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and KIT-1. The FDA approved the drug based on the progression-free survival benefit (4.6 months versus 1.6 months; HR, 0.35; 95% CI, 0.26-0.48; P < .001) observed in the phase 3 Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE) trial, where the study compared pazopanib to placebo. The pazopanib arm showed no overall survival benefit compared with the placebo arm. Of note, liposarcoma was excluded from the phase 3 trial due to a poor response in the phase 2 trial.[62] Hepatotoxicity, cardiotoxicity, and thyroid dysfunction are some of the most common adverse effects. Rarely, reports of reversible posterior leukoencephalopathy syndrome have been documented.[63][64]

Multiple antiangiogenic agents, such as bevacizumab, sorafenib, sunitinib, pazopanib, vandetanib, DC-101, and TNP-470, have shown antisarcoma activity in mouse models. Few of these drugs showed clinical activity in phase 1 trials; however, the success of most could not be replicated in phase 2 trials.[61]  Pazopanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of advanced STS, regardless of histology, in patients who have previously received chemotherapy. Pazopanib is administered orally at a daily dose of 800 mg. Pazopanib is an inhibitor of vascular endothelial growth factor receptor–mediated angiogenesis and blocks the growth-promoting receptor tyrosine kinases, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and KIT-1. The FDA approved the drug based on the progression-free survival benefit (4.6 months versus 1.6 months; HR, 0.35; 95% CI, 0.26-0.48; P < .001) observed in the phase 3 Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE) trial, where the study compared pazopanib to placebo. The pazopanib arm showed no overall survival benefit compared with the placebo arm. Of note, liposarcoma was excluded from the phase 3 trial due to a poor response in the phase 2 trial.[62] Hepatotoxicity, cardiotoxicity, and thyroid dysfunction are some of the most common adverse effects. Rarely, reports of reversible posterior leukoencephalopathy syndrome have been documented.[63][64] Eribulin (E7389)

Multiple antiangiogenic agents, such as bevacizumab, sorafenib, sunitinib, pazopanib, vandetanib, DC-101, and TNP-470, have shown antisarcoma activity in mouse models. Few of these drugs showed clinical activity in phase 1 trials; however, the success of most could not be replicated in phase 2 trials.[61]  Pazopanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of advanced STS, regardless of histology, in patients who have previously received chemotherapy. Pazopanib is administered orally at a daily dose of 800 mg. Pazopanib is an inhibitor of vascular endothelial growth factor receptor–mediated angiogenesis and blocks the growth-promoting receptor tyrosine kinases, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and KIT-1. The FDA approved the drug based on the progression-free survival benefit (4.6 months versus 1.6 months; HR, 0.35; 95% CI, 0.26-0.48; P < .001) observed in the phase 3 Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE) trial, where the study compared pazopanib to placebo. The pazopanib arm showed no overall survival benefit compared with the placebo arm. Of note, liposarcoma was excluded from the phase 3 trial due to a poor response in the phase 2 trial.[62] Hepatotoxicity, cardiotoxicity, and thyroid dysfunction are some of the most common adverse effects. Rarely, reports of reversible posterior leukoencephalopathy syndrome have been documented.[63][64] Eribulin (E7389) Eribulin mesylate (E7389) is an analog of halichondrin B approved for metastatic breast cancer. Eribulin mesylate blocks the G2 and M phases of the cell cycle via a tubulin-based antimitotic mechanism. The antimitotic mechanism inhibits spindle formation in the cell cycle, leading to cancer cell apoptosis.[65] The FDA has approved eribulin for patients with unresectable or metastatic liposarcoma whose tumors progressed after anthracycline chemotherapy, based on the results of the phase 3 trial (E7389-G000-309).[66] In a preplanned subset analysis of the phase 3 trial results, patients with leiomyosarcoma showed efficacy comparable to that of single-agent dacarbazine. The median overall survival for eribulin versus dacarbazine (12.7 months versus 13.0 months, respectively; HR, 0.93 [95% CI, 0.71-1.20]; P = .57) and the median progression-free survival (2.2 months versus 2.6 months, respectively; HR, 1.07 [95% CI, 0.84-1.38]; P = .58) and objective response rate (5% versus 7%) were not significantly different.[67] The FDA has not yet approved the drug for leiomyosarcoma. However, eribulin provides a reasonable option for patients with leiomyosarcoma. Eribulin is administered intravenously at a dosage of 1.4 mg/m² over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. Close monitoring of liver and renal function is necessary, with appropriate dose adjustments in patients with impairment of either organ. Adverse effects of eribulin include neutropenia, peripheral neuropathy, and QTc interval prolongation.

