Second-line selective internal radiotherapy slows colorectal liver metastases progression

Administering a device-based selective internal radiation therapy (SIRT), in addition to systemic treatment in the second-line setting, extends time to progression in colorectal liver metastases (CLM) patients, as shown in the phase III EPOCH trial.

Results for the primary endpoints of overall progression-free survival (PFS) and hepatic PFS (hPFS) were both more favourable among patients who underwent add-on SIRT than among those who received chemotherapy alone.

Median PFS was 8.0 vs 7.2 months (hazard ratio [HR], 0.69, 95 percent confidence interval [CI], 0.54–0.88; p=0.0013), while median hPFS was 9.1 vs 7.2 months (HR, 0.59, 95 percent CI, 0.46–0.77; p<0.0001), respectively. [J Clin Oncol 2021;doi:10.1200/JCO.21.01839]

Moreover, the delayed progression benefit with add-on SIRT was consistently seen for patients with KRAS-mutated tumours, left-side primary tumour, hepatic tumour burden of 10–25 percent, ≤3 lesions, who received additional biologic agent, and with resected primary disease.

Called transarterial yttrium-90 radioembolization (TARE), this SIRT approach makes use of microscopic glass beads that contain radioactive yttrium-90. These glass beads are specifically delivered to target tumours through a catheter.

Because radioactive beads can be placed where they are needed, “radiation delivery to the tumour is optimized and nontarget parenchymal exposure is minimized,” according to the investigators.

“This is the first arterial radiotherapy device to impart a delay in overall progression in a universally systemic disease using level I evidence. It also confirms the ability of interventional therapy trials to achieve uniform technical standardization across international sites, suggesting generalizability of the findings,” they said.

The investigators stressed that EPOCH may have broader clinical applicability, given that the patient population is “reflective of real-life settings.”

A total of 428 patients (median age 61 years, 36.2 percent female, 9.8 percent Asian) across North America, Europe, and Asia participated in EPOCH. They were randomized to receive second-line irinotecan- or oxaliplatin-based chemotherapy alone (n=213) or with TARE (n=215). Median time to TARE was 25 days from randomization.

The median follow-up times were 36.0 months in the TARE plus chemo arm and 42.3 months in the chemotherapy only arm. Objective response rates were higher in the TARE plus chemo arm (34.0 percent vs 21.1 percent; p=0.0019), whereas no between-group difference in median overall survival (OS) was seen (14.0 vs 14.4 months; p=0.7229; HR, 1.07, 95 percent CI, 0.86–1.32).

Grade 3 adverse events (AEs) occurred with greater frequency with TARE plus chemo than with chemotherapy only (68.4 percent vs 49.3 percent), although both arms received full chemotherapy dose intensity.

The difference in grade 3 AEs may be attributed to the increased frequency of visits and AE reporting related to TARE procedures, according to the investigators. TARE-specific higher-grade AEs included radiation pneumonitis, cholecystitis, and duodenal ulcer. None of the patients in the TARE plus chemo arm had arterial dissections.

EPOCH is not without limitations, the investigators admitted. “Weaknesses include the dampening of treatment effect by the 13 percent that did not receive planned TARE, as well as operational challenges of lengthy device trials (8 years) in a rapidly evolving treatment landscape.”

Minimal support

In an accompanying editorial, two experts from the University of Colorado Cancer Center in Aurora, Colorado, US, asserted that the data from EPOCH are not enough to support the addition of TARE to standard second-line systemic therapy in unresectable CLM, like the data from the FOXFIRE, SIRFLOX, and FOXFIRE-Global trials in the first-line setting. [J Clin Oncol 2021;doi:10.1200/JCO.21.01993; Lancet Oncol 2017;18:1159-1171; J Clin Oncol 2016;34:1723-1731; J Clin Oncol 2007;25:1099-1106]

“[S]mall improvements in PFS are unlikely to justify lack of improved OS, increased toxicity, and substantial cost,” wrote Drs Robert Lentz and Wells Messersmith.

In the treatment of patients with metastatic colorectal cancer, the goal is to improve quality of life and/or to extend survival, Lentz and Messersmith added. “In all [the mentioned] trials, TARE was unable to accomplish either one. The standard of care for unresectable CLM remains systemic therapy without the addition of liver-directed therapy.”