Continuing Education Activity

This activity reviews the evaluation, diagnosis, treatment, and latest advances in the field of leiomyosarcoma. It will discuss the existing literature and present the most recent evidence regarding treatment options available for patients diagnosed with soft-tissue sarcoma/leiomyosarcoma. It will also review the ongoing phase I-II trials and medications currently under evaluation to treat soft-tissue sarcoma/leiomyosarcoma. This activity will also highlight the interprofessional team's role in managing leiomyosarcoma to optimize patient outcomes.

Objectives:

• Identify the etiology of leiomyosarcoma.
• Outline the management options available for leiomyosarcoma.
• Summarize the latest molecules and clinical trials exploring treatment options for all soft-tissue sarcoma, including leiomyosarcoma.
• Explain interprofessional team strategies for improving care coordination and communication to advance leiomyosarcoma and improve outcomes.

Introduction

Soft-tissue sarcoma (STS) arises mainly from the embryonic mesoderm with some contribution from the neuroectoderm. STS is a rare malignancy that accounts for less than 1% of all adult cancers. It encompasses a heterogeneous group of tumors with over 175 molecular subtypes. Leiomyosarcoma (LMS) is one of the more common subtypes of STS, comprising up to 10-20% of all sarcomas. Classically, LMS would either originate directly from the smooth muscle cells or from the precursor mesenchymal stem cells that would eventually differentiate into smooth muscle cells.

Although these cells are present everywhere, LMS shows a predilection for soft tissues and abdominopelvic organs compared to extremities. The genetic abnormalities in LMS are very complex and make it moderately sensitive to chemotherapy. Although disputed in literature, the behavior of LMS and sensitivity to treatment seems to depend on the organ of origin. An interprofessional approach is deemed necessary for the treatment of LMS. Patients with STS, when treated at centers that experience a high volume of such patients, have been shown to have better outcomes. The advent of targeted agents and immunotherapy, along with our increasing understanding of molecular subtypes of various STS, has ushered in a new era of treatment for STS.

Etiology

There is no definite identifiable factor as a causative factor for LMS. Prior history of radiotherapy (RT), which is one of the most significant risk factors for developing STS, can also lead to the development of LMS.[1] Patients with genetic syndromes like hereditary retinoblastoma (RB1 gene deletion) and Li-Fraumeni syndrome (mutation in the TP53 gene) can develop LMS amongst other STS.[2] The use of tamoxifen has had rare associations with uterine LMS; however, such an association remains anecdotal.[3] LMS has little data in immunocompromised patients (recipients of solid organ transplants and those with congenital mutations).[4] In the pre-HAART era, the Epstein Barr virus correlated with LMS.[5] There is currently no evidence to support the theory that leiomyomas can convert into LMS.[6]

Epidemiology

Leiomyosarcoma, together with liposarcoma, are the most common subtypes of STS.[7] LMS accounts for up to 25% of all newly diagnosed STS.[8] It occurs more commonly in the abdomen, retroperitoneum, large blood vessels, and uterus compared to limbs, where it comprises 10 to 15% of all extremity-associated sarcomas. In the limbs, LMS occurs more commonly in the thigh region. It is a disease of the older population, usually peaking after the seventh decade of life. However, uterine LMS can start after the third decade of life, and the peak incidence occurs in women of the perimenopausal age group (fifth decade of life). While retroperitoneal LMS and LMS associated with blood vessels are more common in women, non-cutaneous soft tissue and cutaneous LMS more commonly occur in men.[2] 

Uterine sarcomas comprise about 3 to 7% of all uterine malignancies.[9] LMS is the most common subtype representing nearly 80% of all uterine sarcomas.[10] It must be noted here that carcinosarcoma of the uterus (previously called malignant mixed Mullerian tumor) is no longer considered a sarcoma but classifies under dedifferentiated endometrial carcinoma.[9]

Pathophysiology

LMS belongs to the group of STS with complex and unbalanced karyotypes, which result in severe genomic instability. The cytogenetic and molecular changes in LMS are not consistent, which makes it a very heterogeneous disease. Some of the most common changes in LMS occur in the form of loss in chromosomes 10q(PTEN) and 13q (RB1) and gain at 17p (TP53). A few noteworthy points to be noted here are as follows.[2]

1. Loss of 13q results in mutation in the RB1 gene (retinoblastoma gene), which is a tumor suppressor gene- identified in 90% of patients with LMS.
2. A lower rate of p53 is observable in LMS compared to other STS.
3. A higher rate of amplification of MDM2 is present in patients with LMS.
4. The deletion of chromosome 10q leads to a mutation in the PTEN tumor suppressor gene, which leads to the activation of the phosphatidylinositol 3-kinase (PI3K)/ (protein kinase B) AKT pathway.
5. Profiling studies have identified new targets, such as Aurora-A and Aurora-B kinases, which are consistently overexpressed in uterine LMS and can be therapeutic targets in the future. 

Histopathology

Classically, LMS arises from the smooth muscle cells or the mesenchymal cells committed to becoming smooth muscle cells in the future.[11] Histologically, LMS of any origin shows intersecting, sharply marginated fascicles of spindle cells with elongated, hyperchromatic nuclei and abundant eosinophilic cytoplasm.[6] Varying degrees of pleomorphism can occur, where extensive pleomorphism resembles any undifferentiated STS.[6] Histologically, LMS can divide into spindle cell and non-spindle cell morphology. The clinical significance of different kinds of LMS is not completely understood, but few anecdotal reports have suggested that the non-spindle morphology may have worse outcomes.[12][13]

