Preclinical Evaluation of 89Zr-Panitumumab for Biology-Guided Radiation Therapy

Abstract

Purpose: Biology-guided radiation therapy (BgRT) uses real-time line-of-response data from on-board positron emission tomography (PET) detectors to guide beamlet delivery during therapeutic radiation. The current workflow requires ¹⁸F-fluorodeoxyglucose (FDG) administration daily before each treatment fraction. However, there are advantages to reducing the number of tracer injections by using a PET tracer with a longer decay time. In this context, we investigated ⁸⁹Zr-panitumumab (⁸⁹Zr-Pan), an antibody PET tracer with a half-life of 78 hours that can be imaged for up to 9 days using PET.

Methods and materials: The BgRT workflow was evaluated preclinically in mouse colorectal cancer xenografts (HCT116) using small-animal positron emission tomography/computed tomography (PET/CT) for imaging and image-guided kilovoltage conformal irradiation for therapy. Mice (n = 5 per group) received 7 MBq of ⁸⁹Zr-Pan as a single dose 2 weeks after tumor induction, with or without fractionated radiation therapy (RT; 6 × 6.6 Gy) to the tumor region. The mice were imaged longitudinally to assess the kinetics of the tracer over 9 days. PET images were then analyzed to determine the stability of the PET signal in irradiated tumors over time.

Results: Mice in the treatment group experienced complete tumor regression, whereas those in the control group were killed because of tumor burden. PET imaging of ⁸⁹Zr-Pan showed well-delineated tumors with minimal background in both groups. On day 9 postinjection, tumor uptake of ⁸⁹Zr-Pan was 7.2 ± 1.7 in the control group versus 5.2 ± 0.5 in the treatment group (mean percentage of injected dose per gram of tissue [%ID/g] ± SD; P = .07), both significantly higher than FDG uptake (1.1 ± 0.5 %ID/g) 1 hour postinjection. To assess BgRT feasibility, the clinical eligibility criteria was computed using human-equivalent uptake values that were extrapolated from preclinical PET data. Based on this semiquantitative analysis, BgRT may be feasible for 5 consecutive days after a single 740-MBq injection of ⁸⁹Zr-Pan.

Conclusions: This study indicates the potential of long-lived antibody-based PET tracers for guiding clinical BgRT.

Figure 1.

Overall scheme of the study.

Figure 2.

Tumor growth kinetics. The investigated dose of 6×6.6 Gy enabled effective tumor control in the treated animals with no local recurrence, thus was clinically relevant to assess stability of PET signal under irradiation.

Figure 3.

PET imaging of ⁸⁹Zr-Pan. (A) Representative PET/CT images acquired on Day 3, 6 and 9 post-injection, showing untreated mice (control; n=5) and mice receiving 6×6.6 Gy radiation (RT; n=5). Representative FDG uptake is shown in the same tumor model (n=4), demonstrating lower contrast than ⁸⁹Zr-Pan. (B) Quantification of tumor uptake, expressed in terms of the percentage (%) of injected tracer dose per g of tissue, as a function of time. Although there is a consistent trend towards lower uptake in irradiated tumors, the difference between treated and untreated tumors meets the significance threshold only on Day 6 (* P = 0.01). (C) Quantification of tumor uptake, expressed as the ratio of tumor to muscle. Significance is only achieved on Day 2 (* P = 0.03). The differential uptake of ⁸⁹Zr-Pan in tumor vs muscle increases over time due to the specificity of antibody binding.

Figure 4.

Feasibility of BgRT based on clinical eligibility criteria. Mouse uptake data was rescaled according to body weight and injected dose to derive human-equivalent values. (A) The current X1 system requires the PET image to meet quantitative endpoints for BgRT to proceed. The activity concentration (AC) is the average tumor uptake within the 80% isocontour line, after background subtraction. The metric is shown for individual mice over time, with the 5 kB/cc threshold shows as a dashed line. (B) The normalized tumor signal (NTS) is the ratio of AC to the standard deviation within the background. The threshold for this metric is 2.7. (C) The passing rate represents the fraction of mice that met both AC and NTS criteria, and would theoretically be eligible for BgRT.