SIRT Offers No Benefit When Added to Chemotherapy for mCRC With Liver Metastases

SIRT Offers No Benefit When Added to Chemotherapy for mCRC With Liver Metastases

Dr. Ricky A. Sharma presents Abstract 3507.
A meta-analysis of three randomized clinical trials fails to support use of selective internal radiotherapy (SIRT) in combination with first-line oxaliplatin and fluorouracil chemotherapy in patients with liver-only and liver-dominant metastatic colorectal cancer. Despite increasing the likelihood of radiologic response and prolonging liver-specific progression-free survival (PFS), SIRT added to first-line chemotherapy yielded no improvement in overall survival (OS) or PFS (Abstract 3507).

These findings come from a pooled analysis of prospective data from 1,103 patients included in the FOXFIRE, SIRFLOX, and FOXFIRE Global trials, which were designed to allow a combined evaluation of OS. Ricky A. Sharma, MA, MB BChir, PhD, FRCP, FRCR, of the Oxford Institute for Radiation Oncology, University of Oxford, in the United Kingdom, presented the findings on behalf of his co-investigators on June 5.

From October 2006 to December 2014, treatment-naive patients in 14 countries underwent random assignment to FOLFOX (fluorouracin, leucovorin, and oxaliplatin) in combination with one round of SIRT using yttrium-90 resin microspheres or to FOLFOX alone. SIRT was delivered during either the first or second chemotherapy cycle. All patients also could have received a biologic (bevacizumab or cetuximab) in combination with FOLFOX, which was started upfront in the FOLFOX control arm and after four or more cycles in the FOLFOX/SIRT arm to avoid adverse interactions with the radiation.

Patients in the three trials were required to have adenocarcinoma of the colon or rectum and liver metastases not amenable to curative resection or ablation. Primary tumor in situ and/or limited extrahepatic metastases was permitted.

Among the 1,103 patients, a total of 844 deaths occurred over a median follow-up of 43.3 months. Comparison of the two arms revealed no difference in OS (hazard ratio [HR] 1.04, 95% CI [0.90, 1.19]; p = 0.609) or PFS (HR 0.90, 95% CI [0.79, 1.02]; p = 0.108). The SIRT arm did excel over the comparator arm with respect to liver-specific PFS (HR 0.51, 95% CI [0.43, 0.62]; p < 0.001) and the rates of best radiologic response (HR 1.52, 95% CI [1.18,1.96]; p < 0.001). However, these advantages were counterbalanced by a higher likelihood of extrahepatic progression or death in the SIRT arm (HR 1.76, 95% CI [1.47, 2.11]; p < 0.001).

The outcomes might have been dampened in the FOLFOX-SIRT arm compared with the FOLFOX arm, Dr. Sharma noted, because of the lower likelihood of receiving bevacizumab during the study (36% vs. 47%), and of receiving subsequent systemic therapy after the study (approximately 68% vs. 74%).

An unexpected and intriguing finding that emerged from the subgroup analysis was a marked improvement in OS with the addition of SIRT to FOLFOX in patients with right-sided tumors (HR 0.67, 95% CI [0.48, 092]). These data are being explored and validated, according to Dr. Sharma, but should not alter clinical practice at present.

Adverse events of grade 3 or higher occurred significantly more often in the SIRT arm than in the comparator arm (74.0% vs 66.5%; p = 0.009) and were predominantly composed of increases in hematologic adverse events.

Discussant Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center, congratulated the investigators on their tremendous effort, which represents the largest trial of radiation therapy in metastatic colon cancer and took more than a decade to complete.

In light of the data, however, Dr. Cercek concluded that SIRT does not have a role in first-line therapy for metastatic colorectal cancer.

“We often see that our patients with metastatic colon cancer succumb to liver disease. We believe that it’s important to treat the liver, and if we were just able to control the liver, perhaps that would translate into survival,” Dr. Cercek said. “In this study of more than 1,000 patients, this was not the case.”  

–Kara Nyberg, PhD