Chemotherapy Regimens For Breast Angiosarcoma

  • Lucy Luikinga Graduate Student studying MSc Women’s Health, UCL

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Introduction

Overview of breast angiosarcoma

Angiosarcoma of the breast is a rare form of breast cancer making up only 0.1% to 0.2% of cases.1 This rare form of soft tissue cancer arises in the inner linings of blood and lymphatic vessels of the breast or arms. Due to this location, the cancer can quickly spread around the body in a process called metastasis.1,2 As a result, breast angiosarcoma, unfortunately, has a poor patient outcome with a five year survival rate of 40%,3 and disease recurrence being seen in roughly half of patients.4

The disease can be classed as either primary or secondary. The primary form is seen in patients who have not had previous treatment for breast cancer. This form presents as distinct, often rapidly growing, discoloured nodules.5 This is seen in patients with a common age range of 30-50 years.6 On the other hand, the secondary form is present in patients who have had prior treatment for breast cancer and is typically associated with radiation therapy. However, it is also linked to breast lymphedema.5 Breast lymphedema occurs after the radiation or surgical removal of lymph nodes during treatment for breast cancer. Proper drainage of the lymphatic system is interrupted leading to swelling in the affected area (7). The secondary form can be harder to identify as it commonly presents as painless bruise-like patches which can be dismissed as harmless.5 Compared to the primary form of the disease, the age of incidence for secondary breast angiosarcoma falls around 20 years later, most commonly at ages 67-71, or 10.5 years after radiotherapy.6

Diagnosis is determined in a number of ways. And whilst identifying the form of the angiosarcoma is important, determining the size, location, and the stage of a tumour is important in deciding which treatment options will be the most effective. 

Currently common treatment options include:

  • Surgery
  • Radiotherapy 
  • Chemotherapy 

Importance of chemotherapy

Due to the aggressive and rapid progression of this disease, a treatment that is rapid and effective is key to improving a patient’s outcome. Hence, meeting these requirements, chemotherapy is one of the treatment methods.

Chemotherapy is a class of drug regimen that targets rapidly dividing cells in the body. Cancer cells divide more rapidly than most healthy human cells, hence why the treatment can be effective.  There are various types of regimes that can be used to treat patients. The particular chemotherapy regime is decided by the clinician by taking into account:

  • The tumour itself
    • Progression
    • Size 
    • Location 
    • Primary or secondary
  • The patient
    • Comorbidities 
    • Prior cancer treatment 

Recurrence of the disease with treatment is over 50%.8 Therefore chemotherapy can provide another method of clearing residual cancer cells.

Chemotherapy can be used after surgeries to clear any remaining cancer cells which decreases the chance of cancer recurrence. It can also be used before surgery in order to make tumours more operable. Occasionally it can be used in combination with radiotherapy when surgery is not possible. 

The different types of chemotherapy regimens, their purpose, and effectiveness in treating breast angiosarcoma will be further explained. 

Chemotherapy regimens

There are two main chemotherapy regimens used in the treatment of breast angiosarcoma. These are called neoadjuvant chemotherapy and adjuvant chemotherapy. 

Neoadjuvant chemotherapy

Purpose and drugs

    Neoadjuvant chemotherapy occurs before any surgical excision of a tumour in order to shrink its size. 

    This can be useful for a number of reasons:

    1. By doing this the surgical extraction of the tumour is less of an invasive procedure making it safer for the patient.
    2.  Additionally, if the tumour is initially too large for operation, neoadjuvant chemotherapy can be used to shrink the tumour to an operable size. 
    3. It is also useful for clearing micrometastasis. These are small groups of cancer cells that have moved from the initial tumour site. They are undetectable via imaging and can be missed in surgical removal. Therefore clearance by chemotherapy can reduce recurrence of the disease.
    4. This regimen also reduces the need for mastectomies, a procedure where one or both of the breasts are surgically removed in order to prevent the spread of cancer around the body.  

