New data presented by Volker Heinemann in an oral abstract session at the European Society of Medical Oncology’s 18th World Congress on Gastrointestinal Cancer suggest that patients with liver-dominant mCRC treated first-line with the combination of mFOLFOX6 and SIR-Spheres Y-90 resin microspheres in the recently published SIRFLOX study experienced a much more profound response to treatment in the liver than those who received chemotherapy alone.
According to depth of response analysis—a relatively new methodology that has been shown to correlate with overall survival and post-progression survival in earlier mCRC studies—there was a significantly greater depth of response (75% versus 67.8% mean reduction in liver tumour burden; p=0.039) in patients who received SIR-Spheres Y-90 resin microspheres combined with chemotherapy. Patients also had a statistically significant, two-month longer time to depth of response or maximal tumour shrinkage (median 266 versus 206 days; p<0.001), compared to those who received chemotherapy alone.
The analysis also revealed that the treatment effect following SIR-Spheres Y-90 resin microspheres was most evident in the patients who entered the study with a greater baseline liver tumour burden (>12% of the liver having been replaced by tumour, a statistical cut-point that was pre-determined in order to identify potential predictors of depth of response). This group of more compromised patients, representing over half the patients in SIRFLOX, experienced a statistically significant, 20% greater depth of response (77.5% versus 57.2%; p=0.003) and over three-month longer time to depth of response (median 298 versus 196 days; p<0.001) compared to those treated with chemotherapy alone. SIR-Spheres Y-90 resin microspheres was also associated with a doubling of median progression-free survival (PFS) in the liver by competing risk analysis (27.2 versus 13.1 months; p=0.003) in these patients.
Conversely, patients who had a smaller liver tumour burden (≤12%) on study entry were more than six times more likely to experience a complete response or disappearance of all liver tumours following SIR-Spheres Y-90 resin microspheres compared to those who received only chemotherapy (11.3% versus 1.7%; p=0.003).
Heinemann, professor of Medical Oncology at the Comprehensive Cancer Centre, Ludwig-Maximillian University, Munich, Germany, and European principal investigator of the SIRFLOX study states that, “As treatment for metastatic colorectal cancer has improved over the past two decades, life expectancies have increased four-fold. But this increased survival benefit in turn has raised the barrier of proof of efficacy for new therapies or combinations of therapy that have emerged.”
“Oncologists have for some time observed that progression-free survival is not always a good predictor of overall survival for patients with metastatic colorectal cancer, as has been seen in some studies with biologic agents,” Heinemann explains. “For this reason, in recent years we have seen an important surge of activity to find better surrogate markers for overall survival in mCRC, particularly regarding the effect of treatment on patients’ depth of response. The greater depth of response and time to maximal response following SIR-Spheres Y-90 resin microspheres, together with the prolonged progression-free survival in the liver, are very encouraging and increase our anticipation for the survival data we hope to see in 2017.”
The depth of response concept and methodology were developed by Heinemann and his colleagues in Munich, in collaboration with other experts in treating colorectal cancer. In the SIRFLOX depth of response analysis, a novel volumetric model was used to estimate each patient’s spherical liver tumour volume, based on the length of up to five target liver tumours, which were selected during a central independent blinded imaging review of the patients’ baseline and subsequent radiographic images. Depth of response was then measured by tracking tumour shrinkage until it reached its lowest point, or nadir. In previous depth of response analyses of the FIRE-3 study with the biologic agent cetuximab, Heinemann observed a statistically significant correlation between depth of response and overall survival. This observation has also been supported by an evaluation of the TRIBE study.
“We were able to complete this depth of response analysis because the original SIRFLOX methodology included extensive radiographic data to determine response to treatment using traditional RECIST criteria. But that is the beauty of this methodology; when the right dataset is available we do not need any new information to estimate the volumes and shed potentially important new light on the original findings,” Heinemann added.
The predictive value of this approach will be further tested when overall survival data on the combined SIRFLOX, FOXFIRE and FOXFIRE global studies of the association of mFOLFOX6 and SIR-Spheres Y-90 resin microspheres in the first-line treatment of colorectal cancer liver metastases become available in 2017.