Leiomyosarcoma

Etiology

Although there are no definite causative factors for leiomyosarcoma, certain risk factors have been associated with developing STSs, including leiomyosarcoma. The significant risk factor for STS is a history of radiation exposure or radiotherapy, particularly at a young age.[5] STSs may also be part of genetic syndromes, such as retinoblastoma (due to RB1 gene deletion) and Li-Fraumeni syndrome (caused by a mutation in the TP53 gene).[6] 

Epidemiology

Leiomyosarcoma accounts for 10% to 20% of all newly diagnosed STS.[7] In recent years, advancements in molecular diagnostics have enhanced the accuracy of diagnosis. Leiomyosarcoma most commonly occurs in the retroperitoneum, followed by the uterus, extremities, and trunk. Uterine sarcomas comprise about 3% to 7% of all uterine malignancies, with leiomyosarcoma being the most common subtype, accounting for nearly 80% of all uterine sarcomas.[8][9]

The incidence of leiomyosarcoma increases with age, reaching its peak in the seventh decade of life. The exception to this is uterine leiomyosarcoma, which occurs most commonly in perimenopausal women. 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.[6] 

Pathophysiology

Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers.[10] 

Histopathology

Histology

Leiomyosarcomas originate from the smooth muscle cells or their mesenchymal precursors.[11] 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 undifferentiated STSs.[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.[12] On microscopy, the hallmarks of leiomyosarcoma include nuclear atypia, >5 to 10 mitoses per high-power field (HPF), and tumor necrosis (see Image. Leiomyosarcoma of the Uterus).[13] Tumor necrosis is typically coagulative, with viable tumor cells sharply demarcated from areas of necrosis. This is in contrast to the infarctive necrosis typically seen in benign tumors such as leiomyomas, where an area of regeneration surrounds the zone of necrosis. The pattern and type of necrosis can help differentiate benign from malignant lesions. Uterine leiomyosarcoma can further be divided into spindle cells (classic type), epitheloid (more than 50% epithelial cells), myxoid (hypocellular with basophilic stroma), and other rare types. Lesions that arise from smooth muscle cells but lack the definitive characteristics of leiomyosarcoma are labeled smooth muscle tumors of uncertain malignant potential (STUMP).[12]

Immunohistochemistry

Leiomyosarcoma stains positive for smooth muscle–specific markers such as 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, epitheloid leiomyosarcoma can be confused for a carcinoma due to its tendency to stain positive 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 and leiomyomas.

Compared to leiomyoma, leiomyosarcoma has a lower expression of estrogen (40% in leiomyosarcoma versus 70% in leiomyoma) and progesterone receptors (38% in leiomyosarcoma versus 88% in leiomyoma).[14].

History and Physical

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.[6][8]

Evaluation

The appropriate workup of a suspected sarcoma is critical. Initial cross-sectional imaging using either a computed tomography (CT) scan or magnetic resonance imaging (MRI) helps identify the extent of the lesion, its relationship to surrounding structures, and potential targets for biopsy. Although CT excels at assessing retroperitoneal and visceral lesions, MRI is effective for evaluating tumors originating in the extremities and head and neck.[15] As part of the initial workup, patients often obtain the imaging modality that is more readily available. Once a sarcoma is suspected, an image-guided core needle biopsy is required for diagnosis; fine-needle aspiration is insufficient for establishing a diagnosis.[16] For palpable lesions, image guidance improves the accuracy of core needle biopsies.[17] For abdominopelvic lesions, using a retroperitoneal approach is crucial to avoid peritoneal seeding and potential sarcomatosis. For superficial lesions, the biopsy must be conducted with consideration of potential surgical incision, ensuring that the biopsy tract is included in any surgical specimen. Incisional and excisional biopsies should be avoided, and with current techniques, an open surgical biopsy 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, seedling of sarcomatous tissue, and alteration of subsequent surgical approach. 

A chest and abdominal CT scan is mandatory, given the risk of hematogenous metastasis. In cases of uterine leiomyosarcoma, an endometrial biopsy may yield a diagnosis; however, a negative biopsy does not rule out leiomyosarcoma. Any leiomyoma that continues to grow beyond menopause should be evaluated to rule out leiomyosarcoma.[6][8] 

