Although systemic treatments are utilized for angiosarcoma, an aggressive and rare subset of a rare cancer, the efficacy achieved with these options is not as good as it needs to be. Immunotherapy may be able to address the unmet need for a systemic treatment in this disease, according to Michael J. Wagner, MD.

“Immunotherapy is the very exciting thing in all oncology, but I would say especially for angiosarcoma,” Wagner, an assistant professor with the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, told 

. “Part of that is based on case reports where a number of patients were treated with immunotherapy which is often made available to patients. Even though there is not an indication necessarily on the label of the approval of the drug, because we can access them, we have a fair bit of experience.”

accounts for 2% of all soft tissue sarcomas, which are rare malignancies that account for only 0.7% to 1% of estimated new cancer diagnoses in 2022.

 Moreover, the American Cancer Society predicted 13,190 new cases of soft tissue sarcoma would be diagnosed this year.

In findings from 1 study evaluating outcomes from 4537 patients diagnosed with primary angiosarcoma from 1973 to 2014, investigators observed a median overall survival (OS) of 82.1 months (95% CI, 76.48-87.72). Moreover, the 5-year OS rate was 26.3% (95% CI, 24.9%-27.7%), although that was found to vary by disease site. For those who had disease in the breast, extremities, head and neck, other, trunk, and unknown site, the 5-year OS rates were 43.7% (95% CI, 39.6%-47.8%), 33.9% (95% CI, 29.4%-38.4%), 26.2% (95% CI, 23.5%-28.8%), 9.6% (95% CI, 7.9%-11.3%), 37.5% (95% CI, 34.1%-40.8%), and 5.2% (95% CI, 1.2%-9.1%), respectively.

Angiosarcoma can appear in the head and neck, soft tissues, visceral organs, bone, retroperitoneum, and even the foot.

Survival for those with this disease is “dismal” and has not significantly improved over time. In the study, the 5-year OS rate was 30.3% (95% CI, 25.4%-35.1%) for patients diagnosed between 1973 and 1984 vs 24.3% (95% CI, 22.4%-26.2%) in those diagnosed between 2005 and 2014.

Predictably, survival is even worse for patients diagnosed with metastatic disease. In another study, investigators utilized Surveillance, Epidemiology, and End Results datasets to identify patients with metastatic angiosarcoma from 2010 to 2016 and to examine survival predictors of the disease. Results showed that among 284 patients, the OS rate at 3 years was 3.8%; moreover, the cancer-specific survival rate at that time point was just 5.2%.

Angiosarcoma is mostly a spontaneous tumor; however, investigators have observed a transformation from a benign vascular lesion to this disease. Additionally, exposure to radiation is a common cause of angiosarcoma, particularly in survivors of breast cancer who have received radiation to the chest wall.

“Really, less than 1% of people who receive radiation will eventually develop an angiosarcoma,” Wagner noted. “One other risk factor that we are learning from some of the new [research] that is being done at several centers, but especially at the Broad Institute, [is that] ultraviolet light exposure, just like with melanoma and other skin cancers, is probably associated with certain angiosarcomas—especially [those] of the scalp and of the face. We can actually now harness that information, and it is guiding some clinical trials and treatment.”

Diagnosis of angiosarcoma can be difficult, according to Wagner; it can be hard to identify this disease compared with a benign proliferation of cells because morphological differences are subtle. Angiosarcoma generally appears as abnormal, pleomorphic, malignant endothelial cells.

Wagner noted that angiosarcoma can look like several other conditions. Just as the disease is difficult to diagnose, it is difficult to treat.

“One way to think about it is, this is a cancer of blood vessels, so it [has] a very infiltrative growth pattern,” Wagner explained. “Even if a surgeon were to just remove, for example, a purple spot that you can see on the skin, if you just cut a relatively small margin around that area, I can almost guarantee you that that margin would be positive with cancer cells right up to the edge of the area that was removed. The surgeries [are] pretty large and extensive; [the disease requires] sometimes very disfiguring [procedures] to truly remove all of the cancer cells.”

