Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate

Abstract

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Figures

Fig. 1. 13C coil setup and the schematic steps for the delivery of hyperpolarized [1-13C]pyruvate

(A to C) 13C transmit coil (A) and endorectal 1H/13C receiver coil (B) used for acquiring data. The location of the coils is outlined on (A) and (B), with the layers inside the endorectal coil being seen in (C). The dimensions of the elements in the endorectal coil were 4 inches × 1 inches, with the total length of the coil being 12 inches. (D) Steps involved in transferring the hyperpolarized agent from the polarizer to the patient, and mean times required for each of them.

Fig. 2. 1D 13C dynamic MRSI data

Images are from a representative patient with a current PSA of 12.2 ng/ml, a small volume of biopsy-proven Gleason grade 4 + 3 prostate cancer in the left midgland, and who received the lowest dose (0.14 ml/kg) of hyperpolarized [1-13C]pyruvate. (A) Axial T2-weighted image showing slices (dashed lines) obtained from 1D spectral localization. The slice that overlaps the left prostatic peripheral zone (right side of image) contained a small focus of reduced T2 signal intensity corresponding to the region of biopsy-proven cancer (red arrows). The slice overlapping the right peripheral zone (left side of image) contains only normal prostate tissue. (B) Flux of [1-13C]pyruvate to [1-13C]lactate catalyzed by LDH (top). Dynamic 13C spectra were obtained from the same patient in (A) at 36 s after injection of hyperpolarized [1-13C]pyruvate (bottom). The cancer spectrum demonstrated a lactate SNR of 25 owing to a high flux of hyperpolarized [1-13C]pyruvate to [1-13C]lactate. (C) Plot of 1D localized dynamic hyperpolarized pyruvate and lactate data from the slice that overlapped the region of prostate cancer. (D) Plot of 1D localized dynamic hyperpolarized pyruvate and lactate data from the slice that overlapped a contralateral region of the prostate.

Fig. 3. 2D 13C dynamic MRSI data

Images are from a representative patient with a current PSA of 3.6 ng/ml, who had biopsy-proven prostate cancer in the left apex (Gleason grade 3 + 4) and received the highest dose of hyperpolarized [1-13C]pyruvate (0.43 ml/kg). (A) A focus of mild hypointensity can be seen on the T2-weighted image, which was consistent with the biopsy findings. (B to D) 2D localized dynamic hyperpolarized [1-13C]pyruvate and [1-13C]lactate from spectral data that were acquired every 5 s from voxels overlapping the contralateral region of prostate (turquoise), a region of prostate cancer (yellow), and a vessel outside the prostate (green). The dynamic data were fit as described previously (22).

Fig. 4. 2D single–time point MRSI data

Images were obtained from a patient with serum PSA of 9.5 ng/ml, who was diagnosed with bilateral biopsy-proven Gleason grade 3 + 3 prostate cancer and received the highest dose of hyperpolarized [1-13C]pyruvate (0.43 ml/kg). The axial T2-weighted image shows a unilateral region of reduced signal intensity (red arrows), which is consistent with a reduction in the corresponding ADC. The 1H spectral arrays supported these findings, with voxels with reduced citrate and elevated choline/citrate (highlighted in pink) on the right side of the gland and voxels with normal metabolite ratios on the left side. The 13C spectral arrays show voxels with elevated levels of hyperpolarized [1-13C]lactate/[1-13C]pyruvate (highlighted in pink) on both the right and left sides of the prostate. The location of colored regions in the metabolite image overlay had a ratio of [1-13C]lactate/[1-13C]pyruvate greater than or equal to 0.6.

Fig. 5. 3D single–time point localized MRSI data

Images were obtained from patient A in Table 2, who had a serum PSA of 4.5 ng/ml, was originally diagnosed with bilateral biopsy-proven Gleason grade 3 + 3 prostate cancer, and received the highest dose of hyperpolarized [1-13C]pyruvate (0.43 ml/kg). The upper panel shows an axial T2-weighted images and corresponding spectral array with the area of putative tumor highlighted by pink shading. A region of tumor was observed on the T2-weighted images (red arrows), as well as on ADC images and 1H MRSI data (fig. S1). A region of relatively high hyperpolarized [1-13C]lactate was observed in the same location as the abnormalities that had been observed on the multiparametric 1H staging exam. The lower panels show axial T2 images with and without metabolite overlays for different axial slices from the same patient. The colored regions in these overlays have a ratio of [1-13C]lactate/[1-13C]pyruvate ≥0.2. These demonstrated a large volume of bilateral cancer.

Fig. 6. Further representative examples of 3D single–time point MRSI data

The axial T2-weighted images and overlays of hyperpolarized [1-13C]lactate/[1-13C]pyruvate are from the three patients labeled as B to D in Table 2. All three of the patients had biopsy-proven Gleason grade 3 + 3 prostate cancer and received the highest dose of hyperpolarized [1-13C]pyruvate (0.43 ml/kg). Patient B had a current PSA of 5.1 ng/ml, patient C had a PSA of 9.8 ng/ml, and patient D had a PSA of 1.9 ng/ml. The SNR and metabolite ratios in the regions highlighted in color on the image overlays are given in Table 2.