Treatment / Management

The management of leiomyosarcoma depends on the disease site, tumor size, grade, and patient-dependent factors. The potential options include surgical resection, radiation, and chemotherapy. A multidisciplinary approach at high-volume sarcoma centers is highly recommended. The primary goals of treatment with curative intent include achieving surgical resection with negative margins, reducing local recurrence, improving functional outcomes, and reducing the risk of distant metastasis.[6] Radiotherapy (RT) in STS improves local control, preserves function, and reduces local recurrence but does not improve survival.[18] The timing of radiotherapy also remains a topic of debate for both retroperitoneal and extremity or trunk leiomyosarcoma as major trials continue to accrue patients.[19] Details of treatment are provided in the following sections.(A1)

Differential Diagnosis

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, classical cytogenetics, and molecular testing, aids in diagnosis. The World Health Organization (WHO) recognizes more than 70 different subtypes of sarcoma.[7] Diagnoses to consider due to similar presentation or histopathological similarity include meningioma, gastrointestinal stromal tumors, leiomyoma, dedifferentiated liposarcoma, endometrial stromal sarcoma, STUMP, inflammatory myofibroblastic tumor, and perivascular epithelioid cell tumor.

Surgical Oncology

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 surgery is to perform an R0 resection while making every attempt to preserve critical neurovascular structures. Historically, amputation was often used in cases where negative margins could not be obtained. However, to maintain limb function or preserve critical structures, for example, sciatic nerve), an R1 or an R2 resection is acceptable.[20][21] While positive margins are associated with higher local recurrence rates, overall survival is determined by distant metastases. Available data suggest that a microscopically positive margin treated with appropriate adjuvant therapy does not significantly increase the rate of distant metastasis or reduce overall survival.[21] In cases where a close margin is anticipated preoperatively, radiation before surgery increases the likelihood of a negative margin. When a positive margin is encountered postoperatively, options may include re-excision, adjuvant radiation, or close observation. (see Image. Excision of Leiomyosarcoma of the Rectum)

Leiomyosarcoma of Retroperitoneum

Sarcomas of the retroperitoneum often present as large tumors and commonly originate from the smooth muscle lining of medium to large 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.[22] Because leiomyosarcomas are usually well-defined, compression of adjacent organs, rather than invasion, is a common intraoperative finding and sometimes allows for the preservation of surrounding organs. Tumor rupture and spillage are uniformly associated with poor outcomes and should be avoided.[23] Preoperative radiation is considered ineffective in reducing local recurrence and improving survival in retroperitoneal leiomyosarcoma. However, it may be used to facilitate resection in cases where preoperative imaging is concerning for a close margin.[24] (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 premenopausal patients.[25] Unlike carcinomas, the rate of lymph node involvement in leiomyosarcoma is low (5%-11%), and lymph node dissection is unnecessary.[26] 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.[25] 

Metastatic and Recurrent Disease

The current National Comprehensive Cancer Network (NCCN) guidelines recommend pulmonary metastasectomy for oligometastatic disease in highly selected patients with no other sites of distant disease.[27] Local recurrences should be managed with surgical resection if amenable to complete tumor extirpation.[27]

Radiation Oncology

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 of treatment for localized disease in extremities, trunk, and head or neck regions.[6] Two prospective randomized trials evaluating external beam radiotherapy and postoperative brachytherapy demonstrated better local control rates by adding adjuvant radiotherapy to surgery in patients with STS of the extremities and trunk.[18][28] Although the benefit of adjuvant radiotherapy is apparent in high-grade and low-grade STS, high-grade tumors derive a greater degree of benefit. Interstitial brachytherapy and intensity-modulated radiotherapy are two additional approaches for delivering radiotherapy to the extremity or trunk STS. They have never been compared to external beam radiotherapy in prospective trials for patients with STS.[29] 

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. There is also potential downstaging of a borderline resectable sarcoma of an extremity with the possibility of salvaging the limb. However, preoperative radiotherapy is associated with a higher rate of wound healing complications (35% for preoperative radiotherapy compared to 17% with postoperative radiotherapy). On the other hand, 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, it is associated with higher rates of fibrosis, edema, and joint stiffness.[30][31]

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 supporting this approach exists, and it is recommended that an interprofessional sarcoma group be involved before considering such an approach.[31] Adding adjuvant radiotherapy is superior to surgery alone in patients with positive margins.[20] Two prospective studies from Memorial-Sloan Kettering[28] and the National Cancer Institute (NCI)[18] demonstrate a low local recurrence rate if adjuvant radiotherapy is in the treatment plan for patients with positive surgical margins.

