Liver-Directed Therapy With SIRT, Using Y-90 Resin Microspheres, Plus FOLFOX-Based First-Line Chemotherapy for mCRC

Results of the SIRFLOX study presented at 2015 ASCO Annual Meeting

The addition of selective internal radiation therapy (SIRT), using Y-90 resin microspheres, to FOLFOX-based first-line chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver-dominant metastases did not improve overall progression-free survival (PFS). However, such regimen achieved a 7,9 month improvement in median PFS in the liver, representing a 31% reduction in risk of disease progression in the liver with no negative impact on duration of systemic therapy. The toxicities were acceptable and as predicted. The results from the SIRFLOX study were presented at the 2015 ASCO Annual Meeting (29 May – 2 June, Chicago, USA) by Associate Professor Peter Gibbs, co-principal investigator of the study and Consultant Medical Oncologist at The Royal Melbourne Hospital, Australia.

The results of the 530-patient SIRFLOX randomised controlled study, open new possibilities for combining radiation targeted at liver metastases with first-line systemic treatment for mCRC.
"We found that while liver tumours began to grow again after a median of 12.6 months in patients with mCRC who received only first-line chemotherapy, those who also received first-line treatment with SIR-Spheres Y-90 resin microspheres had their liver tumours controlled for a median of 20.5 months. The additional 7.9 months of treatment benefit with the combined first-line SIRFLOX regimen was statistically significant, with a p-value of 0.002 and a hazard ratio of 0.69. This translates to a 31 percent reduction in the risk of tumour progression in the liver for patients treated with Y-90 resin microspheres," Prof. Gibbs said.

"This finding matters a great deal," he explained, "because the liver is almost invariably the organ where colorectal cancer spreads to first. While half the patients initially diagnosed with colorectal cancer survive thanks to surgical removal of the primary tumour before the disease has spread elsewhere in the body, liver metastases eventually cause the death of the majority of the remaining hundreds of thousands of patients each year whose tumours spread but are inoperable."

Prof. Gibbs also told the ASCO audience that liver treatment response rates were significantly higher in patients who received Y-90 resin microspheres in combination with first-line chemotherapy, which consisted of a FOLFOX-based regimen, with or without the addition of bevacizumab. "We observed a hepatic response rate of 78.7 percent in this group, compared to 68.8 percent in the chemotherapy-only group. This was statistically significant, with a p-value of 0.042. Moreover, the rate of complete responses in the liver of SIRFLOX patients who received SIR-Spheres Y-90 resin microspheres, though relatively small at 6.0 percent, was more than three times higher than the 1.9 percent complete response rate among the chemotherapy-only patients. The statistical significance of this finding is very strong, with a p-value of 0.02," Prof. Gibbs stated.

The SIRFLOX study implications

Prof. Ricky Sharma of the University of Oxford, UK who discussed the study results during the session said that interventional oncology has always been seen as a supportive treatment intended for symptom relief. However, it is a rapidly advancing new clinical specialism that encompasses radiology, oncology and minimally invasive surgery. The addition of SIRT, using Y-90 resin microspheres, to FOLFOX-based first-line chemotherapy can increase response rate in the liver and extend control of liver metastases in patients with mCRC by more than 7 months. Slightly higher toxicities were observed in term of neutropenia, thrombocytopenia and 1-4% incidence of ulceration in the upper gastrointestinal tract or liver complications.

Further data from the study are anticipated in next 3 years, in particular subgroup analyses (liver only/liver dominant disease burden, effect of bevacizumab, etc. that might help in how to select patients for SIRT), depth of response, quality of life, cost-effectiveness,  overall survival (OS).   

At a press conference following Prof. Gibbs's SIRFLOX presentation, Prof. Guy van Hazel, co-principal investigator of SIRFLOX and Clinical Professor of Medicine at the University of Western Australia, Perth, said that "SIRFLOX gives us the data to validate the first-line use of selective internal radiation therapy, or SIRT, with SIR-Spheres Y-90 resin microspheres in mCRC. Until now, we have not had a randomized clinical study large enough to provide Level One evidence supporting first-line use of this treatment."

"This step forward matters to medical oncologists and their patients, because until the development of Y-90 resin microspheres, there was essentially no place for radiation therapy in the treatment of liver tumours. There was never a question that radiation would work in the liver, but the problem of administering the radiation in a way that spared healthy liver tissue from its effects prevented it from being an 'equal partner' with surgery and chemotherapy in treating mCRC, as it is in almost all other forms of cancer," Prof. van Hazel added.

