SIRT Added to Chemotherapy Extends Survival in Right-Sided Colorectal Cancers

Adding selective internal radiation therapy (SIRT) to chemotherapy improved overall survival (OS) by 5 months compared with chemotherapy alone for patients with liver-only or liver-dominant right-sided primary (RSP) metastatic colorectal cancer (mCRC), according to results from a post hoc analysis of 2 randomized, controlled trials (n = 1103).¹

According to results from Gibbs et al, the median OS was 22.0 months in the SIRT arm compared with 17.1 months for patients treated with a modified FOLFOX (mFOLFOX6; folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) regimen with or without bevacizumab (Avastin), representing a 36% reduction in the risk of death (HR, 0.641; 95% CI, 0.461-0.890; P= .008). In multivariable models, treatment with SIRT remained statistically significant in RSP tumors after adjusting for prognostic and stratification variables (HR, 0.621; 95% CI, 0.445-0.867; P= .005).

OS in left-sided primary (LSP) tumors was nearly the same regardless of SIRT, with a median OS of 24.6 (SIRT) versus 26.6 months (chemo), which was still superior to outcomes in RSP tumors treated with SIRT (HR, 1.120; 95% CI, 0.918-1.368;P= .264). Although SIRT did not extend OS in RSP tumors to the level found in LSP tumors, the coauthor of the analysis, Navesh K. Sharma, DO, PhD, told Targeted Therapies in Oncology that the improvement in survival is still impressive. “A 5-month survival benefit in those patients is huge,” said Sharma, an associate professor in the Department of Radiation Oncology at Penn State Cancer Institute. “It brings them close to the left-sided primary data that we have.”

Sharma emphasized that both studies compared SIRT with chemotherapy, as opposed to outcomes in RSPs versus LSPs. He said it was unclear why SIRT appeared to improve OS compared with chemotherapy alone. “That’s the million-dollar question,” he said. “Since right-sided primary tumors tend to do worse, it might be that the radiation is making up for the changes that allow right-sided primary tumors to be more aggressive.”

The median OS in the total population was 24.3 months for SIRT versus 24.6 months in the control arm (HR, 1.021; 95% CI, 0.863-1.207;P= .810).

Typically, right-sidedness is associated with poorer prognosis for patients whose colorectal cancer (CRC) has metastasized into the liver. Results from an analysis of more than 1.4 million patients treated in 66 clinical trials showed that, at a median follow-up of 65 months, LSP tumors were associated with an 18% reduced risk of death (HR, 0.82; 95% CI, 0.79-0.84;&nbsp;P<.001).²

There is a significant unmet need for additional first-line therapeutic strategies for patients with RSP, because this population derives little to no benefit from EGFR inhibitors. As noted by Holch et al, RSP CRC can be treated with chemotherapy plus bevacizumab, but the optimal treatment has not been established.³

Adding SIRT to mFOLFOX6 chemotherapy showed promising results in early studies, leading to randomized trials exploring oxaliplatin-based chemotherapy alone or combined with SIRT. In the SIRFLOX, (n = 530), FOXFIRE (n = 364), and FOXFIRE-Global (n = 209) trials, patients with mCRC and liver metastases were randomly assigned 1:1 to mFOLFOX6 or mFOLFOX6 plus SIRT in the frontline. SIRT was administered using liver-directed SIR-Spheres yttrium-90 resin microspheres.