Uterine LMS is the most common form of LMS. Uterine LMS subcategorize into spindle cell, epitheloid, myxoid, and rare types. On gross inspection, most uterine LMS are large solitary lesions with irregular and infiltrative borders. They are usually present intramurally; however, 5% can originate from the cervix. If a specimen contains multiple leiomyomas, then the biggest one must be evaluated for LMS. LMS lacks the whorled appearance of benign leiomyoma and has alternating areas of necrosis and hemorrhage.[12] Necrosis within the uterine LMS is an important feature. Tumor cell necrosis (also called bad necrosis), characterized by an abrupt transition from viable to necrotic cells, is seen in up to 80% of uterine LMS. Infarct necrosis (also called good necrosis) is a feature of benign leiomyoma and few uterine LMS. When there is difficulty in determining the type of necrosis in a tumor with high atypia/ mitotic count, it is called a smooth-muscle tumor of uncertain malignant potential (STUMP).[12]

The uterine LMS accounts for 1 in 800 uterine smooth muscle cell tumors, which raises the possibility that LMS is a de novo entity.[12] Micro-RNA analysis (miRNA) have shown different expression profiles between LMS and leiomyoma, further establishing the existential differences between the two entities.[14] However, the existence of 'leiomyoma-like' areas within the LMS 'labeled' tumor, and similar genetic alternations (deactivation of the X-linked chromosome) in both benign leiomyoma and malignant LMS suggest that a minority of LMS may be arising from being leiomyomas.[12] 

Immunohistochemistry

LMS is usually identifiable on light microscopy. Immunohistochemical (IHC) stains are used for confirmation or in highly undifferentiated tumors. Stains like desmin, smooth-muscle actin and h-caldesmon, may be used to confirm the smooth-muscle origin. For epithelioid tumors, histone deacetylase-8 and myocardin are considered superior to desmin and h-caldesmon. Immunopositivity for p16 and p53 with a high Ki-67 proliferation index has also demonstrated high sensitivity and specificity for differentiating LMS and leiomyomas. Compared to leiomyoma, LMS has a lower expression of estrogen (40% in LMS versus 70% in leiomyoma) and progesterone receptors (38% versus 88%).[15].

Most uterine LMS express the platelet-derived growth factor receptor-alfa, Wilms’ tumor gene 1, aromatase, and gonadotropin-releasing hormone receptor. The expression of CD117 (KIT mutation) is seen consistently amongst LMS, but this does not translate into oncogenic mutation. Hence drugs targeting KIT mutation (Imatinib) are not effective for uterine LMS. Uterine LMS consistently lacks epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (ERBB2) expression.[16]

Resection Margins

Concerning surgical margins, resection of the tumor classifies under three categories.

• R0 resection- No cancer cells are seen microscopically at the resection margin.
• R1 resection- Cancer cells are only seen microscopically at the resection margin. 
• R2 resection- Tumor is present at the margins at the time of resection, which can be seen by the naked eye.

History and Physical

The clinical presentation of leiomyosarcoma is non-specific, and they often present as a mass causing compression or displacement of adjacent organs. The patients with uterine LMS may present with abnormal uterine bleeding or abnormal uterine growth, and the diagnosis often follows a pathological examination of the hysterectomy specimen.[2][9]

Evaluation

There is no specific laboratory or radiographic test that can help in the diagnosis of leiomyosarcoma. An imaging test, including a CT scan or MRI, is needed to stage the disease. Whereas CT is better at retroperitoneal and visceral lesions, MRI is better at evaluating tumors arising in the extremities and head and neck.[17] As the disease spreads mainly via the hematogenous route, it is essential to rule out lung or liver metastasis. In the case of uterine LMS, an endometrial biopsy may yield a diagnosis; however, a negative biopsy does not rule out LMS. Any leiomyoma that continues to grow beyond menopause must undergo an evaluation to rule out LMS.[2][9] A biopsy of the suspected lesion is needed to make a definitive diagnosis. A core needle biopsy or an open-incisional biopsy (must be performed by an experienced surgeon) is necessary to obtain adequate tissue to identify histologic subtype and grade to distinguish it from other sarcomas. Fine-needle aspiration is inadequate to establish a diagnosis.[18]

Treatment / Management

Treatment of LMS depends upon the stage of presentation, and it requires an interprofessional approach in centers experienced at treating sarcoma patients. Whereas localized tumors are best managed by surgical resection, to achieve negative margins (R0 resection), the metastatic disease is considered incurable. The goal of treatment is to control the symptoms, decrease tumor bulk and prolong survival.[2] Radiotherapy (RT) in STS improves local control and preserves function, reduces local recurrence, but does not improve survival.[19] The timing of RT also remains a matter of debate for both retroperitoneal and extremity/trunk LMS as major trials continue to accrue patients.[20] Details of treatment follow in subsequent sections.

Differential Diagnosis

The clinical presentation of a patient with STS is vague and non-specific. Morphologic diagnosis based on microscopic examination remains the gold standard. Ancillary testing (including using IHC, classical cytogenetics, and molecular testing) aids in diagnosis. The WHO recognizes more than 70 different subtypes of sarcoma.[8] Diagnoses to consider due to similar presentation or histopathological similarity include:

• Meningioma
• Gastrointestinal stromal tumors (GIST)
• Leiomyoma
• Dedifferentiated liposarcoma
• Endometrial stromal sarcoma
• Smooth muscle tumors of uncertain malignant potential (STUMP)Inflammatory myofibroblastic tumor
• Perivascular epithelioid cell tumor

Surgical Oncology

The general principles of surgery for any STS also apply to the patients diagnosed with LMS. The trials presented in this section include patients with LMS; however, the histology is not limited to LMS.

Soft-tissue Sarcoma of the Extremity/Trunk

Historically, amputation was the standard of care for patients with STS of the extremity. As evidence built up in favor of wide local excision and RT, amputation was only for patients experiencing local recurrence.[21][22] The primary goal of surgery is to perform an R0 resection (see histopathology section for definition). However, in pursuit of maintaining the functionality of the limb or preserving critical structures (vessels, nerves, etc.), an R1 or even an R2 resection is acceptable.[22][23] Numerous studies over the years have not been able to establish a consensus on the definition of an 'adequate margin.'[22] The United Kingdom guidelines for STS 'consider' a margin of more than 1 cm or an equivalent, like an intact fascia, as an adequate margin.[24] In a patient with STS, who has an unplanned positive margin, a re-resection should be evaluated/attempted in a bid to achieve a negative margin. Despite adding RT for patients who have a positive margin after resection, the outcome is poor compared to those with a negative margin. Hence, achieving a negative margin remains the goal of surgical resection.

