Immunoembolization as a Treatment for Uveal Melanoma Hepatic Metastases

Uveal melanoma is an orphan disease with an aggressive, rapid course of progression and frequent metastases to the liver. Unlike cutaneous melanoma, there are no effective FDA-approved systemic therapies, but immunoembolization can help to control tumor progression and prolong survival. In this Q&A, Carin Gonsalves, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania, describes immunoembolization, patient selection, and important tips for colleagues who may encounter patients with uveal melanoma.

How is metastatic uveal melanoma typically treated?

Patients with less than 50% liver replacement by tumor can be treated with immunoembolization or radioembolization.  These tumors can also be treated with chemoembolization. However, due to systemic toxicities, including bone marrow toxicity, associated with the preferred chemotherapy agent used to treat uveal melanoma hepatic metastases, immunoembolization is typically performed first because systemic toxicities and adverse effects are relatively low.

What does immunoembolization involve?

A cytokine, known as granulocyte-macrophage-colony stimulating factor (GM-CSF), is administered into the hepatic artery stimulating the immune system, causing it to recognize the cancer as foreign. Lobar treatments are performed approximately 4 weeks apart. Following administration of GM-CSF, gelfoam embolization is performed, which keeps the medicine in the liver longer and causes tumor necrosis. Tumor necrosis releases antigens, which stimulates the immune system as well. The goal of immunoembolization is to create an in situ tumor vaccine.

What are some other treatment options for patients with uveal melanoma?

Radioembolization is an option for uveal melanoma, and is a common procedure performed throughout the country. We recently completed a prospective trial of 48 patients who received radioembolization, and we have submitted the paper for publication consideration.  Our results have shown a median overall survival of 18.5 months and 19.2 months with a 1-year survival of 60.9% and 69.6% in treatment-naïve patients and patients who failed prior immunoembolization treatment, respectively. Radioembolization may end up being the standard of care in most areas, as immunoembolization is not commonly performed by interventional radiologists at other institutions.

What is important for interventional radiologists to understand about uveal melanoma?

It is important to recognize that uveal melanoma is very aggressive. When a patient has uveal melanoma, time is of the essence. We would like to see patients referred here while their tumor is small so that they have more treatment options available to them. Sometimes, tumor progression is very rapid. A patient may present with limited disease within the liver and a month later, repeat imaging reveals rapid growth of hepatic tumors.

Years ago, overall survival with uveal melanoma was less than 6 months, and 1-year survival was 10% to 15%. As we develop more treatment options for these patients, the median survival has improved and is now approximately 2 years at our institution using various liver-directed therapies.

Even if a patient is ultimately not going to be referred to Jefferson for treatment, we are able to help our colleagues by reviewing patient images and offering recommendations for treatment.

Can you tell us more about patient selection?

Patients usually need to have less than 50% tumor burden in the liver to be eligible for immunoembolization or radioembolization. Patients who have an allergy to contrast and require pretreatment with steroids are typically not candidates for immunoembolization. Steroids used to prevent an allergic reaction to contrast will decrease the immune response following immunoembolization, causing the treatment to be ineffective. For patients who present with greater than 50% tumor burden within the liver, chemoembolization with Carmustine (BCNU) is recommended.  In addition, chemoembolization is recommended for patients who fail other liver-directed therapies.

You mentioned that current overall survival is about 2 years. Do you anticipate any future treatments that will further prolong survival?

We are hopeful that the combination of immunoembolization with dual agent immune checkpoint inhibitors may increase the survival of patients with metastatic uveal melanoma. We have tried a single agent checkpoint inhibitor, such as ipilimumab, together with immunoembolization, and results were about the same as with immunoembolization alone. We are currently conducting a prospective trial using a combination of ipilimumab and nivolumab with immunoembolization to see if this approach will prolong survival and prevent the development of extrahepatic disease. Additionally, we are running a multicenter trial with radioembolization combined with ipilimumab and nivolumab, again with the hopes of prolonging survival for these patients.

Another promising new treatment is a drug called IMCgp100. This is a systemic treatment, and it is actually the first systemic treatment that has shown promising results for metastatic uveal melanoma. Only about 50% of Caucasian patients are eligible for this treatment because a specific tissue type is needed, but early phase 1 studies have shown a 73% overall survival at 1 year. Many of these patients likely had immunoembolization or some other liver-directed therapy and developed extrahepatic metastases, and then went on to participate in this trial. Combining immunoembolization and systemic IMCgp100 may improve survival outcomes for patients with metastatic uveal melanoma and may be a potential area of future research once IMCgp100 becomes FDA approved.

From a technical standpoint, are there any challenges to performing immunoembolization?

Patients undergoing immunoembolization can become hypotensive and bradycardic. Typically, this occurs during the procedure and more rarely immediately after the procedure.  Fluid resuscitation is the typical treatment for this side effect. If a patient has this side effect once, it is best to hydrate the patient prior to subsequent immunoembolization procedures.  

Is there anything else that is important for colleagues to know?

Uveal melanoma is unlike any other metastatic disease. Treatments must be close in proximity to the initial imaging study to best assess tumor response after treatment. Typically, we perform lobar treatments 4 weeks apart rather than 6 or 8 weeks. Imaging is checked after every two treatments to assess tumor response. Complete or partial tumor response as well as stable disease is considered a good response with this type of melanoma. In other words, because uveal melanoma is very aggressive, if tumors remain stable, we consider this a treatment success. As long as we can keep the growth of tumors under control, patients will have a better prognosis. Furthermore, it is important to know that uveal and cutaneous melanoma are very different diseases. Medications, such as immune checkpoint inhibitors, are much more effective against cutaneous melanoma compared to uveal melanoma, with reported response rates of less than 10%. Therefore, combination systemic and liver-directed therapies should be considered when treating patients with metastatic uveal melanoma.