Internal radiation therapy: Better response in metastatic colorectal cancer patients

Patients with metastatic colorectal cancer with greater baseline liver tumor burden (≥12%), who were treated with the combination of mFOLFOX6 and selective internal radiation therapy SIR-Spheres Y-90 resin treatment, experience a statistically significant greater depth of response than patients receiving chemotherapy alone.

The analysis, presented as an oral abstract at the European Society of Medical Oncology's 18th World Congress on Gastrointestinal Cancer, June 29-July 2, in Barcelona, Spain, showed that the depth of response analysis (DpR) rate was not statistically different for patients with smaller liver tumor burden (≤12%) at study entry.
"This analysis is the first in the history of metastatic colorectal cancer where the initial tumor burden has been factored in. It shows that initial tumor burden does play a role," said study presenter Volker Heinemann, from the Ludwig-Maximillian University in Munich, Germany.
Selective internal radiation therapy (SIRT), also known as radioembolisation, allows tumors to be selectively irradiated, leaving healthy tissue relatively unaffected.

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

The spheres, which are 32 microns in diameter, deliver high doses of ionizing pure beta radiation to tumors. Key to maintaining radiation doses to the normal liver at tolerable levels is a procedure where interventional radiologists prophylactically occlude extra hepatic vessels branching off the hepatic artery to prevent deposition of radioactive microspheres outside the liver.

Patients with metastatic colorectal cancer randomly assigned to groups
Although granted CE Mark approval for unresectable liver tumors in the European Union (EU) in 2002, until this year there had not been large randomized controlled trials for SIRT in combination with modern first-line standard of care.

In the phase III SIRFLOX study, published in the Journal of Clinical Oncology this February, between October 2006-April 2013, 530 patients with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to FOLFOX (±bev) plus SIRT (n=267) or FOLFOX (±bev ) alone (n=263).

Results showed median PFS at any site was 10.2 months in the FOLFOX (±bev) plus SIRT arm versus 10.7 months in the FOLFOX (±bev) only arm (HR 0.93, 95% CI, 0.77 to 1.12; P=0.43); and that median PFS in the liver by competing risk analysis was 12.6% in the FOLFOX plus SIRT arm versus 20.5% in the FOLFOX arm (HR 0.69, 95% CI, 0.55 to 0.90; P=.002).

Although SIRT did not influence PFS at any site, the results showed it induced a 7.9-month prolongation of PFS in the liver.

'Likelihood of clinical benefit in the liver with SIRT is greater'
In the current analysis, Heinemann and colleagues developed the DpR concept where a novel volumetric model was used to estimate each patient's spherical liver tumor volume, based on the length of up to five target tumors.

DpR was then measured by tracking tumor shrinkage until it reached its lowest point, or nadir. In previous DpR analyses of the FIRE-3 study with the biological agent cetuximab, Heinemann observed a statistically significant correlation between DpR and overall survival.

In the current analysis, the team identified patients from the SIRTEX study who had baseline tumor loads ≥12% (n=245 patients) and those who had tumor loads ≤ 12% (n=239 patients).

Results showed for those patients with ≥12% tumor burden the depth of response was 77.5% for those receiving FOLFOX (±bev) + SIRT compared with 57.2% for those receiving FOLFOX (±bev) (P=0.003).

Furthermore, results showed that the time to nadir was 196 days for those receiving FOLFOX (±bev) versus 298 for FOLFOX(±bev) +SIRT (p≤0.001). In contrast, for patients with ≤12% tumor burden, the depth of response was 72.5% for those receiving FOLFOX (±bev) +SIRT versus 80.6% for those receiving FOLFOX (±bev) (p=0.763).

And the time to nadir was 196 for those receiving FOLFOX (+bev) versus 298 for those receiving FOLFOX (±bev) + SIRT (p<0.001).

Differences in PFS between the two treatment groups were also more marked for those with higher tumor burden. For those with ≥12% tumor burden, PFS was 27.2 months for FOLFOX(±bev) + SIRT versus 13.1 months for FOLFOX(±bev) (HR 0.69, 95% CI 0.439-0.844, p=0.003). For those with ≤12% tumor burden, PFs was 15.1 months for FOLFOX(±bev) + SIRT versus 12.2 months for FOLFOX(±bev) (HR 0.778 95% CI 0.571-1.060, p=0.112).

"The greater depth of response and time to maximal response following SIR-Spheres Y-90 resin microspheres, together with the prolonged PFS in the liver, are very encouraging and increase our anticipation for the survival data we hope to see in 2017.

At the moment it appears that in patients with higher tumor burdens the likelihood that we reach a clinical benefit in the liver with SIRT is greater."

Study presenter Volker Heinemann, Ludwig-Maximillian University, Munich, Germany

Since the tumor vasculature may be more evolved in larger metastases, he speculated it may be more able to trap the SIRT microspheres.