Soft Tissue Sarcoma of Retroperitoneum

The general principles of resection are the same as those for the STS of the extremity/trunk. The best outcomes take place with an R0 resection. Due to the massive size of retroperitoneal sarcoma, accurate pathologic assessment of all margins on the resected tumor specimen is challenging. For any patient who has an intraoperative rupture of the tumor, R2 resection and/or piecemeal resection of the tumor correlates with a higher local recurrence rate.[25] Two retrospective studies evaluated the benefit of radical resection of nearby organs (even without obvious tumor involvement, whenever feasible, adjacent organs/structures should be systematically resected) and reported lower local recurrence rates at 3 to 5 year follow up.[26][27] However, this approach comes with considerable morbidity. In general, any surgery for retroperitoneal sarcoma should be done to achieve a macroscopically negative margin with a single specimen encompassing the entire tumor and the adjacent organs, ultimately aiming to minimize the chances of R1 resection.[28] 

Uterine Leiomyosarcoma

Uterine LMS is a separate entity from retroperitoneal LMS. The standard surgical approach for both early and advanced-stage disease is to perform a hysterectomy and en bloc resection of any viable tumor. Oopherectomy is not a procedural choice unless the tumor involves ovaries. It is not yet clear if lymph node involvement translates into a worse outcome. The metastasis rate to lymph nodes is quite low (5 to 11%), which makes lymph node sampling undesirable, especially if there is no evidence of metastatic disease. The American Association of Gynecological laparoscopists (AAGL) and the Federal drug agency (FDA) have strongly discouraged using power morcellation if malignancy is suspected. If morcellation occurs inadvertently, then the patient should at least undergo subsequent trachelectomy (if the cervix is present in situ), peritoneal biopsies (including surrounding previous port sites), and either omental biopsy or omentectomy as part of a reexploration surgery. Additional imaging such as PET/CT to evaluate for disseminated disease is also a viable option before second-look surgery.[9] 

Radiation Oncology

The general principles of RT for any STS also apply to the patients diagnosed with non-uterine LMS. Uterine LMS is a separate subgroup of patients diagnosed with LMS, covered in a separate section.

Perioperative RT for STS is the gold standard of treatment for localized disease in extremities, trunk, and head/neck region.[2] Two prospective randomized trials, evaluating external beam RT (EBRT) and post-operative brachytherapy (BRT), demonstrated better local control rates by adding adjuvant RT to surgery in patients with STS of the extremities and trunk.[19][29] Although the benefit of adjuvant RT is apparent in both high-grade and low-grade STS, high-grade tumors derive a greater degree of benefit. Interstitial BRT (IBRT) and intensity-modulated RT (IMRT) are two other approaches for delivering RT to STS of extremity/trunk. They have never been compared to EBRT in prospective trials for patients with STS.[30] 

The timing of RT (preoperative and postoperative) is a matter of debate. Preoperative RT 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. There is also potential downstaging of a borderline resectable sarcoma of an extremity with the possibility of salvaging the limb. However, preoperative RT is associated with a higher rate of wound healing complications (35% for preoperative RT compared to 17% with postoperative RT). On the other hand, postoperative RT allows for a definitive assessment of the tumor (grade, margin status, etc.) and carries a lower rate of post-op wound healing complications. However, it is associated with higher rates of fibrosis, edema, joint stiffness.[31][32]

In patients with "superficial or contained STS" up to a size of 5cm who undergo complete excision of the tumor with wide margins (more than 1cm clean margin) can be monitored clinically without the need for postoperative RT. There is no evidence supporting this approach, and an interprofessional sarcoma group must have involvement before adopting such an approach.[32] In patients with positive margins, adding adjuvant RT is superior to surgery alone.[22] Two prospective studies from Memorial-Sloan Kettering[29] and the National Cancer Institute[19] demonstrate a low local recurrence rate if adjuvant RT is in the treatment plan for patients with positive surgical margins.

It bears mentioning here that although adding peri-operative RT improves the local outcomes, it has not shown any benefit in terms of overall survival (OS) or distant recurrence-free survival (RFS).[32]

Considerations in Retroperitoneal Sarcoma

At this point, no consensus exists on the timing or benefit of perioperative RT for patients diagnosed with retroperitoneal STS. The first randomized trial from the National Cancer Institute (NCI), published in 1993, clearly demonstrated that intraoperative RT improved local control but did not show a difference in overall survival and distant metastasis.[20] A retrospective study of the National Cancer Database (NCDB) reported an overall survival benefit of pre-operative and post-operative RT compared to patients who received surgery alone. However, this study has limitations from a lack of details regarding the dose, complications, etc.[33] A phase I-II trial led by the Italian-Spanish sarcoma group enrolled 86 patients with retroperitoneal STS to receive ifosfamide (14gm/m2) with RT (50.4 Gy). The study reported local and distant recurrence in 37% and 26% of patients, respectively, at five years follow-up. The study reported a DFS and OS of 44% and 59%, respectively.[34] The results of the European Organization for Research and Treatment of Cancer (EORTC)-Soft Tissue and Bone Sarcoma Group (STBSG) 62092-22092 are eagerly awaited at this point.