Eribulin mesylate (E7389) is an analog of halichondrin B approved for metastatic breast cancer. Eribulin mesylate blocks the G2 and M phases of the cell cycle via a tubulin-based antimitotic mechanism. The antimitotic mechanism inhibits spindle formation in the cell cycle, leading to cancer cell apoptosis.[65] The FDA has approved eribulin for patients with unresectable or metastatic liposarcoma whose tumors progressed after anthracycline chemotherapy, based on the results of the phase 3 trial (E7389-G000-309).[66] In a preplanned subset analysis of the phase 3 trial results, patients with leiomyosarcoma showed efficacy comparable to that of single-agent dacarbazine. The median overall survival for eribulin versus dacarbazine (12.7 months versus 13.0 months, respectively; HR, 0.93 [95% CI, 0.71-1.20]; P = .57) and the median progression-free survival (2.2 months versus 2.6 months, respectively; HR, 1.07 [95% CI, 0.84-1.38]; P = .58) and objective response rate (5% versus 7%) were not significantly different.[67] The FDA has not yet approved the drug for leiomyosarcoma. However, eribulin provides a reasonable option for patients with leiomyosarcoma. Eribulin is administered intravenously at a dosage of 1.4 mg/m² over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. Close monitoring of liver and renal function is necessary, with appropriate dose adjustments in patients with impairment of either organ. Adverse effects of eribulin include neutropenia, peripheral neuropathy, and QTc interval prolongation. Immunotherapy

Eribulin mesylate (E7389) is an analog of halichondrin B approved for metastatic breast cancer. Eribulin mesylate blocks the G2 and M phases of the cell cycle via a tubulin-based antimitotic mechanism. The antimitotic mechanism inhibits spindle formation in the cell cycle, leading to cancer cell apoptosis.[65] The FDA has approved eribulin for patients with unresectable or metastatic liposarcoma whose tumors progressed after anthracycline chemotherapy, based on the results of the phase 3 trial (E7389-G000-309).[66] In a preplanned subset analysis of the phase 3 trial results, patients with leiomyosarcoma showed efficacy comparable to that of single-agent dacarbazine. The median overall survival for eribulin versus dacarbazine (12.7 months versus 13.0 months, respectively; HR, 0.93 [95% CI, 0.71-1.20]; P = .57) and the median progression-free survival (2.2 months versus 2.6 months, respectively; HR, 1.07 [95% CI, 0.84-1.38]; P = .58) and objective response rate (5% versus 7%) were not significantly different.[67] The FDA has not yet approved the drug for leiomyosarcoma. However, eribulin provides a reasonable option for patients with leiomyosarcoma. Eribulin is administered intravenously at a dosage of 1.4 mg/m² over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. Close monitoring of liver and renal function is necessary, with appropriate dose adjustments in patients with impairment of either organ. Adverse effects of eribulin include neutropenia, peripheral neuropathy, and QTc interval prolongation. Immunotherapy Immunotherapy has not shown much promise in the STS subgroup overall. The evidence is limited that immunotherapy works for patients diagnosed with STS, except for a few case reports. Results from 2 trials evaluating nivolumab and pembrolizumab did not demonstrate any benefit in the leiomyosarcoma subgroup.[68][69] The phase 2 Alliance A091401 trial evaluated the role of single-agent nivolumab versus the combination of nivolumab and ipilimumab in patients with heavily treated, unselected, metastatic sarcoma. A total of 38 patients were evaluable in each arm. One-third of all the patients had uterine or extrauterine leiomyosarcoma. Of the 8 patients who achieved a response in either arm, 3 had leiomyosarcoma. The objective response rate for single-agent nivolumab was 8%, compared with 16% in the arm treated with nivolumab and ipilimumab. The median overall survival was 14.3 months in the combination arm, but the rate of grade 3 and 4 events was 14%. The lower rate of adverse events was attributed to the lower ipilimumab dose (1 mg/kg). These findings suggest that a high tumor mutational burden, characteristic of leiomyosarcoma, may have led to greater activity of the combination of nivolumab and ipilimumab in this tumor type.[68] Currently, multiple agents are under investigation in combination with chemotherapy and radiotherapy, which are in phase 1 to 2 studies. The FDA has not yet approved the combination of ipilimumab and nivolumab in STS.