Then, additional efforts are made to ensure that all the cancer is eliminated, according to Wagner. “[We] will often use radiation, and sometimes chemotherapy, as well,” Wagner said. “Even despite all that, the likelihood of recurrence is unfortunately still relatively high. Especially for patients who do have recurrences or develop metastases, we are still trying to figure out the best way to treat [this disease].”

Surgery is the standard practice for localized disease, but Wagner added that there is no systemic standard of care for angiosarcoma. Patients who are at greater risk for recurrence are likely to receive chemotherapy and/or radiation as well as surgery.

“If [the disease has] spread, then there are [several] chemotherapies and even some targeted agents that are approved and used frequently for sarcomas in general; [however, there are] some differences in the treatment of angiosarcoma, where [patients] tend to actually be more responsive to taxanes, for example, especially the cutaneous angiosarcomas,” Wagner explained

“There are some older, really standard chemotherapies that we use. We are just hoping to build upon that [benefit] by adding newer agents and doing some of these multi-institutional clinical trials.”

The lack of clinical trials is an ongoing challenge faced in the realm of angiosarcoma. Because of the small patient population, oncologists rely on cooperative groups such as SWOG, ECOG, and the Alliance for Clinical Trials in Oncology to lead research efforts in this disease.

Wagner credited the Count Me In project led by the Broad Institute and the Dana-Farber Cancer Institute with having produced “groundbreaking” insights into angiosarcoma. Count Me In, a collaborative research project that analyzes and shares anonymous data freely to encourage discoveries across cancers, discovered the association between ultraviolet exposure and angiosarcoma in findings published in 2020.

Moreover, Wagner was the lead author of the small, prospective, open-label, multicenter, phase 2 DART trial (NCT02834013) evaluating ipilimumab (Yervoy) plus nivolumab (Opdivo) in patients with metastatic or unresectable angiosarcoma. Here, patients (N = 18) received 1 mg/kg of ipilimumab every 6 weeks in combination with 240 mg of nivolumab every 2 weeks.

Although only 16 patients could be evaluated for efficacy, investigators observed 1 complete response and 3 partial responses, translating to an objective response rate (ORR) of 25% (95% CI, 9%-45%). Two responses to the dual immunotherapy regimen continued beyond 12 months. Moreover, 2 other patients experienced stable disease that lasted for longer than 6 months.

The 6-month progression-free survival (PFS) rate was 38% (95% CI, 20%-71%), and the median survival had not been reached at a median follow up of 12.1 months.

“One-quarter of the patients had their tumors shrink on the immunotherapy and some of those patients are actually still doing very well,” Wagner said. “That, I think, is 1 of the [approaches that] we are most excited about—especially for angiosarcoma.”

Wagner is not alone in his optimism for immunotherapy in angiosarcoma. A retrospective study done in 25 patients who received pembrolizumab (Keytruda) at the University of Texas MD Anderson Cancer Center revealed an objective response rate of 18% with the immunotherapy, and a disease control rate of 59%. The median PFS was 6.2 months, and the median OS was 72.6 months.10 Importantly, 72% of these patients had metastatic disease and 80% had undergone at least 2 previous lines of systemic therapy before starting pembrolizumab.

Investigators at MD Anderson are currently recruiting patients with locally advanced, metastatic, or recurrent angiosarcoma to participate on the phase 2 SiARA trial (NCT05026736). On the trial, patients (n = 30) will receive the investigational anti­–PD-1 monoclonal antibody sintilimab (Tyvyt) on day 1 of a 21-day cycle for up to 24 months.

Additionally, Juneko Grilley-Olson, MD, a medical oncologist with the Duke Cancer Institute, is the principal investigator for the Alliance A091902 study (NCT04339738), which is evaluating paclitaxel with and without nivolumab in patients with soft tissue sarcomas, including angiosarcoma, who have not received taxane drugs, and nivolumab plus cabozantinib (Cabometyx) in those previously treated with taxanes. The co-primary objectives of the research are PFS for paclitaxel with and without nivolumab and ORR for nivolumab/cabozantinib.

