Targeted Therapies And Immunotherapy

Introduction

Myxofibrosarcoma (MFS) is a rare malignant tumour classified as a type of Soft Tissue Sarcoma (STS), originally thought to be a variant of Malignant Fibrous Histiocytoma (MFH), another type of STS. MFS normally affects the elderly individuals of age above 50 years old,but it can affect people of any age and is more common in men than women. MFS can be found in the upper and lower extremities, like the legs, arms, head, neck, chest, abdomen, back, etc. Unlike many other STS, MFS has a high risk of local recurrence, which means another tumour regrows even after treatment compared to other STS and has a lower occurrence of migration to other parts of the body (metastasis). Finally, MFS can be subdivided into 3 grades: low-, intermediate-, and high-grade.

Symptoms and causes 

The cause of MFS is largely unknown, but risk factors like previous radiation treatment, genetic changes, or exposure to chemicals can play a role in the risk of being diagnosed with myxofibrosarcoma.¹ A physical characteristic of MFS can be a slow enlarging mass with firm nodules or lumps found in the subcutaneous tissue, the layer beneath the skin.

Other symptoms include:

• Bloating
• Constipation or Frequent Urination
• It starts becoming painful
• Swelling

Diagnosis and Challenges of Treatment

There are normally 3 ways in which a GP can diagnose someone with myxofibrosarcoma:

• Physical examination: looking for a lump/nodule and any corresponding symptoms
• Ultrasound: Used to evaluate any surface level (superficial) or palpable soft tissue masses
• MRI: Another preferred diagnostic instrument to evaluate soft tissue masses

There are challenges to diagnosing MFS, a GP can misdiagnose MFS as other tumours or sarcomas, and in terms of treatment, MFS is very likely to recur after treatment and can prove difficult to manage.

Pathophysiology and histopathology

When studying a tumour specimen of MFS, low-grade MFS shows no metastatic potential, while intermediate- and high-grade MFS will show some form of metastasis. Other main characteristics of a tumour tissue specimen include curved, elongated, thin-walled blood vessels and myxoid stroma, a mucous-like extracellular matrix that is normally secreted by tumour cells instead of healthy cells. 

The pathogenesis of MFS is described as the mutation of a complex set of chromosomes (karyotypes) that lack any specific irregularity. A study by Lee et al. (2010) found that the MET gene, important for cell growth and survival, was found to be overexpressed in association with high-grade MFS, and this overexpression was found in 67% of cases of localised MFS. Furthermore, a study by Lewin et al. found that the oncogene p53, a tumour suppressor, is the most commonly mutated gene in MFS with other studies corroborating their findings. More studies have identified even more mutated genes in patients with high-grade MFS, like RB transcriptional repressor (RB1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and cyclin-dependent kinase inhibitor 2B (CDKN2B) were observed.²

Treatment

Surgery

Surgery is the standard treatment for localised MFS, normally requiring a wide resection, which requires the removal of large areas surrounding a tumour. The operation is based on the tumour size, location, stage, etc. CT and MRI are used to help determine the location and extent of tumour burden. Fujiwara et al. (2020) recommend a minimum resection margin of at least 1 cm to minimise a local recurrence. Anything below that creates a positive margin, such as a tumour found on the edge of a tumour specimen, is an indication of the tumour not being fully removed. A positive margin has been linked to an increased risk of local recurrence and a reduced survival rate in patients with MFS. 

Radiotherapy

Radiotherapy (RT) is a treatment using intense energy sources like X-rays to kill cancer cells. Normally used in conjunction with surgery, done after post-operation. This is important as a study found that 53 of the patients (77%) had received radiation by itself, and 6 out of 11 (55%) had experienced local recurrence.³ Additional evidence in 1996 was that researchers found that patients with MFH who had received both postoperative and adjuvant RT were effective in reducing recurrence but couldn’t improve the disease-specific survival rate of the patient. It is also recommended that radiotherapy can be used against low-grade MFS as a post-operative procedure. However, the effectiveness of RT against high-grade MFS is still being determined, and more studies are required.