    There are various chemotherapeutic drugs used in the neoadjuvant treatment of breast angiosarcoma. Here are those that are commonly used and a brief description of how they work:9,10,11,12

    • Anthracyclines
      • E.g. doxorubicin, epirubicin
      • Stop the replication of DNA which causes cells to undergo a form of programmed death called apoptosis 
    • Taxanes
      • E.g., paclitaxel, docetaxel
      • Destabilise the proteins that assist in cell division causing apoptosis 
    • 5-fluorouracil, Capecitabine
      • Block a protein needed for DNA repair, this leads to cell death 
    • Cyclophosphamide
      • Disrupts the DNA structure leading to apoptosis 
    • Carboplatin
      • Changes DNA structure preventing its replication, leads to cell death

    Effectiveness and side effects

    Treatment of breast angiosarcoma with neoadjuvant chemotherapy has been shown to improve the 5-year survival rates of patients. However with the percentage of patients with the disease being so small, more research is required to determine a complete picture of the effectiveness of this therapy.

    The side effects that can be expected when going through this treatment are unpleasant so it’s important for patients to know what to expect and how they can be managed.

    Side effects seen in general when using neoadjuvant chemotherapy:

    • Nausea and vomiting 
    • Mouth sores 
    • Redness and/or soreness at site of IV
    • Inflammation, rashing, and or itching skin
    • Fatigue 
    • Fever 
    • Coughing 
    • Increased risk of infection 
    • Hair loss
    • Bleeding or bruising easily 
    • Headache 

    Unfortunately these are only the most commonly seen side effects and each drug can bring more specific adverse reactions to patients. 

    Adjuvant chemotherapy

    Purpose and drugs

    Adjuvant chemotherapy occurs after the surgical removal of a tumour in order to clear any remaining cancer cells. This prevents or slows the recurrence of cancer in the patient. 

    The types of drugs used in adjuvant therapy for breast adenocarcinoma are the same as those used in neoadjuvant therapy, the difference just being the time of deliverance. 

    Effectiveness and side effects

    In general breast cancer treatment, adjuvant chemotherapy has been shown to reduce the  risk of death somewhere between 7% to 33%.13 Again, due to the relative rarity of the disease there are no specific reliable statistics for breast angiosarcoma. 

    Since the same chemotherapeutic drugs are used in adjuvant chemotherapy and neoadjuvant chemotherapy, the similar general side effects are seen. 

    Palliative chemotherapy

    Purpose and drugs

    Palliative chemotherapy refers to the treatment of a cancer patient with the aim of improving quality of life rather than curing the disease. This is often used when a cancer has spread to other sites around the body and is resistant to prior treatments that have been tried. By using palliative chemotherapy, the patient can be alleviated of symptoms brought by the disease, making their time more comfortable 

    Drugs that are commonly used for palliative chemotherapy include cisplatin, as well as the other drugs mentioned previously in sections for adjuvant and neoadjuvant chemotherapies.

    Effectiveness and side effects

    Palliative chemotherapy is able to offer the patient an average 3 to 12 months of extra time to spend with relatives and loved ones.14 However, some may argue that palliative chemotherapy can bring unwanted side effects that reduce a patient's quality of life. These include those mentioned beforehand for adjuvant and neoadjuvant chemotherapies.  Furthermore,it is  more likely for a patient to die in an Intensive Care Unit rather than at home, which may be unfavourable to some. 

    This option is something that will be individual for the patient and discussion for what is best for the patient should be carried out with the primary healthcare giver. 

    Research findings

    Studies and trials (just a brief info)

    Unfortunately there is little literature available on clinical trials done specifically for the treatment of breast angiosarcoma. Below are a few clinical trials and studies that have been done specifically in the context of this disease and chemotherapy.

    Key findings and limitations (just a brief info)

    Bevacizumab and paclitaxel:15 The purpose of this trial was to explore the result of treating angiosarcomas with the addition of bevacizumab to paclitaxel once per week through the treatment cycle. The results showed that the median number of months survival rates were 19.5 in the treated with the combination and 15.9 in the control patients. However higher levels of toxicity were seen in the combination group, with one drug-related death. The data did not support further research into this treatment. 

