Introduction

Leiomyosarcoma, a common subtype of soft tissue sarcoma (STS), accounts for up to 10% to 20% of all sarcomas. Arisen from either smooth muscle cells or their mesenchymal cell ancestor, leiomyosarcoma mainly occurs in the retroperitoneum, uterus, and extremities, in descending order of frequency.^1,2   

Until now, the causative factors for leiomyosarcoma have not been accurately defined; however, certain risk factors have been associated with the development of STSs, including leiomyosarcoma.

The  major risk factors for STS include:^3,4

• A history of radiation exposure or radiotherapy, specifically at a youthful age
• STSs may also be part of genetic syndromes, like retinoblastoma and Li-Fraumeni syndrome

The treatment of leiomyosarcoma is based on the disease site, tumour size, grade, and patient-dependent factors. The possible options for managing STS include (Surgical resection, radiation, and chemotherapy). In case of high-volume sarcoma centres, it is highly recommended to follow a multidisciplinary approach.⁴

Generally, surgery is primarily applicable to any sarcoma and also pertains to patients diagnosed with leiomyosarcoma. Additionally,  the patients with leiomyosarcoma and due to the complexity of this type of STS, leiomyosarcoma is considered moderately sensitive to chemotherapy.⁴  Because of that, there is an increasing interest in neoadjuvant (preoperative) chemotherapy. This article provides an overview of who will benefit more from neoadjuvant chemotherapy and possible reasons for that.

Understanding neoadjuvant chemotherapy

Chemotherapy can be applied in neoadjuvant, adjuvant, combined, and metastatic settings. Neoadjuvant therapy is a treatment taken before the main treatment. This treatment is given in addition to the initial therapy, which can inhibit or reduce the growth of concealed cancer cells.

It serves as a first step for 

• Shrinking a tumour before surgery is the main treatment
• Improving resectability
• Achieving negative margins
• Enabling earlier control of microscopic disease (local and distant)

Additionally, it can give an important clue in terms of the responsiveness of the tumour to chemotherapy.^5,6

The classification of  the chemotherapeutic agents

The chemotherapy agents are generally classified based on  the mechanism of action:

1. Alkylating Agents  

Include: cyclophosphamide, ifosfamide, cisplatin, oxaliplatin.

• Antimetabolites

 Includes: azacitidine, decitabine,  methotrexate, pemetrexed, fluorouracil (5-FU).

• Antimicrotubule Agents

Include:  doxorubicin, daunorubicin, paclitaxel, docetaxel, vinblastine, vincristine.

• Antibiotics 

 Include: actinomycin D, bleomycin.

• Miscellaneous

It includes: hydroxyurea, tretinoin, and arsenic trioxide.

However, these groups of agents that include (anthracyclines, ifosfamide, trabectedin, gemcitabine, paclitaxel, dacarbazine, and eribulin) have therapeutic effects in STSs and are commonly used in clinical treatment.  Some studies admit that the neoadjuvant chemotherapy  showed an interesting effect on patients with STS, where this treatment doesn’t accompany adverse effects

Patient selection^7,8

Not all patients  with Leiomyosarcoma can have a good effect  after treatment with neoadjuvant chemotherapy, and the studies show that some criteria for who will benefit from this treatment, and these criteria include:

• High-grade STS: Tumours with a high risk of metastasis and recurrence are more potentially to respond to neoadjuvant chemotherapy
• Large tumours: If the size of the tumour is over 5 cm, it is often considered high-risk and may benefit from neoadjuvant chemotherapy
• Locally advanced STS: Patients with tumours which have spread to the same site and are not considered metastatic yet may be candidates to go under this type of treatment
• Extremity and trunk wall sarcomas: These are the most common areas where neoadjuvant chemotherapy is often used to improve surgical outcomes
• Certain subtypes: Synovial sarcoma, pleomorphic sarcoma, liposarcoma, and leiomyosarcoma are recognised to be more chemosensitive and may respond better to neoadjuvant chemotherapy
• Patients where limb-salvage is a goal: Neoadjuvant chemotherapy can help make limb-salvage surgery more attainable by decreasing tumour size and enabling more conservative surgical approaches

Evidence from clinical studies

Due to the increasing interest in neoadjuvant chemotherapy, various studies have been done, and the results of these studies, like a retrospective study examining STS and bone sarcoma, have shown that the neoadjuvant chemotherapy was not accompanied by worse outcomes.9 In addition to another trial that includes 252 patients who are going to receive neoadjuvant chemotherapy followed by surgery and postoperative cycle, it concludes that neoadjuvant chemotherapy could offset the negative impact of positive margins upon surgical resection and ameliorate local control and survival.¹⁰

Challenges and controversies

These types of managing LMS  have some limitations that reduce the efficacy that we are looking for, and limitations can be ordered:

• Risk of chemoresistance
• Delay in definitive surgery
• Toxicity and impact on quality of life
• Lack of standardised guidelines

Conclusion

To conclude, Leiomyosarcoma is one of the most common subtypes of soft tissue sarcoma. Managing this type of sarcoma relies on surgery, but chemotherapy and radiation are commonly used. Recently, neoadjuvant chemotherapy holds promise in select LMS patients due to its effect of increasing the rate of survival and inhibiting the growth of the tumour. This type of therapy showed good effects with patients with a significant criterion that is determined by tumour biology, location and resectability. However, this management has limitations because of the lack of trials and the need for more research to guide individualised care.