Chemotherapy

Another form of therapy similar to radiotherapy is chemotherapy, which is normally a drug that has to be taken. Used as palliative care for patients with MFS, the standard chemotherapeutic drugs used as the first-line treatment would be anthracycline (doxorubicin) and ifosfamide, either alone or in combination, against recurrent and metastatic MFS. An alkylating agent can also be combined with doxorubicin.³ If that fails, there’s a second line of drugs, which are gemcitabine, paclitaxel, or trabectedin. Some studies have cast doubt on its effectiveness, like a study in 1993 testing standard first-line chemotherapy treatment, which showed that patients with advanced STS only have a 20-30% response rate to the drug.⁴ But its efficacy is still to be determined.

Immunotherapy

T cells normally express inhibitory receptors, which activate the immunosuppressive signalling pathway, modulating the immune response to protect tissues from immune damage. So tumour cells exploit this by expressing inhibitory ligands, PD-L1, to bind to this particular inhibitory receptor on T cells, PD-1. A study by Yamashita et al. (2022) found that 0-35.6% of high-grade MFS cases had positive levels of PD-L1, and Smolle et al. (2021) discovered that PD-1, PD-L1, and Tumour-Infiltrating Lymphocytes (TIL) were more prevalent in patients with MFS than other sarcomas. So upcoming immunotherapy treatments against MFS use monoclonal antibodies to target not only PD-1 but also PD-L1, acting as Immune Checkpoint Inhibitors (ICIs) to reactivate the immunosuppressive signalling pathway. Other therapeutic drugs, like Tyrosine Kinase Inhibitors (TKIs), are also used to combat MFS by inhibiting the mechanism that aids the growth of tumours, The list of TKIs include⁵ 

• Pazopanib
• Sunitinib 
• Sorafenib 
• Regorafenib
• Cediranib 
• Apatinib 
• Anlotinib 

In a recent retrospective study in 2021, 7 out of the 61 patients who had MFS and received both ICIs and TKIs had an overall response rate to the drug of 42.9%, showing its effective response against MFS which shows the combination of immunotherapeutic drugs is highly effective.

The Future and Novel Strategies

Unfortunately, there isn’t a definitive cure for MFS due to its rarity compared to other STS; treatment is the management of the disease rather than the eradication of it. Many of these therapies can have debilitating side effects, and affected patients can suffer from the treatments with no certainty that they will respond to the treatment. But new non-invasive strategies are being tested, like high-intensity focused ultrasound (HIFU), which uses a heating technique to kill the tumour via hyperthermia⁶ or percutaneous image-guided cryoablation, which is an image-guided version providing an accurate image of the tumour site and utilising hypothermia instead of HIFU mentioned before; it can be used as a palliative or curative treatment to control tumour size and growth. Currently, studies are being done to test the effectiveness and safety of these two techniques, showing promising results with patients responding well with no complications.

FAQs

What is the overall survival rate of myxofibrosarcoma?

The 5-year survival rate of MFS is much higher than the average survival rate of other more common sarcomas, which is 57%, while MFS is around 65-67%. Moreover, the median time patients with MFS survive is 155 months but can range from 0.1 months to 215 months.⁸

What are the red flags for myxofibrosarcoma?

The red flags for MFS can be applied to any other soft tissue sarcoma. The University of Nottingham puts it as ‘ lumps that are growing, changing, larger than a golf ball, deep (reaching the fascia), increasing in size, painful, or recurring after removal.’⁹

If myxofibrosarcoma does metastasise, where does it head?

Myxofibrosarcoma metastasis is quite rare; however, when metastasis does occur, the most common site of infection is likely the lymph nodes, which is the central hub where most of our most important immune cells reside, like T cells and B cells, which are important for our adaptive immune response. But there’s also a likelihood it can spread to the lungs as well.

Summary

Myxofibrosarcoma is a rare soft tissue sarcoma that often occurs at a range of 50-70 years and commonly affects males. They are very hard to treat due to being misdiagnosed and their high chance of recurrence after treatment. Some targeted therapies and immunotherapies are used to manage the disease; the most common ones are surgery, which is accompanied by radiotherapy or chemotherapy post-operation. New immunotherapeutic drugs are also used either alone or in combination with other immunotherapeutic drugs if standard treatment fails; those include immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). New novel treatments like HIFU and image-guided cryoablation, which are both minimally invasive, are being tested, and their results prove promising.