by ecancer reporter Janet Fricker

For patients with metastatic colorectal cancer (mCRC) that had spread only to the liver at study entry adding selective internal radiation therapy (SIRT) to a FOLFOX based first-line chemotherapy increased median progression free survival by 8.7 months compared to chemotherapy alone, finds the latest subgroup analysis from the SIRFLOX study.

The study, presented at the ESMO 17th World Congress on Gastrointestinal Cancer, 1-4 July, Barcelona, Spain, showed that SIRT was more effective for patients with liver only metastasis compared to those with more general metastasis.

The study represents the largest interventional randomised oncology study ever conducted, and the largest randomised study of a liver directed therapy.

SIRT, also known as radioembolisation, allows tumours to be selectively irradiated leaving healthy tissue relatively unaffected.

For the SIRT technique tens of millions of Yttrium-90 labelled coated resin microspheres (Sirtex) are injected into the hepatic arterial supply of the liver via a catheter inserted into the femoral artery through an incision in the groin.

The spheres, which are 32 microns in diameter, deliver high doses of ionizing pure beta radiation to tumours, while maintaining the radiation dose to the normal liver at tolerable levels.

Key to the success of the procedure is the initial work-up where interventional radiologists use trans-femoral catheters to access the hepatic arterial vasculature, map the unique vascular anatomy, and identify the vessels feeding tumours.

At this stage extra-hepatic vessels branching off the hepatic artery will be prophylactically occluded to prevent deposition of radioactive microspheres outside the liver.

While SIRT was granted CE Mark approval in the EU in 2002 for unresectable liver tumours and has been reviewed by NICE for the treatment of primary and secondary liver cancer, including those with colorectal cancer liver metastases and cholangiocarcinoma, there have never been large randomized controlled trials for the procedure in combination with modern first-line standard-of-care chemotherapy.
Such data is needed to convince medical oncologists of the clinical utility of the concept.

The SIRFLOX study set out to explore whether combining SIRT with first-line chemotherapy improved control of CRC liver metastases and improved overall survival.

For the study between October 2006 and April 2013, 530 patients with non-resectable, liver only or liver dominant (liver plus lung and/or lymph node metastases) metastatic CRC were randomised 1:1to either modified (m) FOLFOX6 / -bevacizumab (n=263) or mFOLFOX6 /-bevacizumab SIRT (n=267).

Data presented at ASCO 2015 in Chicago showed that the median overall progression free survival for all patients (those with all types of metastases) was10.7 months for the mFOLFOX6 SIRT group compared to 10.2 months for those treated with chemotherapy alone (HR 0.93, 95% CI: 0.77-1.12, p=0.43).

The failure to achieve an overall progression free survival advantage with SIRT it was felt, was due to inclusion of 40% of patients with extra-hepatic disease and 45% with primary tumours still in place.

For the current ESMO GI analysis, the investigators explored the 318 patients with metastases that had spread only to the liver at the time they entered the study separately from the 212 patients who had both liver and extra hepatic metastases at study entry.

The results showed that for those with metastases limited to the liver median PFS in the liver was 21.1 months for those treated with mFOLFOX6 SIRT compared to 12.4 months for those treated with chemotherapy alone (p=0.003; HR 0.64)

For those with liver and extra-hepatic metastases the median PFS in the liver was 16.7 months for those who received mFOLFOX6 SIRT versus 12.6 months for those who received chemotherapy alone (p=0.147, HR 0.77).

“The liver remains the organ to which colorectal cancer spreads first, and for those patients who are ineligible for potentially curative liver-resection, liver failure due to the growth of liver metastases will unfortunately be the ultimate cause of their death, which makes our findings especially relevant for mCRC patients diagnosed with liver metastases,” said Guy van Hazel, the co-principal investigator of the SIRFLOX study from the University of Western Australia, Perth.

Commenting on the study Chris Verslype, from University Hospital Leuven, Belgium, said, “We feel that we should restrict this kind of therapy –radioembolization – to those patients who have very limited extrahepatic disease, where we can probably make a difference in the long run for our patients.”

The results of the combined SIRFLOX, FOXFIRE and FOXFIRE global studies, with a total anticipated accrual of 1,103, expected in 2017, will demonstrate whether the addition of SIRT to chemotherapy influences overall survival for patients with mCRC.

Reference

Poster number 0-019. G van Hazel, V Heinemann, N Sharma et al.  SIRFLOX: Randomized trial comparing first-line mFOLFOX6 - bevacizumab versus mFOLFOX6 - bevacizumab selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC) – analysis by presence or absence of extra-heptatic metastases and bevacizumab treatment.