Considerations in Uterine Leiomyosarcoma

The role of RT in uterine LMS is different from extrauterine LMS. A phase III trial from EORTC (protocol 55874) evaluated the role of adjuvant EBRT in patients with stage I and II uterine LMS. The results showed no significant difference in local recurrence rates, distant recurrence rates, or OS between the two groups. Although the results did not achieve statistical significance, researchers noted a trend towards reducing overall survival in the RT arm.[35] The French sarcoma group study (SARCGYN study) tested the combination of chemotherapy followed by RT versus RT alone. In the cohort of 81 patients, 53 patients had LMS. The chemotherapy included a combination of doxorubicin, cisplatin, and ifosfamide (4 cycles to be given after RT). The trial demonstrated a 3-year disease-free survival benefit in the combination arm, although no OS benefit was demonstrated at the 3-year and 5-year benchmark.[36] Due to the lack of obvious benefit of adjuvant RT, it is not recommended in an optimally resected uterine LMS. In the advanced stage, incompletely resected, or metastatic disease, RT can be an option on a case to case basis.[9] 

Neoadjuvant Chemoradiation for Extremity/Trunk Soft-tissue Sarcoma

Although perioperative RT is the standard of care for STS of extremity/trunk, the addition of chemotherapy to RT is still a topic of debate. The experience from non-sarcoma tumors has shown the positive radio-sensitizing effect of adding chemotherapy to RT. The Radiation Therapy Oncology Group (RTOG) 9154 conducted a prospective phase II trial to evaluate the benefit of adding chemotherapy to RT in extremity and truncal STS patients. While grade 3 toxicity was quite high in these patients, 5-year distant DFS and OS were 64% and 71%, respectively.[37] Many other chemotherapy regimens have undergone testing since then. Amongst all of them, ifosfamide has been found to be the most effective drug. Patients who developed tumor necrosis on ifosfamide had the lowest rates of local recurrence. Likewise, an escalating dose of gemcitabine and ifosfamide was given concurrently with preoperative RT (50 Gy) in patients with STS of extremity/trunk, which resulted in 5-year local control, distant metastasis-free, and OS rates of 85%, 80%, and 86%, respectively.[38] Despite encouraging results, neoadjuvant chemoradiation for STS/LMS remains experimental in the case of STS/LMS.

Medical Oncology

Leiomyosarcoma is a tumor with complex and unbalanced karyotypes, characterized by severe genomic instability, which results in multiple genetic aberrations. As a result, LMS is considered moderately sensitive to chemotherapy.[39] 

Adjuvant Chemotherapy after Surgery

After surgery, adjuvant chemotherapy for a patient diagnosed with STS has been primarily tested in patients with extremity and truncal STS.[40] While adjuvant therapy has proven to benefit the pediatric age group, the same has been controversial for adult STS. The Sarcoma Meta-Analysis Collaboration (SMAC) published their first meta-analysis in 1997, which included 14 trials investigating the role of adjuvant chemotherapy in STS. It is worth noting that the chemotherapy offered in these trials had doxorubicin as the only active component even when combined with another drug. The analysis showed a statistically significant improvement in both local and distant RFS, but the benefit in OS could not reach statistical significance. Despite this, the analysis demonstrated a 6% absolute benefit over ten years.[41] The SMAC published an updated meta-analysis in 2008, including four more trials that included patients treated with the combination of ifosfamide and doxorubicin. This analysis again showed the same benefit in local RFS, distant RFS, and overall RFS. However, this analysis showed a statistically significant OS benefit (Odds ratio (OR) for death 0.56, 95% CI 0.36 to 0.85). Subgroup analysis of patients receiving the combination of doxorubicin and ifosfamide had an absolute risk reduction of 11%, which could not be proven for the doxorubicin-only group.[42]

The Italian sarcoma group (ISG) conducted a randomized trial evaluating the role of adjuvant chemotherapy in high-risk patients with spindle cell STS of extremities or pelvis. The group receiving adjuvant chemotherapy (epirubicin/ifosfamide with mesna) showed a better distant metastasis recurrence rate (45% versus 28%) and a better OS at four years (69% versus 50%). However, the statistical significance was lost at a 7-year follow-up, and the local and distant relapse rates also became similar (44 versus 45%).[43] The EORTC performed a randomized trial (Protocol 62931) investigating the role of adjuvant doxorubicin and ifosfamide to localized STS. All patients with positive margins received adjuvant RT, as well. This study did not report any difference in the RFS or OS amongst the two groups. A significant limitation of this study is that ifosfamide was used at a lower dose (5 g/m^2), which may have led to inferior results.[44]

Current guidelines suggest that in patients with high-grade or intermediate-grade STS, which is more than 5 cm in size, doxorubicin and ifosfamide based adjuvant chemotherapy can be considered as a viable option (Category 2B, NCCN Version 4.2019)

Neoadjuvant Chemotherapy

In theory, neoadjuvant chemotherapy can help shrink the tumor, hence improving resectability, achieving negative margins, and earlier control of microscopic disease, both local and distant). In addition to this, it can also provide an essential clue in terms of the responsiveness of the tumor to chemotherapy. Multiple trials In a retrospective study examining both STS and bone sarcoma, neoadjuvant chemotherapy was not associated with worse outcomes.[45] One of the early intergroup phase III trial evaluating the role of neoadjuvant chemotherapy (MAID regimen) in patients with large high-grade extremity STS and bone sarcomas reported a CR/PR rate of 32%. This study demonstrated a benefit in high-grade, borderline resectable lesions, or those tumors with pulmonary metastases, particularly in younger patients.[46] A European phase II/III trial in patients with STS of extremity/trunk reported no difference in DFS (56% and 52%) in patients receiving surgery with or without neoadjuvant chemotherapy. The trial's limitations include using a lower dose of chemotherapy and inconsistent definition of high-risk sarcomas, where even low-grade tumors larger than 8 cm categorized as high-risk sarcoma.[47]

The ISG enrolled 252 patients to receive neoadjuvant chemotherapy, followed by surgery and then randomized them to receive two more postoperative cycles (epirubicin and ifosfamide). The patients who had a positive or a negative margin on surgery had a similar OS. Those patients who had a positive surgical margin and received adjuvant RT along with neoadjuvant chemotherapy had a cumulative local recurrence rate of zero. This study concluded that neoadjuvant chemotherapy could offset the negative impact of positive margin upon surgical resection and improve local control and survival.[48]

Histology tailored approach underwent evaluation 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 DFS (62% vs. 38%) and OS (89% vs. 64%) favored the standard chemotherapy. Barring the myxoid liposarcoma subgroup, where trabectedin showed equal efficacy compared with standard chemotherapy, all other disease subgroups performed poorly with histology tailored therapy. This trial showed that a histology tailored approach is not needed when considering neoadjuvant chemotherapy.[49]

Chemotherapy in Metastatic or Unresectable STS

First-line Treatment

There is no established 'best' first-line chemotherapy regimen in metastatic LMS. In a patient diagnosed with unresectable metastatic disease, the goal of therapy is to palliate the symptoms and to improve the quality of life. 

