Overview
Myxofibrosarcoma (MFS) is a rare type of soft tissue sarcoma which generally occurs in elderly patients. Like many cancers, the treatment of MFS is a multimodal one, with a combination of radiotherapy, surgery, and chemotherapy being used. However, chemotherapy is usually utilised when the cancer has spread from its original source, or metastasized.1
MFS is a rare type of soft tissue sarcoma (STS) occurring mostly in elderly people. Some extreme cases in patients under 30 years old have been recorded, but these are extremely uncommon. MFS can manifest in any part of the body, but is most common in the extremities, showing a slight propensity towards the legs. It also shows a slight prevalence towards people assigned male at birth, but in both sexes it has a high local recurrence rate and a relatively low incidence of distant metastasis when compared to other sarcomas.2 In fact, the rate of recurrence of myxofibrosarcoma is the highest among all STS, with a rate ranging from 20-60% over 5 years.3 MFS can be low grade or high grade, with the versions of the disease exhibiting slightly different properties. Low-grade MFS shows a higher rate of multiple local recurrences and lower metastatic potential when compared to high-grade MFS.4 This grading is based on tumour differentiation and mitotic count, markers of how developed the tumour has become. It is estimated that around 15-38% of local recurrences evolve to higher grades of the disease with increased metastatic potential.2
Chemotherapy in MFS
In myxofibrosarcoma cases, chemotherapy is not the initial treatment patients undergo. The disease is normally combated in its early stages with a combination of radiotherapy and surgery.2,4 However, MFS has a high recurrence rate, with the recurrent tumours often having higher metastatic potential. Chemotherapy is used in cases when the tumour has recurred after initial treatment or metastasized and spread, or in cases where the initial tumour is inoperable. However, outcomes of MTS being treated with chemotherapy are very poor, and in metastatic MTS it is mostly used as palliative care.
Common chemotherapy regimens
First-line treatments:
- Doxorubicin: Anthracycline used as first-line treatment, stops the growth of cancer cells by blocking the enzyme topoisomerase II. Is commonly used in many soft tissue sarcomas.5
- Doxorubicin (with ifosfamide): Ifosfamide is an alkylating and immunosuppressive agent, and adds to the cytotoxicity of doxorubicin. Usually used in high-grade, metastatic MFS.
Second-line treatments:
- Gemcitabine (with docetaxel): Gemcitabine is a drug that inhibits the synthesis of DNA in the cells, while docetaxel is a compound that stabilises microtubules, preventing cell division and causing cell death.6
- Trabectedin: Alkylating agent that interacts with the minor groove of DNA, disrupting cell division and promoting cell death.7
While chemotherapy is the standard of care for advanced, metastatic MFS, it is still an ineffective treatment and does not produce very positive outcomes. The overall response rate to doxorubicin, either alone or in combination with ifosfamide, is around 20-30%. However, with second-line treatments such as gemcitabine, the response rate drops to 10%.2 Progression-free survival (PFS) is the length of time after treatment when a patient lives with the disease, but it does not get worse. The average PFS for first-line chemotherapy treatments in MFS is 4-6 months, and it is very similar to second-line treatments, being 4-7 months. Overall survival for MFS patients treated with chemotherapy does not exceed 16 months. This shows how generally ineffective chemotherapy is at treating MFS, and while it can be successful in some cases, metastatic MFS is generally a poor prognostic and palliative care is normally given.2
Chemotherapy also comes with a range of challenges and limitations that limit its effectiveness and safety as a treatment for MFS. Firstly, the drugs used, such as doxorubicin or gemcitabine, target mechanisms of cell division. This makes sense, as cancers divide very rapidly and uncontrollably, however, the drugs do not make a distinction between dividing cancer cells and normal dividing body cells. Cancer cells divide more and are more seriously affected by the treatment as a result, but significant damage is done to normal cells, causing harmful side effects. These can include fatigue, nausea, hair loss, and diarrhoea, among many others. Many chemotherapy regimens are also immunosuppressive, which increases the likelihood of patients contracting unrelated illnesses which could affect their treatment.5,7 All of these side effects can limit the usage of high doses, and will severely impact quality of life.
Tumour heterogeneity is a challenge that limits the effectiveness of general chemotherapies. This refers to regional differences between the cancer cells in the same tumour, where some cancer cells may be affected by treatment while others may not.8 Many cancers are often diagnosed with biopsies from only one region, which may not be representative of the tumour as a whole. In these cases, taking biopsies from different areas of the tumour may help to create a more accurate image of its makeup, which will help make the chemotherapy more personalised and possibly more effective.
