Uveal Melanoma: Better Survival With Liver-Directed Therapy

Alexander M. Castellino, PhD

June 12, 2018

Chicago — For patients with uveal melanoma, the most common eye cancer in adults, survival outcomes have improved in recent years, after treatment modalities shifted from systemic to liver-directed therapies.

The finding comes from researchers at the Thomas Jefferson University in Philadelphia, Pennsylvania, and was presented at the recent American Society of Clinical Oncology (ASCO) 2018 annual meeting.

"Our study is the largest, real-world data showing improvement of the outcomes of metastatic uveal melanoma patients over the last 50 years with newer liver-directed treatments, including radioembolization," lead author Rino S. Seedor, MD, told Medscape Medical News.

During the past 50 years, treating liver metastases in uveal melanoma has been a journey, she explained, from systemic chemotherapy in the 1970s to transarterial chemoembolization (TACE) with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), drug-eluting beads with doxorubicin, immunoembolization, and radioembolization.

For their study, Seedor and colleagues carried out a retrospective chart review of consecutive patients with uveal melanoma with liver metastasis who were treated at their institution. They grouped patients into those treated between 1971 and 1993 (cohort 1; n = 101) and those treated between 2000 and 2017 (cohort 2; n = 655).

"Novel liver-directed therapies were being developed between 1993 and 1999, and these years represent the transitional years. Including patients from these years would have provided mixed results," Seedor said.

Eye tumor characteristics were similar across the two cohorts (location of tumor, tumor maximum diameter, thickness, and T stage). First eye treatment included enucleation, radioactive plaque, and external radiotherapy.

For liver metastases, 81% of patients in cohort 1 received systemic therapy; in cohort 2, 88% of patients first received liver-directed therapies, which included immunoembolization (n = 270), TACE (n = 131), drug-eluting beads with doxorubicin (n = 42), and radioembolization (n = 36).

Median overall survival (OS) from metastases to death improved from 4.8 months for patients in cohort 1 to 16.8 months for those in cohort 2 — an approximately fourfold increase (P = .0271). Median OS from uveal diagnosis to death was also prolonged — from 3.4 years for patients in cohort 1 to 5.0 years for those in cohort 2 (P < .0001).

After adjusting for variables such as year of diagnosis and time from diagnosis of primary uveal melanoma to liver metastasis, patients in cohort 1 were at a 77% increased risk for early death after development of liver metastasis compared to patients in cohort 2 (hazard ratio, 1.77; P = .0271).

The investigators also noted some of the limitations of their study — it was a single-institution study, a retrospective analysis, and cohort 1 had a small number of patients. The missing information for the period between 1993 and 2000 represented the transition between systemic to liver-directed therapies, they commented.

Takami Sato, MD, medical oncologist and senior author on the study, pointed out that liver-directed therapies are undertaken at institutions in which there is collaboration between medical oncologists and interventional radiologists. Most institutions that currently provide systemic treatment for liver metastases use checkpoint blockades either through a single agent, which provides responses of less than 5%, or in combination, which provides response rates between 10% and 15%.

"Response rates with liver-directed therapies at Thomas Jefferson University have been around 30%," Sato told Medscape Medical News.

He indicated that newer systemic therapies under investigation, such as IMCgp100, which have shown potential survival benefit, could be combined with the liver-directed therapies to further improve the outcome of uveal melanoma patients with hepatic metastases.

Prolonged Survival With Radioembolization

Another presentation at the meeting, from researchers at the same institution, gave details on radioembolization for the treatment of liver metastases, which showed that it can lead to prolonged survival.

Interventional radiologist Carin F. Gonsalves, MD, told Medscape Medical News: "At our institution we have a dozen patients who have far exceeded expectations and are still alive after 5 years," she said.

Gonsalves said that liver-directed treatment should be considered in all cases of liver metastases, and multidisciplinary collaboration is essential. "At our institution, medical oncology and interventional oncology have weekly clinics and weekly conferences where we review uveal melanoma cases," she said.

Gonsalves said that radioembolization is a one-time treatment, unlike other liver-directed treatments, which are often given multiple times until disease progression. "In radioembolization, we treat once and then we watch," she said

She presented findings from the first prospective phase 2 study that used radioembolization with Y-90 resin microspheres — spherical microparticles that contain the radioactive isotope yttrium-90 and emit radiation to kill cancer cells — in patients with uveal melanoma and liver metastases.

The trial involved 24 treatment-naive patients and 24 patients whose condition had progressed on immunoembolization.

The study was conducted between November 2011 and January 2017. Gonsalves admitted that this trial took a long time to complete, owing to strict inclusion criteria (patients with extrahepatic metastases were not eligible for the study) and the time it took to get insurance approval for each patient. Angiographic studies were needed to confirm the feasibility of treatment.

Patients received unilobar or lobar treatments 3 to 5 weeks apart. Whether patients received unilobar or bilobar treatment was patient- and disease-dependent. Patients were followed for 1 month for acute toxicity and every 3 months for delayed toxicity.

Patients who had not previously been treated for liver metastases received a median dose of 32.6 mCi given to a single lobe (n = 7) or to both lobes (n = 17). Median progression-free survival (PFS) was 8.1 months, and median OS was 18.5 months.

One-year OS was 61%. In these patients, radiographic partial responses were reported in seven patients, stable disease in 13 patients, and disease progression in three patients.

Patients whose condition had progressed after immunoembolization received a median dose of 35.0 mCi given to a single lobe (n = 5) or both lobes (n = 19). In these patients, median PFS was 4.3 months, and median OS was 19.1 months. One-year OS was 70%. Radiographic partial responses were reported in six patients, stable disease in eight patients, and disease progression in 10 patients.

Extrahepatic disease occurred in 17 patients in cohort A and 15 patients in cohort B.

Although patients with liver metastases most often die from their disease, localized treatment of liver metastases has improved survival in meaningful ways, Gonsalves said. She recommended that patients be provided the option for localized treatment for liver metastases.

American Society of Clinical Oncology (ASCO) 2018. Abstracts 9592 and 9535, presented June 4, 2018.

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