Although adding perioperative radiotherapy improves the local outcomes, it has not shown any benefit in terms of overall survival or distant recurrence-free survival.[31]

Considerations in Retroperitoneal Sarcoma

At this point, no consensus exists on the timing or benefit of perioperative radiotherapy for patients diagnosed with retroperitoneal STS. The first randomized trial conducted by the NCI, published in 1993, clearly demonstrated that intraoperative radiotherapy improved local control but did not show a difference in overall survival and distant metastasis.[19] A retrospective National Cancer Database (NCDB) study reported an overall survival benefit of preoperative and postoperative radiotherapy compared to patients who received surgery alone. However, this study has limitations due to a lack of specific information concerning factors such as dose, complications, and other pertinent details.[32] A phase 1 to 2 trial led by the Italian-Spanish sarcoma group enrolled 86 patients with retroperitoneal STS to receive ifosfamide at a dose of 14 g/m² with radiotherapy at a dose of 50.4 Gy. The study reported local and distant recurrence in 37% and 26% of patients, respectively, at the 5-year follow-up. The study reported disease-free survival and overall survival of 44% and 59%, respectively.[33] Results of the European Organization for Research and Treatment of Cancer (EORTC)-Soft Tissue and Bone Sarcoma Group (STBSG) trial (NCT01344018; EORTC 62092-22092) were posted on clinicaltrials.gov in April 2023. For up to 7 years, this phase 3 randomized clinical trial compared abdominal recurrence-free survival between two groups: one receiving preoperative radiotherapy plus surgery (n=133) and the other undergoing surgery alone (n=133), in patients with untreated nonmetastatic retroperitoneal sarcoma. Abdominal recurrence or death occurred in 45.9% of patients treated with surgery alone and in 45.1% of patients treated with preoperative radiotherapy plus surgery. 

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. The results showed no significant difference between the two groups in local recurrence rates, distant recurrence rates, or overall survival. Although the results did not achieve statistical significance, researchers observed a trend toward reducing overall survival in the radiotherapy arm.[34] The French sarcoma group study (SARCGYN study) tested the combination of chemotherapy followed by radiotherapy versus radiotherapy alone. In the cohort of 81 patients, 53 patients had leiomyosarcoma. The chemotherapy included a combination of doxorubicin, cisplatin, and ifosfamide (4 cycles to be given after radiotherapy). The trial demonstrated a 3-year disease-free survival benefit in the combination arm, although no overall survival benefit was shown at the 3-year and 5-year benchmarks.[35] 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, radiotherapy can be an option on a case-to-case basis.[8] 

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 non-sarcoma tumors has shown the positive radio-sensitizing 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 STS of the extremity and trunk. Although grade 3 toxicity was relatively high in these patients, 5-year distant disease-free survival and overall survival were 64% and 71%, respectively.[36] Many other chemotherapy regimens have undergone testing since then. Among all of them, 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.[37] Despite encouraging results, neoadjuvant chemoradiation for STS or leiomyosarcoma remains experimental.

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, leiomyosarcoma is considered moderately sensitive to chemotherapy.[38] 

Adjuvant Chemotherapy after Surgery

After surgery, adjuvant chemotherapy for a patient diagnosed with STS has primarily been tested in patients with extremity and truncal STS.[39] Although 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 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. The analysis showed a statistically significant improvement in both local and distant recurrence-free survival, but the benefit in overall survival could not reach statistical significance. Despite this, the analysis demonstrated a 6% absolute benefit over 10 years.[40] 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 recurrence-free survival, distant recurrence-free survival, and overall recurrence-free survival. However, this analysis showed a statistically significant overall survival 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 showed an absolute risk reduction of 11%, which was not observed in the doxorubicin-only group.[41]

The Italian Sarcoma Group (ISG) 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) showed a better distant metastasis recurrence rate (45% versus 28%) and a better overall survival at 4 years (69% versus 50%). However, at a 7-year follow-up, the statistical significance was lost, and the local and distant relapse rates also became similar (44% versus 45%).[42] The EORTC conducted a randomized trial (ERTOC 62931) to investigate the role of adjuvant doxorubicin and ifosfamide in localized STS. All patients with positive margins also underwent adjuvant radiotherapy. This study did not report any difference in the recurrence-free survival or overall survival among the two groups. A significant limitation of this study is the use of ifosfamide at a lower dose (5 g/m²), which might have led to inferior results.[43]

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, thereby improving resectability, achieving negative margins, and enabling earlier control of microscopic disease, both local and distant. In addition, it can provide an essential clue in terms of the responsiveness of the tumor to chemotherapy. In a retrospective study examining STS and bone sarcoma, neoadjuvant chemotherapy was not associated with worse outcomes.[44] One of the early intergroup phase 3 trials 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.[45] A European phase 2 to 3 trial in patients with STS of the extremity or trunk reported no difference in disease-free survival (56% and 52%) in patients receiving surgery 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 sarcoma.[46]

