Immunoembolization for treatment of metastatic uveal melanoma

David J Eschelman

Immunoembolization was developed for the treatment of this disease in hopes of both providing local control for the hepatic metastases and delaying onset of other metastases by creating an in situ tumour vaccine, writes David J Eschelman.

Uveal melanoma is the most common primary intraocular malignant tumour in adults.  The tumour is rare, with approximately 2,000 patients newly diagnosed annually in the USA.  Despite successful treatment of the primary tumour, half of patients develop metastases for which there is currently no cure. The liver is the predominant organ of involvement in >90% of patients with metastases; in half of patients it remains the only site of metastasis. Unfortunately, systemic therapies that are effective for cutaneous melanoma are generally not successful in controlling metastatic uveal melanoma. Therefore, liver-directed therapy remains an appropriate treatment for these patients since their survival is generally determined by control of these very aggressive liver metastases.

Immunoembolization was developed for the treatment of this disease in hopes of both providing local control for the hepatic metastases and delaying onset of other metastases by creating an in situ tumour vaccine. Destruction of the tumour by embolization may control tumour progression locally and provide tumour antigens to the local immune system. Concurrent use of biological response modifiers induces an inflammatory response in the tumour and surrounding tissue which may improve antigen presentation to the local immune system. The local stimulation of the immune system may result in development of a systemic immune response against tumour cells to hopefully suppress growth of untreated tumours.

This treatment is most appropriate for patients deemed unresectable with less than half of their liver replaced with metastases. Also, immunoembolization has generally not been effective for patients with tumours larger than 5–6cm.  MRI of the abdomen, preferably using a hepatobiliary contrast agent along with diffusion weighted imaging, is much more sensitive at detecting very small hepatic metastases to fully evaluate the extent of disease than CT scans. In our institution, patients with this disease are discussed in a weekly multidisciplinary conference and are evaluated initially and after every two treatments in a weekly multidisciplinary clinic.

Immunoembolization is performed using 1500mcg of granulocyte-macrophage colony-stimulating factor (GM-CSF) emulsified in Lipiodol, followed by Gelfoam slurry to a point of near arterial stasis. GM-CSF increases myeloid cell production, stimulates macrophages, increases cytotoxicity of monocytes toward tumour cell lines, and promotes maturation of dendritic cells. Patients are also given a small dose (two million units) of Interleukin-2 (IL-2) in a “sandwich” technique after half of the GM-CSF/Lipiodol emulsion is administered, since IL-2 is not stable in Lipiodol. When using 2,000mcg of GM-CSF in a phase II clinical trial, there was a paradoxical response in patients with very limited tumour burden.  Therefore, we currently treat patients using 1,500mcg GM-CSF.

In patients with bilobar disease, we treat each lobe separately at four week intervals, and then repeat imaging after two treatments. Multiple repeated treatments are necessary to maintain control. Side-effects usually consist of mild post-embolization syndrome and flu-like symptoms; these are generally less significant after the first two treatments. Patients should not receive steroids (including prophylaxis for iodinated contrast allergies) while undergoing treatment using immunoembolization, since this may suppress the immunologic response. Patients are observed overnight in the hospital after immunoembolization to optimise management of post-procedure symptoms such as nausea, vomiting, fevers, and abdominal pain. 

Approximately two-thirds of patients will have at least stable disease. Unfortunately, immunoembolization is not effective in one-third of patients, and other treatments such as radioactive microspheres or chemoembolization may be pursued when tumour progression is encountered.

Approximately 10–15% of patients treated with immunoembolization have prolonged periods of relative tumour stability lasting for several years and can undergo treatment breaks with continued imaging surveillance. When the tumours start growing again, immunoembolization may be resumed—often with success. The median overall survival is 21.5 months, and onset of systemic metastases was delayed for 10–12 months in patients undergoing immunoembolization.  A recently published phase II double-blind, randomised clinical trial comparing bland embolization to immunoembolization demonstrated an overall survival benefit in patients (with 20–50% of the liver replaced with tumour) who underwent immunoembolization.

We are exploring the effects of combining immunoembolization with immune checkpoint inhibitors such as ipilimumab and pembrolizumab, in hopes of potentiating the immune response.

David J Eschelman is co-director, Division of Interventional Radiology, Thomas Jefferson University Hospital, and associate professor of Radiology, Sidney Kimmel Medical
College of Thomas Jefferson University, Philadelphia, USA. He has reported no disclosures pertinent to this article