Immunotherapy has not shown much promise in the STS subgroup overall. The evidence is limited that immunotherapy works for patients diagnosed with STS, except for a few case reports. Results from 2 trials evaluating nivolumab and pembrolizumab did not demonstrate any benefit in the leiomyosarcoma subgroup.[68][69] The phase 2 Alliance A091401 trial evaluated the role of single-agent nivolumab versus the combination of nivolumab and ipilimumab in patients with heavily treated, unselected, metastatic sarcoma. A total of 38 patients were evaluable in each arm. One-third of all the patients had uterine or extrauterine leiomyosarcoma. Of the 8 patients who achieved a response in either arm, 3 had leiomyosarcoma. The objective response rate for single-agent nivolumab was 8%, compared with 16% in the arm treated with nivolumab and ipilimumab. The median overall survival was 14.3 months in the combination arm, but the rate of grade 3 and 4 events was 14%. The lower rate of adverse events was attributed to the lower ipilimumab dose (1 mg/kg). These findings suggest that a high tumor mutational burden, characteristic of leiomyosarcoma, may have led to greater activity of the combination of nivolumab and ipilimumab in this tumor type.[68] Currently, multiple agents are under investigation in combination with chemotherapy and radiotherapy, which are in phase 1 to 2 studies. The FDA has not yet approved the combination of ipilimumab and nivolumab in STS. Tumors that Exhibit Specific Gene Mutations Microsatellite instability-high: The FDA granted accelerated approval for pembrolizumab in May 2017 for adult and pediatric patients with unresectable or metastatic solid tumors exhibiting microsatellite instability-high or mismatch repair deficiency. The eligible patients included those whose tumors progressed after prior treatment and those with no satisfactory alternative treatment options.[70] The approval was granted based on the 149 patients included in the KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158 trials.[70] Neurotrophic tyrosine kinase inhibitor — entrectinib:

The FDA granted accelerated approval for pembrolizumab in May 2017 for adult and pediatric patients with unresectable or metastatic solid tumors exhibiting microsatellite instability-high or mismatch repair deficiency. The eligible patients included those whose tumors progressed after prior treatment and those with no satisfactory alternative treatment options.[70] The approval was granted based on the 149 patients included in the KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158 trials.[70] Neurotrophic tyrosine kinase inhibitor — entrectinib: Entrectinib has approval for patients who have a solid tumor that harbors the neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. The FDA approved entrectinib in April 2019 based on an integrated analysis of the phase 2 Spectrum of Antitumor Activity of Entrectinib (STARTRK-2), phase 1 STARTRK-1, and the phase 1 ALK Inhibitor Activity (ALKA-372-001) trials. These trials were conducted across 15 countries and 150 clinical trial sites. Entrectinib demonstrated an objective response rate of 57%.[71] Dacarbazine Dacarbazine is an alkylating agent that has activity in STS. The drug has shown a response rate of 30% in combination with doxorubicin versus doxorubicin alone and a response rate of 49% in combination with gemcitabine versus dacarbazine alone.[56][72] Results from a recent phase 2 trial evaluating the combination of sorafenib and dacarbazine in patients with metastatic leiomyosarcoma (approximately 60% of patients), synovial sarcoma, and malignant peripheral nerve sheath tumor showed that the trial achieved its primary end point of a disease control rate of 46% at 18 weeks.[73] The dose depends on the protocol used. Myelosuppression and hepatotoxicity are significant adverse events. Pegylated liposomal doxorubicin