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 cardiotoxicity is a limiting factor in the use of doxorubicin.[50] Over many years, various chemotherapeutic agents have been combined with anthracyclines (doxorubicin or epirubicin) in hopes of achieving a better outcome. Although none of the regimens have ever demonstrated an improved OS, the combination arms have certainly improved the progression-free survival (PFS) and response rates. The phase III trial- EORTC STBSG 62012 was a pivotal trial 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 PFS improved (7.4 months versus 4.6 months), the OS benefit at one-year (60% vs. 51% patients P-0.76 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 negative trial, the combination of doxorubicin and ifosfamide is reserved for patients where tumor shrinkage is needed before the surgery or when the tumor is close to a critical structure.[50] 

The drug olaratumab, a 'platelet-derived growth factor receptor alpha' blocking antibody, was granted accelerated approval by the FDA in June 2016 based on the results of phase II JGDG study that included patients with locally advanced unresectable or metastatic STS. However, the phase III trial (ANNOUNCE trial) reported at ASCO 2018 did not demonstrate the same OS benefit, which led to the suspension of the drug by the FDA.

Gemcitabine Based Regimens

Gemcitabine has shown activity in STS both as a single agent and in combination with other chemotherapy agents. The infusion rate, fixed at 10mg/m^2/min, is superior to the 30-min infusion, which is more common.[51] The phase II study, 'Comparison of Gemcitabine Versus Gemcitabine Plus Docetaxel in Unresectable Soft Tissue Sarcoma' (SARC002), showed an improved objective response, PFS, and OS with gemcitabine plus docetaxel compared with gemcitabine alone in advanced, previously treated STS.[52] The subset of both uterine LMS and extra-uterine LMS were sensitive to the combination of gemcitabine and docetaxel. Following this study's success, the combination of gemcitabine and docetaxel was compared with single-agent doxorubicin in phase III UK-GeDDiS. Between the two groups of doxorubicin and gemcitabine/docetaxel, the authors did not find any statistical difference in the proportion of patients alive at 24 weeks. The median PFS also did not differ between the two groups.[53] It merits noting that this trial used a lower dose of gemcitabine (675mg/m^2) and a regular dose of docetaxel (75mg/m^2), possibly contributing to the lower efficacy and higher toxicity, respectively. The authors of the trial also recommend using doxorubicin-based regimens as the first line of treatment in patients with metastatic STS.[53]

Ifosfamide Monotherapy

Ifosfamide monotherapy is also active in patients with metastatic STS, yielding a response rate of 25% and a median overall survival of 1 year. The drug has a dose-response relationship, where higher doses yield a better response rate, albeit at the cost of higher toxicity. However, this has never translated into a better survival rate. Ifosfamide should be given at 9-10gm/m2 with each cycle, repeated every three weeks. A dose beyond 12gm/m^2 saturates the enzymes and only adds to toxicity. Hemorrhagic cystitis, myelotoxicity, nephrotoxicity, and neurotoxicity are the limiting toxicities with ifosfamide.[54]

A phase III randomized trial evaluated using a high dose of ifosfamide with stem cell rescue in patients with STS. No OS benefit was demonstrated in the trial.[55] An older meta-analysis of 1337 patients enrolled in EORTC-STBSG trials, evaluating the role of ifosfamide in the first-line setting, reported a lower activity of the drug in patients with non-uterine LMS.[56] Hence, adding ifosfamide to doxorubicin is not routinely recommended in patients with non-uterine LMS unless the tumor is close to a critical organ/vessel.

Second-line Treatment

Multiple drugs have undergone an evaluation as a second-line treatment for STS/LMS. A gemcitabine-based regimen or an anthracycline-based regimen is an option in the second line based on the agents used as the first-line treatment. However, new targeted agents have provided a lot of options. Monotherapy with trabectedin is the most promising of these and has been approved by the FDA for patients with LMS and liposarcoma. Pazopanib, eribulin, liposomal doxorubicin, dacarbazine, and hormonal therapy (only for uterine LMS) are also active in LMS.

Trabectedin (YONDELIS, ET-743)

Trabectedin has approval in the United States and European Union to treat patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have progressed after first-line anthracycline-based regimen or were ineligible for such a regimen. The approval basis was the PFS benefit (4.2 versus 1.5 months, CI, 0.44 to 0.70, P< 0.01) demonstrated in the phase III trial, where trabectedin was compared with dacarbazine. Although no OS benefit was observed in the trial, the patients in the trabectedin arm had stable disease for a significantly longer time (6.01 versus 4.17 months, P <0.001) and had a higher clinical benefit ratio (34% versus 19%, HR- 2.3, CI: 1.45 to 3.7, P-< .001) compared to those on the dacarbazine arm. The adverse effect profile is quite manageable with myelosuppression, and hepatic toxicity was the most common grade 3/4 toxicity reported in the phase III trial.[57] The French sarcoma group recently concluded a phase II trial to evaluate if trabectedin can be stopped after six cycles. After six cycles, the patients who discontinued therapy experienced a rapid progression of the disease and a significantly low PFS.[58] Currently, trabectedin is being tested in combination with immunotherapy and chemotherapy to improve the efficacy of treatment.

