Combined fractionated external radiotherapy and internal irradiation using 90Y-labelled-Cetuximab: optimization of treatment scheduling and proof of curative potential

Solid tumors can be precisely targeted with external beam radiotherapy (EBRT) but dose is limited by the surrounding tissue. The combination with radioimmunotherapy (= combination of internal and external radiotherapy - CIERT) mediates additional internal irradiation with the potential to strike also distant metastases but affecting different organs at risk. Furthermore, patient stratification is possible using corresponding PET-tracers [1].
We showed the effectiveness of CIERT using 90Y-labelled Cetuximab ([90Y]Y-Cet) and single dose EBRT in a head and neck squamous cell carcinoma xenograft model (FaDu, [2]). The presented project aimed to investigate CIERT using clinical relevant fractionated EBRT with 30 fractions (fx) over 6 weeks. However, the timing of [90Y]Y-Cet is crucial in such settings and was first optimized by modeling [90Y]Y-Cet uptake with near-infrared-labeled Cetuximab (NIR-Cet). The tracer was injected in FaDu-bearing mice at different time points during fxEBRT with differing doses. NIR-Cet uptake was longitudinally followed by in vivo optical imaging to find the optimal schedule for tumor control probability experiments to test the curative potential of CIERT.
NIR-Cet uptake was enhanced after applying low to moderate doses of fxEBRT. Thus, [90Y]Y-Cet was injected after 10 fx of EBRT in CIERT efficacy experiments. CIERT massively increased local control probability compared to EBRT alone or in combination with unlabeled Cetuximab. In the group with the lowest external dose (1 Gy/fx, total dose = 30 Gy) plus [90Y]Y-Cet all tumors were still permanently controlled (observation period = 120 d). In contrast, the total EBRT dose to cure 50% of the tumors without additional [90Y]Y-Cet injection was 63.9 Gy [58.7, 73.9].
Our results indicate a remarkably potential to improve treatment outcome if radiolabeled therapeutics are combined with fractionated external radiotherapy in a clinical relevant setting. Tumor uptake may be improved by application of some EBRT dose prior to injection. This scheduling would also enable patient stratification via a corresponding PET-tracer during ongoing therapy.

[1] A. Dietrich, L. Koi, K. Zöphel, W. Sihver, J. Kotzerke, M. Baumann, M. Krause, Br. J. Radiol. 2015, 88, 20150042
[2] L. Koi, R. Bergmann, K. Brüchner, J. Pietzsch, H.-J. Pietzsch, M. Krause, J. Steinbach, D. Zips, M. Baumann, Radiother. Oncol. 2014, 110, 362-369