Dacarbazine is an alkylating agent that has activity in STS. The drug has shown a response rate of 30% in combination with doxorubicin versus doxorubicin alone and a response rate of 49% in combination with gemcitabine versus dacarbazine alone.[56][72] Results from a recent phase 2 trial evaluating the combination of sorafenib and dacarbazine in patients with metastatic leiomyosarcoma (approximately 60% of patients), synovial sarcoma, and malignant peripheral nerve sheath tumor showed that the trial achieved its primary end point of a disease control rate of 46% at 18 weeks.[73] The dose depends on the protocol used. Myelosuppression and hepatotoxicity are significant adverse events. Pegylated liposomal doxorubicin Pegylated liposomal doxorubicin is a formulation of doxorubicin in poly(ethylene glycol)-coated (stealth) liposomes. The drug has a prolonged circulation time and does not cause cardiotoxicity like doxorubicin. Dermatologic toxicity is the main adverse effect of pegylated liposomal doxorubicin.[74] Results from multiple studies have demonstrated the activity of pegylated liposomal doxorubicin in metastatic STS, either alone or in combination with ifosfamide.[75][76] Pegylated liposomal doxorubicin was also tested against single-agent doxorubicin in an EORTC-STBSG phase 2 trial.[76] Although comparable response rates were reported amongst the 2 groups, as expected, cardiotoxicity was significantly lower in the pegylated liposomal doxorubicin arm. The FDA has not yet approved pegylated liposomal doxorubicin for patients with leiomyosarcoma. Hormonal Therapy As with other gynecological malignant neoplasms, uterine leiomyosarcoma exhibits estrogen receptors in 7% to 70% of patients and progesterone receptors in 17% to 60% of patients. Results from retrospective studies have shown aromatase inhibitor activity with letrozole, anastrozole, or exemestane in uterine leiomyosarcoma, with partial response reported in 9% to 12% of patients.[77][78]

Leiomyosarcoma staging is according to the organ of origin. Uterine leiomyosarcoma staging follows the Federation of Gynecology and Obstetrics staging system. Extrauterine leiomyosarcoma staging follows the American Joint Committee on Cancer (AJCC) staging system. However, the 8th edition of the AJCC has resolved a long-standing source of variability in STS staging. In the latest edition, AJCC has provided a separate staging system for STS of the retroperitoneum, head and neck region, and extremities or trunk.[79] Notably, despite the AJCC 8th edition addressing some significant issues of previous editions, the staging system still does not translate well into survival.[79] Grading of Soft Tissue Sarcoma or Leiomyosarcoma The College of American Pathologists and the AJCC recommend the 3-tiered system of the French Federation of Cancer Centres/Fédération Nationale des Centres de Lutte Contre le Cancer. The relative ease of use and well-balanced components, including a score for dedifferentiation (1-3), mitoses (1-3), and necrosis (0-2), make the French system a suitable scoring system.[80] Tumor differentiation 1: Closely resembles normal adult mesenchymal tissue 2: Histologic typing is uncertain 3: Embryonal or undifferentiated sarcoma, sarcoma of doubtful type, synovial sarcoma, soft tissue osteosarcoma, and Ewing sarcoma or primitive neuroectodermal tumor of soft tissue Mitotic count: measured in the most mitotically active area of sarcoma, 10 successive HPFs are assessed using a 40x objective. 1: 0-9 mitosis/HPF 2: 10-19 mitosis/HPF 3: >20 mitosis/HPF Tumor necrosis 0: No necrosis 1: <50% necrosis 2: >50% necrosis Grading System The grading system entails assigning a cumulative score to the sarcoma based on evaluations of tumor differentiation, mitotic count, and tumor necrosis. For instance, a leiomyosarcoma with a differentiation score of 1, a mitotic count score of 1, and a tumor necrosis score of 0 would be classified as grade 2 (1 + 1 + 0). GX: Grade cannot be assessed G1: Total score = 2–3 G2: Total score = 4–5 G3: Total score = 6–8 AJCC 8th edition staging for soft tissue sarcoma of extremities and trunk: Tumor, Node, Metastasis (TNM) staging: Tumor staging (T): T1: Tumor less than or equal to 5 cm in greatest dimension T2: Tumor greater than 5 cm and less than or equal to 10 cm in greatest dimension T3: Tumor greater than 10 cm and less than or equal to 15 cm in greatest dimension