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 with a positive or a negative margin on surgery had a 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. This study concluded that neoadjuvant chemotherapy could offset the negative impact of positive margins upon surgical resection and improve local control and survival.[47]

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, where trabectedin showed equal efficacy compared to standard chemotherapy, all other disease subgroups exhibited poor outcomes with histology-tailored therapy. This trial showed that a histology-tailored approach is not necessary when considering neoadjuvant chemotherapy.[48]

Chemotherapy in Metastatic or Unresectable Soft Tissue Sarcoma

First-line treatment: No established best first-line chemotherapy regimen exists for metastatic leiomyosarcoma. In a patient diagnosed with unresectable metastatic disease, therapy aims to palliate the symptoms and 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.[49] Over many years, various chemotherapeutic agents have been combined with anthracyclines (doxorubicin or epirubicin) to achieve a better outcome. 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 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 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 negative trial, the combination of doxorubicin and ifosfamide is still considered for patients requiring tumor shrinkage before the surgery or when the tumor is close to a critical structure.[49] 

The drug olaratumab, a platelet-derived growth factor receptor alpha-blocking antibody, was granted accelerated approval by the FDA in June 2016. This decision was based on the results of a phase 2 JGDG study that included patients with locally advanced unresectable or metastatic STS. However, the phase 3 trial (ANNOUNCE trial) reported at the American Society of Clinical Oncology (ASCO) 2018 annual meeting did not demonstrate the same overall survival benefit, which led to the suspension of the drug by the FDA.

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.[50] The phase 2 study, Comparison of Gemcitabine Versus Gemcitabine Plus Docetaxel in Unresectable Soft Tissue Sarcoma (SARC002), showed an improved objective response, progression-free survival, and overall survival with gemcitabine plus docetaxel compared to gemcitabine alone in advanced, previously treated STS.[51] 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 UK-GeDDiS trial. No statistical difference was found between the two groups of 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 two groups.[52] Notably, this trial used a lower dose of gemcitabine (675 mg/m²) and a regular dose of docetaxel (75 mg/m²), possibly contributing to the 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.[52]

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 has a dose-response relationship, where higher doses result in 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 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.[53]

A phase 3 randomized trial evaluated the effectiveness of administering a high dose of ifosfamide with stem cell rescue in patients with STS. No overall survival benefit was demonstrated in the trial.[54] 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.[55] 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 a 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 a lot of options. Monotherapy with trabectedin is the most promising of these and has been approved by the 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 to 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 < 0.001) and had a higher clinical benefit ratio (34% versus 19%; hazard ratio (HR), 2.3; CI, 1.45 to 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 3/4 toxicity in the phase 3 trial.[56] The French sarcoma group recently concluded a phase 2 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 progression-free survival.[57] Currently, trabectedin is being tested in combination with immunotherapy and chemotherapy to improve treatment efficacy.

Pazopanib 

Multiple anti-angiogenic agents, such as 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 1 trials; however, the success of most of these drugs could not be replicated in phase 2 trials.[58] 

Pazopanib is an oral multitarget tyrosine kinase inhibitor approved for use in advanced STS, regardless of histology, for patients who have previously received chemotherapy. Pazopanib is administered at an oral dosage of 800 mg daily. Pazopanib 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 progression-free survival benefit (4.6 months versus 1.6 months; HR, 0.35, 95% CI; 0.26 to 0.48; P < .001) observed in the phase 3 trial (PALETTE) where the study compared pazopanib to placebo. The pazopanib arm had no observable overall survival benefit compared to the placebo arm. Of note, liposarcoma was excluded from the phase 3 trial due to poor response in the phase 2 trial.[59] Hepatotoxicity, cardiotoxicity, and thyroid dysfunction are some of the most common adverse effects. Rarely, reports of reversible posterior leukoencephalopathy syndrome have been documented.[60][61]

Eribulin (E7389)

Eribulin mesylate (E7389) is an analog of halichondrin B approved for metastatic breast cancer. Eribulin mesylate blocks the G2 phase and the M phase of the cell cycle through a tubulin-based antimitotic mechanism. This blockage inhibits the spindle formation in the cell cycle, leading to cancer cell apoptosis.[62] 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 3 trial (E7389-G000-309).[63] In a pre-planned subset analysis of the phase 3 trial results, the patients diagnosed with leiomyosarcoma showed comparable efficacy to 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 to 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 to 1.38]; P = .58) and objective response rate (5% versus 7%) were not significantly different.[64] The FDA has not yet approved the drug for leiomyosarcoma. However, it 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 of the two. Adverse effects of eribulin include neutropenia, peripheral nerve neuropathy, and QTc prolongation.