Pazopanib (VOTRIENT)

Multiple anti-angiogenic agents (bevacizumab, sorafenib, sunitinib, pazopanib, vandetanib, DC-101, and TNP-470)  have shown anti-sarcoma activity in mouse models. Few of these drugs showed clinical activity in phase I trials; however, the success of most of these drugs could not be replicated in phase II trials.[59] 

Pazopanib (VOTRIENT) is an oral multitarget tyrosine kinase inhibitor approved for use in advanced STS, regardless of histology, who had previously received chemotherapy. It is administered at 800mg orally every day. It is an inhibitor of vascular endothelial growth factor receptor (VEGF)-mediated angiogenesis and blocks the growth-promoting receptor tyrosine kinase (RTKs), including platelet-derived growth factor receptor, fibroblast growth factor receptor, and KIT-1. The FDA approved the drug based on the PFS benefit (4.6 months versus 1.6 months, HR - 0.35, CI 95%: 0.26-.48; P <.001) observed in the phase III trial (PALETTE) where the study compared pazopanib to placebo. There was no observable OS benefit in the pazopanib arm compared to the placebo arm. Of note, liposarcoma was excluded from the phase III trial due to poor response in the phase II trial.[60] Hepatotoxicity, cardiotoxicity, and thyroid dysfunction are some of the most common adverse effects. Rarely have there been reports of reversible posterior leukoencephalopathy syndrome.[61][62]

Eribulin (HALAVEN, E7389)

Eribulin mesylate (HALAVEN, E7389) is an analog of halichondrin B approved for metastatic breast cancer. It blocks the G2 phase and the M phase of the cell cycle via tubulin based antimitotic mechanism, which blocks the spindle formation in the cell cycle and leads to apoptosis of the cancer cell.[63] The FDA has approved eribulin for patients with unresectable or metastatic liposarcoma whose tumor progressed after anthracycline chemotherapy, based on the results of the phase III trial (E7389-G000-309).[64] In a pre-planned, subset analysis of the phase III trial results, the patients diagnosed with LMS showed comparable efficacy to single-agent dacarbazine. The median OS for eribulin versus dacarbazine (12.7 versus 13.0 months, respectively (HR = 0.93 [95% CI 0.71–1.20]; P = 0.57) and the median PFS (2.2 vs 2.6 months, respectively, (HR = 1.07 [95% CI 0.84–1.38]; P = 0.58) and ORR (5% vs 7%) were not significantly different.[65] The FDA has not yet approved the drug for LMS. However, it provides a reasonable option for patients with LMS. Eribulin is administered at 1.4 mg/m^2 intravenously 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 of the two. Neutropenia, peripheral nerve neuropathy, and QTc prolongation are adverse effects of eribulin.

Immunotherapy 

In general, immunotherapy has not shown much promise in the STS subgroup overall. Barring a few case-reports, there is a scarcity of evidence of immunotherapy working for patients diagnosed with STS. Two trials evaluating nivolumab and pembrolizumab did not demonstrate any benefit in the subgroup of LMS.[66][67] The phase II trial, ALLIANCE A091401, 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. A third of all, the patients had uterine or extra-uterine LMS. Out of the eight patients who achieved a response in either arm, three had LMS. The ORR for single-agent nivolumab was 8% compared to a 16% response observed in the arm treated with nivolumab and ipilimumab. The median OS 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 dose of ipilimumab (used at 1mg/kg). The authors argue that a high tumor mutational burden, which is characteristic of LMS, may have lead to a higher activity of the combination of nivolumab and ipilimumab in LMS.[66] Currently, multiple agents are under evaluation in combination with chemotherapy and radiotherapy, which are in phase I-II stage. The FDA has not yet approved the use of the combination of ipilimumab and nivolumab in STS. 

Tumors that Exhibit Specific Gene Mutations

Microsatellite Instability High (MSI-H)

• The FDA granted accelerated approval to Pembrolizumab in May of 2017 for adult and pediatric patients with unresectable or metastatic solid tumors that exhibit MSI-H or mismatch repair deficiency (dMMR). The eligible patients included those whose tumors progressed after prior treatment and those with no satisfactory alternative treatment options.[68] The approval was granted based on the 149 patients included in the KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158  trials.[68]

Neurotrophic Tyrosine Kinase (NTRK) Inhibitor - Entrectinib (ROZYLTREK) [69]

• Entrectinib has approval for patients who have a solid tumor that harbors the 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 phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which researchers conducted across 15 countries and 150 clinical trial sites. Entrectinib demonstrated an ORR of 57%.

Dacarbazine

Dacarbazine is an alkylating agent that has activity in STS. It 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. [54][70] A recent phase II trial evaluating the combination of sorafenib and dacarbazine in patients with metastatic LMS (approximately 60% patients), synovial sarcoma, and malignant peripheral nerve sheath tumor met its primary endpoint of achieving disease control rate at 18 weeks at 46%.[71] The dose depends on the protocol used. Myelosuppression and hepatotoxicity are significant adverse events. 

Pegylated Liposomal Doxorubicin (DOXIL)

Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin in poly(ethylene glycol)-coated (stealth) liposomes. It has a prolonged circulation time and does not cause cardiotoxicity like doxorubicin. Dermatologic toxicity is the main adverse effect of PLD.[72] Multiple studies have demonstrated the activity of PLD in metastatic STS either alone or combined with ifosfamide.[73][74] PLD was also tested against single-agent doxorubicin in an EORTC-SSTSBG phase II trial.[74] Although the authors reported comparable response rates amongst the two groups, as expected, cardiotoxicity was far less in the PLD arm. The FDA has not yet approved PLD for patients with LMS.