“Will adding immunotherapy to standard chemotherapy with paclitaxel actually improve the clinical outcomes? Of course, we do not know the answer to that, but hopefully, we will get an answer in the very near future,” Wagner said. “Studying those new drugs in rare subsets of a rare cancer becomes very difficult. However, I believe that [collaborative efforts]… will hopefully, provide us with additional information as to [how] the field should move forward and how we can improve outcomes for these patients.”

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Angiosarcoma. National Cancer Institute. February 27, 2019. Accessed July 18, 2022. 

Key statistics for soft tissue sarcomas. American Cancer Society. January 12, 2022. Accessed July 18, 2022. 

Zhang C, Xu G, Liu Z, et al. Epidemiology, tumor characteristics and survival in patients with angiosarcoma in the United States: a population-based study of 4537 cases. 

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Tenjarla S, Sheils LA, Kwiatkowski TM, Chawla S. Cutaneous angiosarcoma of the foot: a case report and review of the literature. 

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Ren S, Wang Y, Wang Z, et al. Survival predictors of metastatic angiosarcomas: a surveillance, epidemiology, and end results program population-based retrospective study. 

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Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ. Angiosarcoma. 

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Painter CA, Jain E, Tomson BN, et al. The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research. 

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Wagner MJ, Othus M, Patel SP, et al. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). 

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Ravi V, Subramaniam A, Zheng J, et al. Clinical activity of checkpoint inhibitors in angiosarcoma: a retrospective cohort study. 

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Articles

Although systemic treatments are utilized for angiosarcoma, an aggressive and rare subset of a rare cancer, the efficacy achieved with these options is not as good as it needs to be. Immunotherapy may be able to address the unmet need for a systemic treatment in this disease.

Immunotherapy May Represent an Exciting Development in Angiosarcoma Treatment

Angiosarcoma

Michael J. Wagner, MD, assistant professor, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, explains how immunotherapy may be a promising treatment approach for patients with angiosarcoma.

There is a significant unmet medical need for new treatments in angiosarcoma, according to Wagner. There is no established standard of care for the disease, and efficacy of existing options is not as strong as desired, Wagner says.

Findings from small studies and case reports suggest that immunotherapy could address that unmet need, Wagner adds. For example, Wagner led the phase 2 DART trial (NCT02834013) evaluating ipilimumab (Yervoy) in combination with nivolumab (Opdivo) for patients with metastatic or unresectable angiosarcoma. 

One-quarter of patients in the trial responded to treatment, according to Wagner, who expresses excitement for what these findings could mean for the field going forward.

Videos

Michael J. Wagner, MD, explains how immunotherapy may be a promising treatment approach for patients with angiosarcoma.

Dr Wagner or the Potential Value of Immunotherapy in Angiosarcoma

Michael J. Wagner, MD, assistant professor, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, discusses known risk factors for developing angiosarcoma.

Radiation exposure is a known cause of angiosarcoma, particuarly patients who have had breast-conserving therapy for breast cancer, according to Wagner. However, only a small fraction of those who are exposed to radiation in this way will eventually develop angiosarcoma, Wagner adds.

It has recently been discovered that exposure to ultraviolet light is associated with angiosarcoma, particularly when the disease presents on the face or scalp, Wagner says. Investigators have already started incorporating that information into their clinical trials, Wagner concludes. 

Michael J. Wagner, MD, discusses known risk factors for developing angiosarcoma.

Dr. Wagner on Risk Factors for Angiosarcoma

Michael J. Wagner, MD, assistant professor, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, discusses the importance of cooperative research groups in angiocarcinoma.

Angiosarcoma is a rare subset of an already rare disease, soft tissue sarcomas. Due to the lack of patients, it can be difficult for single institutions to recruit enough participants to conduct clinical trials.

Clinical trials requires collaboration, according to Wagner, who calls cooperative groups like EGOC, the Alliance, and SWOG "critical" for conducting research. Findings from the Angiosarcoma Project discovered the connection between exposure to ultraviolet light and angiosarcoma.

Michael J. Wagner, MD, discusses the importance of cooperative research groups in angiocarcinoma.