AJCC 8th edition staging for soft tissue sarcoma of extremities and trunk: Tumor, Node, Metastasis (TNM) staging: Tumor staging (T): T1: Tumor less than or equal to 5 cm in greatest dimension T2: Tumor greater than 5 cm and less than or equal to 10 cm in greatest dimension T3: Tumor greater than 10 cm and less than or equal to 15 cm in greatest dimension T4: Tumor greater than 15 cm in greatest dimension Node staging (N): N0: No regional lymph node metastasis or unknown lymph node status N1: Regional lymph node metastasis Metastasis staging (M): M0: No distant metastasis M1: Distant metastasis Stage groups: Stage I: Stage IA: T1; N0; M0; G1 Stage IB: T2, T3, T4; N0; M0; G1 Stage II: T1; N0; M0; G2/3 Stage III Stage IIIA: T2; N0; M0; G2/3 Stage IIIB: T3, T4; N0; M0; G2/3 Stage IV: Any T; N1; M0; any G — Any T; any N; M1; any G [79] AJCC 8th edition staging for retroperitoneum : The staging of STS of the retroperitoneum is similar to the staging system used for extremities and trunk. The only difference is that in patients with STS of the retroperitoneum, those with N1 node-positive disease are classified under stage IIIB. In contrast, in STS of the extremities and trunk, patients with N1 node-positive disease are classified as stage IV.[81] AJCC 8th edition staging for head and neck: No staging groups exist in the head and neck region in the AJCC 8th edition because classification would require the application of the French grading system, and very extensive lesions (T4) remain unclassified.[80] T category T1: Less than or equal to 2 cm T2: Greater than 2 but less than or equal to 4 cm T3: Greater than 4 cm T4: Invasion of adjoining structures T4a: Invasion of the orbit, skull base, dura, central compartment viscera, pterygoid muscles, or facial skeletal involvement T4b: Invasion of brain parenchyma, involvement of the central nervous system through the perineural spread, invasion of prevertebral muscle, or carotid artery encasement N category N0: No regional lymph node metastasis N1: Regional lymph node metastasis M category M0: No distant Metastasis M1: Distant metastasis Federation of Gynecology and Obstetrics staging for uterine leiomyosarcoma (2009): Stage I: Tumor limited to the uterus IA: Less than 5 cm in greatest dimension IB: More than 5 cm in greatest dimension Stage II: Tumor extends beyond the uterus, within the pelvis IIA: Adnexal involvement IIB: Involvement of other pelvic tissues Stage III: Tumor invades abdominal tissues IIIA: 1 site

