Benefits of selective internal radiation therapy combined with chemotherapy as a first-line treatment for colorectal liver metastases: beyond the abstract

The SIRFLOX phase III randomised trial was a landmark study for liver-directed therapies for metastatic colorectal cancer (mCRC) (1). A major gain in liver progression free survival (PFS) with the addition of selective internal radiation therapy (SIRT) delivered with yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, Sydney, Australia) to first-line chemotherapy (20.5 vs 12.6 months in SIRT vs control , p=0.002), was impressive; but
how do we interpret this in the context of mCRC survival?

The possible benefits of liver-directed therapies in mCRC are considerable. About 25–30% of patients with CRC will develop liver metastases during the course of their disease (2), and in these patients, liver metastases are the main cause of death (3). Only a few patients are able to undergo surgical resection of liver metastases, and therapies such as SIRT that aim at controlling liver metastases may be therefore crucial for improving the survival of mCRC patients.

In SIRFLOX, despite the improvement in liver PFS with SIRT, there was no improvement of PFS at any site, which raises the question of the clinical significance of the 8 months’ improvement in liver PFS (1). Two observations may shed some light on this question. Firstly, about 40% of patients randomised in SIRFLOX presented with extra-hepatic metastases at the beginning of the study and many patients had an intact primary cancer. Consequently, the improved control of liver metastases with the combined treatment may not provide the same long-term benefits in these patients as it would in patients with hepatic metastases only. Secondly, the SIRFLOX results do not preclude a positive impact of SIRT on overall survival (OS), as delaying a death from liver metastases should translate into a delay in death for some patients. OS results anticipated in 2017 will be part of an individual patient data meta-analysis combining the SIRFLOX data with data from two other first line trials of similar design, FOXFIRE and FOXFIRE-Global. At this stage, we can only speculate on the possible impact of SIRT plus first-line chemotherapy on OS, but previous studies have shown that locoregional treatment of liver metastases can result in improved OS (4). Another interesting observation from SIRFLOX was that the addition of SIRT produced a significantly greater depth of response in the liver than chemotherapy alone (mean reduction in liver tumor burden, 75.0% vs. 67.8%, respectively; p=0.039) (5). Depth of response has been proposed as a better surrogate marker than PFS for gains in OS (6, 7).

While some of these questions will be answered by the combined analysis mentioned above, today we can look at the data from SIRFLOX and conclude that combining SIRT with chemotherapy is feasible as a first-line regimen. The large population (530 patients) included in this interventional radiology trial, which is a remarkable achievement, permitted a thorough assessment of the safety profile of SIRT in combination with chemotherapy and demonstrated that this combined therapeutic modality had an acceptable tolerability profile (1). It would seem reasonable to assume that the delay in disease progression in the liver achieved in SIRFLOX would result in an OS benefit to some of the patients destined to die of their liver disease. Future studies explore the question of which mCRC patients are most likely to benefit from first-line SIRT, the optimal chemotherapy regimen to combine with SIRT, and the optimal timing of SIRT administration. 

Written by: Guy A van Hazel1 and Peter Gibbs2

1University of Western Australia, Perth, Australia

2Western Hospital, Footscray, Victoria, Australia

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Acknowledgments

Guy A van Hazel has received honoraria from Sirtex, has acted in a consulting or advisory Role for Sirtex, Roche and Merck, has received research funding from Sirtex, Boehringer Ingelheim and Merck, and has been paid expenses by Sirtex and Boehringer Ingelheim. Peter Gibbs has received honoraria from Roche, Amgen, Merck, Sirtex and Alchemia, and research funding from Roche. We acknowledge the editorial assistance provided by Martin Gilmour of ESP Bioscience Ltd (Crowthorne, UK) funded by Sirtex, during the preparation of this article.

References

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