Hormonal Therapy

As with other gynecological malignancies, uterine LMS also exhibits estrogen receptor (7 to 70% patients) and progesterone receptor (17 to 60%). Retrospective studies have shown aromatase inhibitor activity (letrozole, anastrozole, or exemestane)  in uterine LMS, with partial response reported in 9 to 12% of patients.[75][76] 

Staging

Leiomyosarcoma staging is according to the organ of origin. Uterine LMS staging is per the Federation of Gynecology and Obstetrics (FIGO) staging an extra-uterine LMS gets staged according to the American Joint Committee of Cancer (AJCC) staging. However, the 8th edition of AJCC has resolved a long-standing variability in soft tissue sarcoma staging. In the latest edition, AJCC has provided a separate staging system for STS of retroperitoneum, head/neck region, and extremities/trunk region.[77] It merits noting that despite the AJCC 8th edition addressing some major issues of previous editions, the staging system still does not translate well into survival.[77]

Grading of Soft Tissue Sarcoma/Leiomyosarcoma

The College of American Pathologists and the AJCC recommend the three-tiered system of the French Federation of Cancer Centres/Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC). The relative ease of use, well-balanced components including a score for de-differentiation (scored from 1 to 3), mitoses (scored from 1 to 3), and necrosis (scored from 0 to 2), make the French system a suitable scoring system.[78] 

Tumor differentiation

• 1- Closely resemble normal adult mesenchymal tissue
• 2- Histologic typing is uncertain
• 3- Embryonal or undifferentiated sarcoma, sarcoma of doubtful type, synovial sarcoma, soft tissue osteosarcoma, Ewing Sarcoma/Primitive neuroectodermal tumor (PNET) of soft tissue

Mitotic Count- measured in the most mitotically active area of sarcoma, ten successive HPF are assessed using a 40x objective.

• 1- 0-9 mitosis/HPF
• 2- 10-19 mitosis/HPF
• 3- more than 20/HPF

Tumor Necrosis

• 0- No necrosis
• 1- Less than 50% necrosis
• 2- More than 50% necrosis

Grading system: This is a cumulative score given to the sarcoma after assessing the tumor differentiation, mitotic count, and tumor necrosis. For example, an LMS tumor with a differentiation sore of 1, a mitotic count score of 1, and a tumor necrosis score of 0 is a grade 2 (1 + 1 + 0) tumor.

• 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 STS of Extremities and Trunk[77]

TNM staging:

• Tumor staging (T):
  • T1: Tumor less than or equal to 5 cm in greatest dimension
  • T2: Tumor over 5 cm and less than or equal to 10 cm in greatest dimension 
  • T3: Tumor over 10 cm and less than or equal to 15 cm in greatest dimension
  • T4: Tumor over 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

AJCC 8th Edition Staging for Retroperitoneum:[79] 

• The staging of STS of the retroperitoneum is very similar to the staging system used for extremities and trunk. The only difference is that in the patients with STS of the retroperitoneum, the N1 node-positive patients are classified under stage IIIB, whereas in the STS of the extremities and trunk, they fall under stage IV.

AJCC 8th Edition Staging for Head and Neck[78]

There are no staging groups in the head/neck region in AJCC 8th edition as it would need the application of the French grading system, and very extensive lesions (T4) remain unclassified.[78]

• 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, the involvement of the central nervous system via 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  

FIGO Staging for Uterine Leiomyosarcoma[9]

FIGO staging for uterine sarcomas (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 one site
  • IIIC: Involves pelvic and/or para-aortic lymph nodes
• Stage IV - tumor invades pelvic organs and/or distant metastasis
  • IVA Invasion of bladder or rectum
  • IVB Distant metastases

Prognosis

In patients diagnosed with LMS, histologic grade, tumor size, and tumor depth are the three most important prognostic factors.

Tumor size, bone, or neurovascular involvement, together with the grade of the tumor, are significantly associated with poor outcomes, specifically in LMS.[80] A SEER database analysis of STS of extremities and trunk, a restaging of the tumors according to AJCC 8th edition, did not perform better in estimating survival compared to older versions. The same author proposed another staging system (Vanderbilt system), which also accounts for the depth of the tumor and has refined the stages accordingly, and seems to perform better in estimating survival.[77]

The location of the tumor is an independent prognostic risk factor. The LMS of the extremities has a better outcome compared to the retroperitoneal LMS.[81] One retrospective study reported a worse survival for uterine LMS than extra-uterine LMS; however, another small study reported a better outcome for uterine LMS (most patients with uterine LMS had a near-complete resection in this study).[82][83] All these studies had limitations because of their retrospective nature and a small number of subjects. Likewise, retrospective data also shows that LMS arising from the vascular surface has the worst prognosis. However, the majority of subjects in this study had the tumor arising from inferior vena cava, and they were generally unresectable.[84] Depth of the tumor is an important prognostic factor independent of tumor size and histologic grade, where deep tumors are associated with worse outcomes.[77][85][86] 

The histologic grade is an independent prognostic factor. It can independently estimate the aggressiveness of cancer, the probability of distant metastasis, and disease-specific survival.[80][87][81] LMS is inherently an aggressive malignancy, with 90% of patients diagnosed with grade 2 to 3 cancer. The histologic subtype is an independent prognostic factor even when adjusted for tumor grade.[85][86] However, the histologic subtypes have never been included in the AJCC staging systems, including the latest AJCC 8th edition. The patients diagnosed with LMS are at high risk of distant recurrence and decreased disease-specific survival compared to other histologies.[87]

Uterine LMS also follows the same pattern in prognostic features. Various studies have reported age, disease stage, surgical margins, tumor size, cellular atypia, mitotic rate, the involvement of lymphovascular channels, lymph node positivity, oophorectomy, or presence/ absence of necrosis as factors that can determine the prognosis.[9] Memorial Sloan Kettering has developed a clinical nomogram that utilizes age, grade, tumor size, mitotic rate, presence of cervical invasion, locoregional metastasis, and distant metastasis; to assess the 5-year overall survival. The nomogram performed better in predicting the overall survival than the more traditional staging system, such as the FIGO and AJCC classifications.[88]. 