    Docetaxel:16 Here a phase II trial involved patients who had cases of angiosarcoma that had spread through the body. They were treated with docetaxel every third week. Results showed this to be a tolerable treatment, and in 8 of the 27 patients there was a partial response or disease stabilisation. The results suggest this treatment could be effective for some patients who have metastatic adenocarcinoma.

    Case studies

    Published cases (just a brief info)

    Due to the rarity of the disease there are only a handful of published case studies outlining the treatment of this disease. A study17 showed that of 193 cases collated in a literature review, only 44 received some form of chemotherapy. Below are a few cases of patients who have been diagnosed with either primary or secondary angiosarcoma of the breast and how their treatment involved chemotherapy. 

    Characteristics, treatments, and outcomes (just a brief info)

    Case Study 1:18 The patient presented with a mass in the right breast that was rapidly growing. Biopsy and ultrasound scans were used to diagnose the cancer, since the patient has no prior history of cancer treatment, the case was classified as primary. The patient received a mastectomy along with lymph node investigation. At the time of the case study being published the patient was on a chemotherapeutic regime (not specified) and alive. 

    Case study 2:19  The patient, a 77 year old woman, had a lump of her left breast which was determined to be angiosarcoma after biopsy and examination. The patient received both radiotherapy and a chemotherapy regime of pegylated liposomal doxorubicin. At the time of publishing the patient was performing well after the end of her chemotherapeutic regime. 

    Guidelines and recommendations

    Existing guidelines and treatment recommendations (just a brief info)

    Currently existing guidelines state that breast angiosarcomas should be treated with surgery to remove the mass. This should then be followed with a form of adjuvant chemotherapy or radiotherapy. Follow-up should be carried out frequently to confirm the disease is in regression.

    If the disease is deemed too aggressive to treat, surgery is impossible, or the patient prefers it, the palliative chemotherapy can be explored. 

    Summary

    Overall, this disease is a rare but aggressive form of breast cancer. It commonly arises in older women who have had prior radioactive treatment for past and separate cases of breast cancer. Although the first line treatment for this disease is surgical removal of the tumour, chemotherapy can be used either before or after treatment, or in a palliative way. At the moment it is unclear what the effectiveness of chemotherapy is in the context of this disease as its rarity means clinical trials focused solely on breast angiosarcoma are very small in number. However, with the field of cancer research continuously improving, new discoveries will no doubt be made. 