In a preplanned meta-analysis of all 3 studies published in 2017, investigators reviewed data on 549 patients randomly assigned to chemotherapy alone and 554 assigned to chemotherapy plus SIRT. At a median follow-up of 43.3 months (range, 31.6-58.4), investigators found no difference in OS between the treatment groups (HR, 1.04; 95% CI, 0.90-1.19;P= .61). The median OS in the experimental arm was 22.6 months (95% CI, 21.0-24.5) versus 23.3 months (95% CI, 21.8-24.7) in the control group. Moreover, patients assigned to SIRT had a higher rate of serious adverse events (AEs; 54% vs 43%).⁴

The median progression-free survival (PFS) for the SIRT group in the analysis from Gibbs et al of 2 of the trials was 11.1 months compared with 10.6 months for the chemotherapy-alone group (HR, 0.902; 95% CI, 0.773-1.053;P= .193).¹The median PFS favored the SIRT group in patients withRSP, 10.8 versus 8.7 months (HR,0.734;95% CI, 0.534-1.010;&nbsp;P= .057).

Further, the median PFS in the liver favored SIRT in both patients with RSP tumors (13.2 vs 9.6 months; HR, 0.580; 95% CI, 0.417-0.808;P= .001) and those with LSP tumors (15.3 vs 12.5 months; HR, 0.792; 95% CI, 0.656-0.956;&nbsp;P= .015). In multivariate analysis, SIRT treatment (HR, 0.708; 95% CI, 0.511-0.981;&nbsp;P= .038), bevacizumab use, extrahepatic metastases, and synchronous disease were all associated with improved PFS in patients with RSP tumors.

Sharma added that SIRT plays a role in patients with LSP tumors who have progressed. This analysis shows that SIRT does not provide a benefit for

these patients in the first line, he said: &ldquo;There was a huge benefit in liver control across the board. In patients who had liver-only metastases, they had almost an 8-month local control benefit in the liver. In patients who do well with chemotherapy but have progression in the liver, SIRT should still be used. That&rsquo;s how it&rsquo;s used today.&rdquo;

In the SIRT arm, 73 patients (74.5%) with RSP tumors had an objective response compared with 51 (63%) in the control arm (P= .323). Among patients with LSP tumors, 73.9% assigned to SIRT had an objective response compared with 69.2% of patients assigned to chemotherapy (P= .263).

Of 179 patients with RSP tumors, 21 (11.7%) had at least 1 partial hepatic resection, of whom 12.2% (12 of 98) had been assigned to SIRT and 11.1% (9 of 81) were assigned to chemotherapy. Resection was associated with improved OS in patients with RSP tumors according to an analysis of multivariate Cox proportional hazards (HR, 0.659; 95% CI, 0.353-0.189;P= .001).

A total of 176 patients with RSP tumors and 526 with LSP tumors were evaluable for safety. Investigators found no significant difference in the incidence of grade &ge;3 AEs between the 2 arms.

Sharma said that, based on these results, investigators cannot conclude that SIRT should be included in first-line therapy. &ldquo;All we can say is that there is a benefit,&rdquo; he said. &ldquo;[Although] every patient benefited locally in the liver, in RSP [tumors], we should think about [SIRT] sooner in the treatment paradigm instead of as just salvage.&rdquo;

References:

1. Gibbs P, Heinemann V, Sharma NK, et al; SIRFLOX and FOXFIRE Global Trial Investigators. Effect of primary tumor side on survival outcomes in untreated patients with metastatic colorectal cancer when selective internal radiation therapy is added to chemotherapy: combined analysis of two randomized con- trolled studies.Clin Colorectal Cancer. 2018. doi: 10.1016/j.clcc.2018.06.001.
2. Petrelli F, Tomasello G, Borgonovo K, et al. Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-anal- ysis.JAMA Oncol.2017;3(2):211-219. doi: 10.1001/jamaoncol.2016.4227.
3. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials.Eur J Cancer.2017;70:87-98. doi: 10.1016/j.ejca.2016.10.007.
4. Wasan HS, Gibbs P, Sharma NK, et al; FOXFIRE trial investigators; SIRFLOX trial investigators; FOXFIRE-Global trial investigators. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Glob- al): a combined analysis of three multicentre, randomised, phase 3 trials.Lancet Oncol.2017;18(9):1159-1171. doi: 10.1016/S1470-2045(17)30457-6.