Immunotherapy 

Immunotherapy has not shown much promise in the STS subgroup overall. Except for 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 leiomyosarcoma subgroup.[65][66] The phase 2 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. One-third of all the patients had uterine or extrauterine leiomyosarcoma. Out 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 to a 16% response 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 dose of ipilimumab (used at 1 mg/kg). Arguing that a high tumor mutational burden, characteristic of leiomyosarcoma, may have led to a higher activity of the combination of nivolumab and ipilimumab in leiomyosarcoma.[65] 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 (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.[67] The approval was granted based on the 149 patients included in the KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158 trials.[67]

Neurotrophic Tyrosine Kinase Inhibitor - Entrectinib[68]

• 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 2 STARTRK-2, phase 1 STARTRK-1, and the phase 1 ALKA-372-001 trials. These trials were conducted across 15 countries and 150 clinical trial sites. Entrectinib demonstrated an objective response rate of 57%.

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.[53][69] 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 achieved its primary endpoint of disease control rate of 46% at 18 weeks.[70] 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.[71] Multiple studies have demonstrated the activity of pegylated liposomal doxorubicin in metastatic STS either alone or combined with ifosfamide.[72][73] Pegylated liposomal doxorubicin was also tested against single-agent doxorubicin in an EORTC-SSTSBG phase 2 trial.[73] Although comparable response rates were reported amongst the two groups, as expected, cardiotoxicity was significantly lower in the pegylated liposomal doxorubicin arm. The Food and Drug Administration (FDA) has not yet approved pegylated liposomal doxorubicin for patients with leiomyosarcoma.

Hormonal Therapy

As with other gynecological malignancies, uterine leiomyosarcoma exhibits estrogen receptors in 7% to 70% of patients and progesterone receptors in 17% to 60% of patients. 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.[74][75] 

Staging

Leiomyosarcoma staging is according to the organ of origin. Uterine leiomyosarcoma staging follows the Federation of Gynecology and Obstetrics (FIGO) staging system. According to the American Joint Committee of Cancer (AJCC) staging, an extrauterine leiomyosarcoma gets staged. However, the 8th edition of AJCC has resolved a long-standing variability in STS staging. In the latest edition, AJCC has provided a separate staging system for STS of the retroperitoneum, head or neck region, and extremities or trunk region.[76] Notably, despite the AJCC 8th edition addressing some significant issues of previous editions, the staging system still does not translate well into survival.[76]

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 (FNCLCC). The relative ease of use and well-balanced components, including a score for dedifferentiation (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.[77] 

• 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, 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:[76]

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: The staging of STS of the retroperitoneum is 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. In contrast, in the STS of the extremities and trunk, they fall under Stage IV.[78] 

AJCC 8th edition staging for head and neck: There are no staging groups in the head and neck region in AJCC 8th edition as it would need the application of the French grading system, and very extensive lesions (T4) remain unclassified.[77]

• 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

FIGO staging for uterine leiomyosarcoma (2009):[8]

• 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 bladder or rectum
  • IVB: Distant metastases

Prognosis

The three 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.[79] Available calculators and normograms have been developed to help determine prognosis.[80]

Histologic grade is the most predictive risk factor. This factor can independently estimate the aggressiveness of cancer, the probability of distant metastasis, and disease-specific survival.[79][81][82] Leiomyosarcoma is inherently an aggressive malignancy, with 90% of patients diagnosed with grade 2 to 3 cancer, and as a result, are at a higher risk of distant recurrence and decreased disease-specific survival compared to other histologies.[81] Larger tumors have a worse outcome, especially with tumors over 10 cm.[83]

Tumor location is an independent prognostic risk factor. Leiomyosarcoma of the extremities has a better outcome compared to retroperitoneal leiomyosarcoma.[82] 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.[76][84][85]

Uterine leiomyosarcoma 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 or absence of necrosis as factors that can determine prognosis.[8] 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 compared to more traditional staging systems, such as the FIGO and AJCC classifications, in predicting the overall survival.[86]. 

In a recent meta-analysis of 580 patients with metastatic STS and lung-only metastasis recorded in the EORTC-STSBG trials, age, time between initial diagnosis and treatment, performance status, and involvement of the primary site were reported to help determine the prognosis of this subgroup of patients. The analysis showed that patients with a nontarget pulmonary lesion (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 overall survival and progression-free survival.[87]

Complications

Complications of leiomyosarcoma are site-specific. Common issues include external compression due to mass effect and early metastasis due to aggressive tumors.