Federation of Gynecology and Obstetrics staging for uterine leiomyosarcoma (2009): Stage I: Tumor limited to the uterus IA: Less than 5 cm in greatest dimension IB: More than 5 cm in greatest dimension Stage II: Tumor extends beyond the uterus, within the pelvis IIA: Adnexal involvement IIB: Involvement of other pelvic tissues Stage III: Tumor invades abdominal tissues IIIA: 1 site IIIB: more than 1 site IIIC: Involves pelvic and para-aortic lymph nodes Stage IV: Tumor invades pelvic organs and distant metastasis IVA: Invasion of the bladder or rectum IVB: Distant metastases [10]

The 3 most important prognostic factors are histologic grade, tumor size, and tumor depth. Tumor size, bone, or neurovascular involvement, together with the grade of the tumor, are significantly associated with poor outcomes, specifically in leiomyosarcoma.[82] Available calculators and normograms have been developed to help determine prognosis.[83] Histologic grade is the most predictive risk factor. Histologic grade can independently estimate cancer aggressiveness, the probability of distant metastasis, and disease-specific survival.[82][84][85] Leiomyosarcoma is inherently an aggressive malignant neoplasm, with 90% of patients diagnosed with grade 2 to 3 cancer; as a result, these patients are at a higher risk of distant recurrence.[84] Larger tumors have a worse outcome, especially with tumors greater 10 cm.[86] Tumor location is an independent prognostic risk factor. Leiomyosarcoma of the extremities has a better outcome compared to retroperitoneal leiomyosarcoma.[85] Uterine tumors and those arising from large visceral blood vessels have been reported to have worse outcomes, although the data are debatable. Tumor depth is an important prognostic factor independent of tumor size and histologic grade, directly correlating with a worse outcome.[79][87][88] Uterine leiomyosarcoma also follows the same pattern in prognostic features. Various studies have reported that age, disease stage, surgical margins, tumor size, cellular atypia, mitotic rate, lymphovascular channel involvement, lymph node positivity, oophorectomy, and the presence or absence of necrosis can determine prognosis.[10] Memorial Sloan Kettering has developed a clinical nomogram that uses age, grade, tumor size, mitotic rate, presence of cervical invasion, locoregional metastasis, and distant metastasis to estimate 5-year overall survival. The nomogram performed better than more traditional staging systems, such as the Federation of Gynecology and Obstetrics and AJCC classifications, in predicting overall survival.[89].

Uterine leiomyosarcoma also follows the same pattern in prognostic features. Various studies have reported that age, disease stage, surgical margins, tumor size, cellular atypia, mitotic rate, lymphovascular channel involvement, lymph node positivity, oophorectomy, and the presence or absence of necrosis can determine prognosis.[10] Memorial Sloan Kettering has developed a clinical nomogram that uses age, grade, tumor size, mitotic rate, presence of cervical invasion, locoregional metastasis, and distant metastasis to estimate 5-year overall survival. The nomogram performed better than more traditional staging systems, such as the Federation of Gynecology and Obstetrics and AJCC classifications, in predicting overall survival.[89]. Results from a recent meta-analysis of 580 patients with metastatic STS and lung-only metastasis recorded in the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) trials showed that age, time from initial diagnosis to treatment, performance status, and involvement of the primary site can help predict prognosis in this subgroup. Results from the meta-analysis also showed that patients with a nontarget pulmonary lesion (pleural involvement) had the worst outcomes. Additionally, the findings confirmed that patients treated with the combination of doxorubicin and ifosfamide in the first-line setting, followed by monotherapy with an anthracycline, ifosfamide, or trabectedin or brostallicin, had the best overall and progression-free survival.[82][90] Available calculators and normograms have been developed to help determine prognosis.[83]

Leiomyosarcoma is a rare but aggressive STS with no clear etiology in most patients and is generally seen in older adults. Patients with soft tissue masses of the trunk or extremities should seek evaluation by a specialist, particularly if the mass is increasing in size. For abdominopelvic tumors, symptoms are often vague and depend on the site of the lesion. Diagnosis and treatment at a center of excellence are highly recommended. The mainstay of treatment is surgical procedure, with radiation and chemotherapy serving as adjuncts. Metastatic disease is fatal and generally shows a poor response to systemic therapy. Participation in clinical trials is crucial to better understanding this disease.