In a recent meta-analysis of 580 patients with metastatic STS and lung-only metastasis, recorded in the EORTC-STSBG trials, the authors report the age, time between initial diagnosis and treatment, performance status, and involvement of the primary site also help determine the prognosis of this subgroup of patients. The analysis showed that patients with a non-target pulmonary lesion (for example, pleural involvement) had the worst outcomes. The study also confirmed that patients treated with the combination of doxorubicin and ifosfamide in the first-line setting followed by monotherapy with anthracycline, ifosfamide, and trabectedin or brostallicin had the best OS and PFS.[89]

D'Angelo et al. have reported using immunohistochemical stains and biological markers to determine the survival of patients with uterine LMS. Several patients with low expression of Ki-67, p53, p16, and Twist and high expression of Bcl-2 had longer recurrence-free survival. These studies are yet to be reciprocated in large cohorts.[90] 

Complications

Complications of leiomyosarcoma are site-specific. External compression due to mass effect and early metastasis due to aggressive tumors are common. 

Deterrence and Patient Education

Patients and healthcare professionals must appreciate the rarity of soft-tissue sarcoma in adults. The diagnosis and treatment pose a particular challenge to the clinician of this tumor, which has proven resistant to multiple treatment regimens. The patients must receive education on the importance of surgical resection and the role of RT in the management of LMS. The patient should understand the pros and cons of neoadjuvant or adjuvant chemotherapy in the management of LMS and a decision reached with their consensus. Finally, all patients should receive encouragement to participate in clinical trials.

Pearls and Other Issues

Pearls for healthcare professionals managing patients with leiomyosarcoma

1. Patients diagnosed with LMS should be treated at centers that experience a high volume of such patients.
2. All patient cases merit discussion at tumor boards, including surgical oncologists/orthopedic oncologists, radiation oncologists, and pathologists trained in diagnosing sarcoma, medical oncologists, and radiologists. 
3. Gynecologists-oncologists should manage patients with uterine LMS in collaboration with the surgical oncologists and the rest of the team listed above. 
4. Histologic grade, tumor depth, and tumor size are the three most important prognostic factors.
5. Surgical resection with a negative margin translates into the best outcomes in terms of overall survival.
6. Perioperative RT reduced the rate of local recurrence and increased local disease-free survival but has not demonstrated a benefit in distant relapse or overall survival.
7. Preoperative RT is associated with fewer complications than postoperative RT, although wound complications are higher with preoperative RT. A gap of 4 to 5 weeks between surgery and RT seems to reduce wound complications with preoperative RT.
8. Neoadjuvant chemotherapy has proven effective in high-risk STS/LMS of the extremity/trunk; however, the evidence is limited.
9. If a decision to use neoadjuvant therapy is made, then a standard chemotherapy regimen with anthracycline and ifosfamide should be used, rather than tailoring it according to the histology.
10. There is no evidence to support the regular use of adjuvant therapy; however, if a decision is made to give adjuvant therapy, then anthracycline and ifosfamide should be used.
11. Anthracycline-based regimens are usually the first-line regimens for metastatic STS/LMS.
12. Gemcitabine-docetaxel combination can be the first-line regimen for uterine LMS.
13. Ifosfamide is less effective in patients with extra-uterine LMS compared to those with uterine LMS.
14. Although the GeDDis trial did not demonstrate a difference between the two arms, doxorubicin remains the first treatment choice. 
15. Trabectedin is an effective treatment in LMS. In patients who respond to trabectedin, the clinician should not discontinue the drug unless the patient develops toxicity or progression of the tumor. 
16. Pazopanib, anlotinib, eribulin, dacarbazine, pegylated liposomal doxorubicin are effective in LMS as single agents.

Enhancing Healthcare Team Outcomes

Leiomyosarcoma is one of the most common subtypes of soft-tissue sarcoma. The clinical presentation is non-specific, and the most common presentation is secondary to the mass-effect from a growing lesion. Uterine LMS may present with abnormal uterine bleeding. The diagnosis follows from histopathology, and clinical imaging helps in determining the stage of the tumor. A pathologist trained in diagnosing STS is needed to assist in establishing histology and grading the tumor accurately. Similarly, a team of musculoskeletal-radiologists and interventional radiologists is necessary for interpreting the images (CT scans and MRI) and determining the best region/route to biopsy the mass. An experienced surgeon can also pursue an open incisional biopsy, although this is seldom needed. 

The patients diagnosed with LMS should receive treatment at centers that regularly experience a high volume of such patients. The principles of treating a patient diagnosed with LMS require close coordination of interprofessional team members between the surgical oncology, radiation oncology, and medical oncology teams. Where limited-stage LMS is almost always treated surgically with perioperative radiation, metastatic LMS is incurable. A team of skilled surgical oncologists/ orthopedic oncologists trained in the management of soft-tissue sarcoma is critical in caring for a patient diagnosed with LMS. Likewise, patients with uterine-LMS should have surgery from a team of gynecologist-oncologist. Radiation oncologists decide the best modality of RT that would be necessary for the treatment of the patient. In addition to this, they also coordinate with surgeons to deliver intra-operative RT. Leiomyosarcomas are very heterogeneous at the molecular level and are moderately chemosensitive. The medical oncologist ensures that a proper regimen gets chosen according to the presentation of the patient. The drugs involved in LMS treatment include a host of cytotoxic and targeted agents that come with unique toxicities. A board-certified oncology pharmacist trained in managing chemotherapy and nurses trained in delivering chemotherapy is a critical part of the interprofessional team to improve patient outcomes by assisting with coordination of care and patient education. The pharmacist will verify all dosing, assist in specific agent selection and alternate regimens, counsel on adverse effects, and collaborate with nursing on administration. Nursing will monitor patients' responses and adverse effects following administration. These examples of interprofessional coordination will optimize results for patients with leiomyosarcoma. [Level 5]

The treatment modalities used for LMS patients have undergone testing in phase II and phase III trials with Level I evidence described above.