    References

    1. Angiosarcoma of the breast [Internet]. 2021 [cited 2023 Oct 13]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/breast-cancer/angiosarcoma-of-the-breast
    2.  Angiosarcoma [Internet]. [cited 2023 Nov 3]. Available from: https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-vascular-tumors/angiosarcoma 
    3. Friedrich A-KU, Reisenbichler ES, Heller DR, LeBlanc JM, Park TS, Killelea BK, et al. Characteristics and long-term risk of breast angiosarcoma. Annals of Surgical Oncology. 2021;28(9):5112–8. doi:10.1245/s10434-021-09689-2
    4. Rosen PP, Kimmel M, Ernsberger D. Mammary angiosarcoma: The prognostic significance of tumor differentiation. Cancer. 1988;62(10):2145–51. doi:10.1002/1097-0142(19881115)62:10<2145::aid-cncr2820621014>3.0.co;2-o
    5. Weinfurtner RJ, Falcon S. Primary and secondary angiosarcoma of the breast. Contemporary Diagnostic Radiology. 2016;39(18):1–5. doi:10.1097/01.cdr.0000491157.42373.ba 
    6. Liberman L, Dershaw DD, Kaufman RJ, Rosen PP. Angiosarcoma of the breast. Radiology. 1992;183(3):649–54. doi:10.1148/radiology.183.3.1584913
    7. Lymphoedema after breast cancer treatment [Internet]. 2023 [cited 2023 Nov 3]. Available from: https://www.cancerresearchuk.org/about-cancer/breast-cancer/living-with/lymphoedema-after-treatment 
    8. Heinhuis KM, IJzerman NS, van der Graaf WT, Kerst JM, Schrage Y, Beijnen JH, et al. Neoadjuvant systemic treatment of primary angiosarcoma. Cancers. 2020;12(8):2251. doi:10.3390/cancers12082251 
    9. Chemotherapy for breast cancer: Breast cancer treatment [Internet]. [cited 2023 Nov 3]. Available from: https://www.cancer.org/cancer/types/breast-cancer/treatment/chemotherapy-for-breast-cancer.html 
    10. Geisberg CA, Sawyer DB. Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage. Current Hypertension Reports. 2010;12(6):404–10. doi:10.1007/s11906-010-0146-y
    11. Mandal A. Carboplatin pharmacology [Internet]. 2023 [cited 2023 Nov 3]. Available from: https://www.news-medical.net/health/Carboplatin-Pharmacology.aspx#:~:text=Mechanism%20of%20action,the%20phases%20of%20its%20cycle.
    12. Capecitabine (Xeloda) [Internet]. 2022 [cited 2023 Nov 3]. Available from: https://www.cancerresearchuk.org/about-cancer/treatment/drugs/capecitabine#:~:text=Capecitabine%20is%20a%20type%20of%20chemotherapy.,also%20have%20it%20with%20radiotherapy
    13.  Rossi L, Stevens D, Pierga J-Y, Lerebours F, Reyal F, Robain M, et al. Impact of adjuvant chemotherapy on breast cancer survival: A real-world population. PLOS ONE. 2015;10(7). doi:10.1371/journal.pone.0132853 
    14. What is palliative chemotherapy? [Internet]. [cited 2023 Nov 3]. Available from: https://getpalliativecare.org/what-is-palliative-chemotherapy/#:~:text=The%20Median%20Duration%20of%20Response%20tells%20you%20how%20long%20your,you%20can%20expect%20to%20live
    15. Ray-Coquard IL, Domont J, Tresch-Bruneel E, Bompas E, Cassier PA, Mir O, et al. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: A randomized phase II trial. Journal of Clinical Oncology. 2015;33(25):2797–802. doi:10.1200/jco.2015.60.8505
    16. Köstler WJ, Brodowicz T, Attems Y, Hejna M, Tomek S, Amann G, et al. Docetaxel as rescue medication in anthracycline- and ifosfamide-resistant locally advanced or metastatic soft tissue sarcoma: Results of a phase II trial. Annals of Oncology. 2001;12(9):1281–8. doi:10.1023/a:1012272007146
    17. Chau B, Loggers ET, Cranmer LD, Mogal H, Sharib JM, Kim EY, et al. Secondary breast angiosarcoma after a primary diagnosis of breast cancer. American Journal of Clinical Oncology. 2023; doi:10.1097/coc.0000000000001045
    18. Mouhoub M, Miry A, Haloui A, Karich N, Kamaoui I, Benkirane S, et al. Primary angiosarcoma of the breast: A case report. Pan African Medical Journal. 2019 Jun 24;33. doi:10.11604/pamj.2019.33.134.17414
    19. Mocerino C, Iannaci G, Sapere P, Luise R, Canonico S, Gambardella A. Multidisciplinary approach to breast angiosarcoma in an elderly patient: Repeated local relapses and significant objective responses. International Journal of Immunopathology and Pharmacology. 2016;29(3):537–42. doi:10.1177/0394632015626424 

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    Lucy Luikinga

    Graduate Student studying MSc Women’s Health, UCL

    Lucy is a graduate student currently completing here MSc at UCL. In her undergrad she completed her industrial placement in a pharmaceutical lab. Now she is moving towards a career in Science Communications. Having assisted in a Research Project on the Menopause and worked in a Pharmacy during the COVID-19 pandemic, Lucy has experience across the field of healthcare.

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