Key facts for clinicians managing patients with leiomyosarcoma include the following: Patients diagnosed with leiomyosarcoma should be treated at centers that experience a high volume of such patients. All patient treatment plans should be discussed at tumor boards, including surgical oncologists or orthopedic oncologists, radiation oncologists, pathologists trained in diagnosing sarcoma, medical oncologists, and radiologists. Gynecologists and oncologists should collaborate with surgical oncologists and the team listed above to diagnose patients with uterine leiomyosarcoma. The 3 most important prognostic factors are histologic grade, tumor depth, and tumor size. Surgical resection with negative margins leads to the best overall survival outcomes. Preoperative radiotherapy decreases local recurrence and increases local disease-free survival but has not shown a benefit for distant relapse or overall survival. Preoperative radiotherapy is associated with fewer complications compared to postoperative radiotherapy, although wound complications are higher with preoperative radiotherapy. A gap of 4 to 5 weeks between surgical procedure and radiotherapy appears to reduce wound complications when preoperative radiotherapy is used. Neoadjuvant chemotherapy has proven effective in high-risk STS or leiomyosarcoma of the extremity or trunk; however, the evidence is limited. If neoadjuvant therapy is chosen, then a standard chemotherapy regimen with anthracycline and ifosfamide should be used rather than tailoring the regimen according to the histology. If adjuvant therapy is administered, then anthracycline and ifosfamide should be used. Anthracycline-based regimens are usually the first-line regimens for metastatic STS or leiomyosarcoma. A gemcitabine-docetaxel combination can be the first-line regimen for uterine leiomyosarcoma. Ifosfamide is less effective in patients with extrauterine leiomyosarcoma compared to those with uterine leiomyosarcoma. Although the Gemcitabine and Docetaxel Versus Doxorubicin as First-Line Treatment in Previously Untreated Advanced Unresectable or Metastatic Soft-Tissue Sarcomas (UK-GeDDiS) trial did not demonstrate a difference between the 2 arms, a doxorubicin-based regimen remains the first-line treatment.

Ifosfamide is less effective in patients with extrauterine leiomyosarcoma compared to those with uterine leiomyosarcoma. Although the Gemcitabine and Docetaxel Versus Doxorubicin as First-Line Treatment in Previously Untreated Advanced Unresectable or Metastatic Soft-Tissue Sarcomas (UK-GeDDiS) trial did not demonstrate a difference between the 2 arms, a doxorubicin-based regimen remains the first-line treatment. Trabectedin is an effective treatment for leiomyosarcoma. Clinicians should not discontinue the drug in patients who respond to trabectedin unless the patient develops toxicity or tumor progression. Pazopanib, eribulin, dacarbazine, and pegylated liposomal doxorubicin are effective as single agents in leiomyosarcoma.

Leiomyosarcoma is one of the most common subtypes of soft tissue sarcoma. The clinical presentation may be nonspecific and depends on the site of origin. A mass suspected to be a sarcoma should have interdisciplinary teams involved from the beginning. An image-guided core needle biopsy is critical to ensure the fascial and peritoneal planes remain intact. Treatment relies on a surgical procedure, but chemotherapy and radiation are commonly used. The timing and sequence of therapies must be carefully planned. Patient outcomes are dependent on timely, evidence-based treatment. Given the rarity of most individual sarcomas, enrolling patients in clinical trials and staying up to date on developments aimed at improving patient outcomes are critical. Ultimately, patient outcomes rely on interdisciplinary communication, cooperation, and action. Inappropriate treatment of sarcomas often begins even before diagnosis, with poorly planned or conducted biopsies. Early involvement of a dedicated, interdisciplinary team is crucial; clinicians should ensure that all patients with suspected sarcoma are referred to a high-volume center as early as possible.