The principal European investigator of SIRFLOX, Prof. Volker Heinemann, Director of the Comprehensive Cancer Center at the University of Munich, Germany, told the press conference audience: "The effect of Y-90 resin microspheres on Progression-Free Survival in the liver, as reported in the SIRFLOX study, is quite pronounced". Prof. Heinemann continued: "Even in the absence of sufficient data to calculate an overall survival benefit or a significant finding for the primary endpoint of Progression-Free Survival at any site, the outcome of SIRFLOX suggests that oncologists who treat mCRC may now wish to consider earlier use of Y-90 resin microspheres than is presently the case, certainly among those patients whose metastatic disease has been diagnosed primarily in the liver."

"With SIRFLOX, the Level One evidence is there for every medical oncologist to see and to evaluate in their practice," he said.

The principal US investigator of SIRFLOX, Dr Navesh Sharma, Assistant Professor of Radiation Oncology and Diagnostic/Interventional Radiology at the University of Maryland Medical Center, which was the largest US clinical site for SIRFLOX, said: "With 530 patients, SIRFLOX is the largest randomized trial ever conducted that combined an interventional radiology procedure with chemotherapy in oncology."

"Physicians have been performing SIRT procedures with Y-90 resin microspheres, in the US and around the world, for more than 10 years. We have always felt that this procedure was a unique approach to deliver large doses of radiation to liver tumours, targeted in a way that spares healthy liver tissue. It is important to observe that in SIRFLOX, the clinical benefit that was observed came with an acceptable level of adverse events from adding Y-90 resin microspheres to first-line chemotherapy in mCRC. Oncologists, especially radiation oncologists, have traditionally been very cautious of irradiating large liver volumes because of the adverse effects associated with such treatments. SIRFLOX has shown us, in an unbiased manner that not only can we deliver high doses of radiation to the liver safely with this approach, but we can do so using concurrent chemotherapy. Concurrent chemo-radiation has been one of the most effective ways to treat cancer in general, especially those of gastrointestinal origin," Dr Sharma said.

SIRFLOX is the first of a group of three studies assessing the results of adding SIR-Spheres

SIRFLOX is the first study assessing the results of adding SIR-Spheres Y-90 resin microspheres to first-line chemotherapy in the treatment of mCRC. The other studies are FOXFIRE, a UK clinical trial that completed enrolment in November 2014, and FOXFIRE Global, an international study that completed enrolment in January 2015. The results of the three studies, which together enrolled more than 1,100 patients with mCRC, will be combined in a pre-planned assessment of the OS benefit of adding SIR-Spheres Y-90 resin microspheres to first-line chemotherapy for mCRC. The combined results are expected in 2017.

The co-principal investigators of FOXFIRE are Prof. Ricky Sharma, Clinical Senior Lecturer in Oncology at the University of Oxford, UK, and Dr Harpreet Wasan of Hammersmith Hospital and the Imperial College Trust, London, UK. Prof. Sharma was also the discussant of SIRFLOX at the ASCO 2015 Annual Meeting. Prof. Peter Gibbs is the principal investigator of FOXFIRE Global.

SIR-Spheres Y-90 resin microspheres

SIR-Spheres Y-90 resin microspheres are a medical device used in an interventional radiology procedure known as SIRT, or radioembolisation, which targets high doses of radiation directly to liver tumours. The treatment consists of tens of millions of radioactive Y-90 coated resin particles. Interventional radiologists inject these resin particles, or microspheres, into the hepatic artery via a catheter inserted into the femoral artery through an incision in the groin.

The Y-90 resin microspheres become lodged in the capillaries that surround liver tumours, where they deliver a high dose of short-range (mean 2.5 mm; maximum 11 mm) beta radiation to the liver tumours, while sparing health liver tissue. The low specific gravity of Y-90 resin microspheres allows the blood flow to evenly distribute the radioactivity within and around the liver tumours.

Key SIR-Spheres Y-90 resin microspheres regulatory authorisations include a full Pre-Market Approval from the US FDA, European Union (CE Mark) and Australian TGA Conformity Assessment certification.

SIR-Spheres Y-90 resin microspheres also have a Premarket Approval (PMA) by the FDA and are indicated in the United States for the treatment of non-resectable metastatic liver tumours from primary colorectal cancer in combination with intra-hepatic artery chemotherapy using floxuridine. SIR-Spheres Y-90 resin microspheres are approved for the treatment of inoperable liver tumours in Australia, the European Union (CE Mark), Argentina (ANMAT), Brazil, and several countries in Asia, such as India and Singapore.

SIR-Spheres® is a Registered Trademark of Sirtex SIR-Spheres Pty Ltd.

Reference

Gibbs P, Heinemann V, Sharma N, et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.