Good afternoon readers! Today’s blog post is devoted to a rare sarcoma, but one that is super important to recognize – it can often be mistaken for other things that are much more common. There are some graphic pictures in this post, so just be aware ahead of time! Also, I am involved in several clinical trials for angiosarcoma including immune therapy, so be aware that I may have a conflict of interest here!

Angiosarcomas are cancers of blood vessels and there are multiple types. Some occur in the skin, known as cutaneous angiosarcomas, where they often look like a purple or reddish spot that can be mistaken for a bruise. Most common places to see these are on the scalp or face, places that get a lot of sun exposure, and this type is more common in older people. here’s a pic –

They can be painless, or they can bleed and become crusty like an overgrown scab that doesn’t heal. These are often found by dermatologists doing routine skin exams for other much more common types of skin cancer, like squamous cell or basal cell carcinomas.

Angiosarcomas can also occur in the breast – a very important one to notice is in women who have had radiation treatment for breast cancer, usually somewhere around 7-10 years before. Women can think these are bruises, but in reality these are super aggressive and really important to pick up. They can be subtle… here’s a pic.

Women can also develop angiosarcoma in the breast with no prior history of breast cancer or radiation, but these are much rarer. In general, patients with a history of radiation can develop several types of sarcoma, including angiosarcomas, in the area of prior radiation. However, the good news is that these occur in less than 1% of patients who have had radiation – but still important to know.

Finally, patients can develop angiosarcoma in other organs – basically anywhere blood vessels are found, which means head to toe. They can grow in the spleen, liver, inside the abdominal cavity, or can start in bones.

---

Treatments

So like any other sarcoma, surgery is an important part of treatment if the angiosarcoma can be removed completely. However, the problem with angiosarcomas is that they often grow with “tentacles” of tumor cells extending way out beyond where you think the tumor actually stops looking at it (particularly the ones in the skin.) Even MRIs or CT scans may not show the tumor well if it is only in the skin. We have historically performed surgery and radiation, trying to get very wide margins (edges of normal tissue) to try to remove these. Unfortunately there is a very high risk that the angiosarcoma will come back even several inches away from where the tumor started. This is a big problem especially in places like the head, neck and scalp where there just isn’t much room to work. These surgeries can be very disfiguring. Even in small angiosarcomas less than 5 cm in size, the chance of the angiosarcoma spreading to somewhere else or coming back in the same place after surgery and radiation is very high compared to other types of sarcoma, in some reports more than 50% of the time.

Because of this, we often will recommend chemotherapy to try to decrease the chance of the angiosarcoma coming back, or to shrink the tumor before an attempt at surgery. The two big families of chemotherapy used for angiosarcomas include the taxanes (most commonly a medication called paclitaxel) and doxorubicin combinations. These treatments will often shrink the tumors for some time, but most patients will eventually have the angiosarcoma grow on treatment, or develop new spots in the skin or other organs. So new treatments are definitely needed for this group of cancers. You can read more about the history of chemotherapy and responses in this review article.

---

New treatments!

So in the last couple of years, we have figured out some really exciting things about angiosarcomas. The cutaneous or radiation-associated angiosarcomas seem to be able to be recognized by the immune system as foreign and bad, which means that immune therapy has been very helpful in angiosarcomas that have become resistant to chemotherapy. In work from the Angiosarcoma Project, led by the absolutely amazing scientist and angiosarcoma survivor Dr. Corrie Painter, PhD, patients’ angiosarcoma tissues have been analyzed by sequencing, or mapping of the genetic mistakes that occur in these tumors. Her team showed that many of the cutaneous angiosarcomas have many many many mistakes, in patterns that look like sun damage from other skin cancers like melanoma. And so we think this may be why angiosarcomas can respond to immune therapy. See my post on immunotherapy for details about how checkpoint inhibitors work. But in a nutshell, these are antibody drugs that are given through an IV that block the “don’t eat me” signals that cancer cells use to avoid detection and killing by the immune system. There are two main “don’t eat me” signals that can be blocked by drugs that have been or are being studied for angiosarcomas – PD1, blocked by drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo), and a new drug called balstilimab (AGEN2034), AND CTLA-4, which is blocked by drugs like ipilimumab (Yervoy) or a new drug called zalifrelimab (AGEN1884). There are many other drugs that block these targets that are approved or in clinical trials for cancer, but for the purposes of angiosarcomas, these are the ones that are in trials right now that we’ll talk about.

So my team in Miami and the pharmaceutical company Agenus who owns zalifrelimab published a paper where we first showed that these drugs could be effective in patients with angiosarcomas, including one patient who had received many different other treatments for angiosarcoma on her nose including surgery, radiation and several types of chemotherapy. She had a complete response, or basically a cure, of her angiosarcoma with zalifrelimab. Additionally, Michael Wagner, MD, PhD recently reported the results of a trial of immunotherapy with ipilimumab/nivolumab for angiosarcomas, which showed that 60% of the patients with cutaneous angiosarcomas had a response to these drugs.

The problem is that so far we haven’t seen as good results with immune therapy by itself in other types of angiosarcomas, like the ones in organs or in breast. So there is now an interest in combining these immune drugs with chemotherapy, to see if the combination may be effective.

Two big ongoing clinical trials for angiosarcomas include the following:

1. Alliance trial – This study is for patients with any type of angiosarcoma (cutaneous, organs, or radiation-associated) that is not curable with standard treatments OR if patients decline standard treatments (surgery/radiation). First, patients who have not ever had paclitaxel chemotherapy will be enrolled to either paclitaxel alone or paclitaxel plus nivolumab. If they progress on that treatment, OR if the patient has already had paclitaxel previously, they can then enroll in the second arm of the study, which is the chemo pill cabozantinib plus nivolumab. Cabozantinib, like other chemo pills called TKIs, block signaling proteins include those that promote bad tumor blood vessel growth. This study is going to be open at many centers across the United States.
2. Agenus trial – This study is for patients who have already had at least one type of chemotherapy and are not curable by surgery/radiation. Patients who have never received PD-1 therapy will be enrolled into balstilimab therapy alone, and patients who HAVE previously received PD-1 therapy (nivolumab, pembrolizumab, etc.) can be enrolled in the combination arm with PD-1/CTLA-4 therapy (balstilimab plus zalifrelimab). This study will be open at many centers across the United States AND Europe.

There are other studies for angiosarcomas as well – here are the search results for angiosarcomas today (1/31/2021). Additionally, many different kinds of sarcomas are being studied in trials combining chemotherapy and immunotherapy, and angiosarcomas may be eligible for these studies. Finally, there are numerous immune therapy drugs in trials that may enroll many types of cancer, in which angiosarcoma patients may be eligible for treatments. And more trials are likely in the works, so it’s worth keeping an eye on these options.

In a nutshell, there are more clinical trials out there for angiosarcomas right now than arguably ever before – so it’s worth talking with your doctor about whether or not a trial may be right for you at some point in your treatment, especially if you’re considering a big surgery to try to remove an angiosarcoma. Shrinking an angiosarcoma before an attempt at surgery, whether with chemotherapy or potentially a clinical trial, could be a better option in the long term. Having an evaluation with a whole team, including surgeons, radiation oncologists, and sarcoma medical oncologists is super important to make sure that you get the best shot at cure of this challenging disease.