Cancers are highly mutagenic, and so many develop resistance to the drugs they are treated with after a few rounds, causing them to lose their effectiveness in the long term. Other compounds then need to be explored, as well as possibly some kind of combination treatment to supplement the loss of effectiveness of the treatment.8
A main challenge when it comes to chemotherapy use in MFS is the lack of data and research surrounding the subject. As MFS is a rare type of STS, not much research has been done into it specifically, and the treatment protocols outlined earlier are mostly extrapolated from other effective treatments for more common types of soft tissue sarcoma. This may explain the poor outcomes in treating MFS patients with chemotherapy, as the drugs and regimens are effective for other STSs but may not be the same when applied to MFS.2
Future directions for MFS treatment
Research into the specific biology of MFS is crucial for the development of more effective treatment options being developed in the future. Targeted medicine could be an alternative to chemotherapy, where we could specifically target the mechanisms of the cell cycle exclusively in the cancer cells, and we would be able to avoid the side effects that come as a result of chemotherapy. Immunotherapy is also an option, where methods can be used to empower the body’s immune system to recognise and fight the cancer. This would also avoid many of the side effects of chemotherapy, but unfortunately, these methods are not widely available to the majority of the population. They could also be used in combination with current chemotherapy methods to help in improving outcomes or preventing recurrences, which are very common in MFS.7
Summary
Myxofibrosarcoma (MFS) is a rare type of soft tissue sarcoma that occurs in a vast majority of cases in elderly patients and appears most commonly in the extremities. It shows a high rate of local recurrence and has a low propensity to metastasize. First-line treatments for MFS include surgery and radiotherapy, and chemotherapy is used in cases where the cancer has recurred after initial treatment or is inoperable. While chemotherapy is the standard in these cases, outcomes are very poor and the therapy is given more commonly as a palliative treatment.
First-line chemotherapy includes doxorubicin, with or without ifosfamide, which is a drug that blocks cell division by inhibiting the enzyme topoisomerase II. Second-line drugs are used when doxorubicin stops yielding an effect, and while no consensus has been reached on the standard, gemcitabine with docetaxel is a common regimen. These chemotherapies have low response rates and the progression-free survival time is low when compared to other cancers. They also come with a range of side effects, including nausea, hair loss, fatigue, and a compromised immune system. These can limit the doses that can be given and therefore the effectiveness of the treatment.
Chemotherapy in MFS is also affected by a range of limitations such as drug resistance, tumour heterogeneity and a lack of data concerning the condition, which limits the specificity of the treatment. Alternative avenues of treatment, such as targeted medicine or immunotherapy, could be used in conjunction with chemotherapy or as an alternative to work around the side effects and be able to give advanced MFS patients a better fighting chance against the disease.
References
- Roland CL, Wang W-L, Lazar AJ, Torres KE. Myxofibrosarcoma. Surgical Oncology Clinics of North America [Internet]. 2016 [cited 2024 Jun 28]; 25(4):775–88. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1055320716300217.
- Vanni S, De Vita A, Gurrieri L, Fausti V, Miserocchi G, Spadazzi C, et al. Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives. Ther Adv Med Oncol [Internet]. 2022 [cited 2024 Jun 28]; 14:17588359221093973. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244941/.
- Mutter RW, Singer S, Zhang Z, Brennan MF, Alektiar KM. The Enigma of Myxofibrosarcoma of the Extremity. Cancer [Internet]. 2012 [cited 2024 Jun 28]; 118(2):518–27. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360945/.
- Myxofibrosarcoma: Prognosis, Treatment & Staging. Cleveland Clinic [Internet]. [cited 2024 Jun 28]. Available from: https://my.clevelandclinic.org/health/diseases/22563-myxofibrosarcoma.
- Doxorubicin and ifosfamide [Internet]. [cited 2024 Jun 28]. Available from: https://www.cancerresearchuk.org/about-cancer/treatment/drugs/doxifos.
- Gemcitabine (Gemzar) [Internet]. [cited 2024 Jun 28]. Available from: https://www.cancerresearchuk.org/about-cancer/treatment/drugs/gemcitabine.
- Nishio J, Nakayama S. Biology and Management of High-Grade Myxofibrosarcoma: State of the Art and Future Perspectives. Diagnostics [Internet]. 2023 [cited 2024 Jun 28]; 13(19):3022. Available from: https://www.mdpi.com/2075-4418/13/19/3022.
- Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol [Internet]. 2018 [cited 2024 Jun 28]; 15(2):81–94. Available from: https://www.nature.com/articles/nrclinonc.2017.166.