Visual Abstract
Abstract
Novel radiopharmaceuticals for PET are being evaluated for the diagnosis of biochemical recurrence (BCR) of prostate cancer (PC). We compared the gastrin-releasing peptide receptor–targeting 68Ga-RM2 with the prostate-specific membrane antigen (PSMA)–targeting 68Ga-PSMA11 and 18F-DCFPyL. Methods: Fifty patients underwent both 68Ga-RM2 PET/MRI and 68Ga-PSMA11 (n = 23) or 18F-DCFPyL (n = 27) PET/CT at an interval ranging from 1 to 60 d (mean ± SD, 15.8 ± 17.7 d). SUVmax was collected for all lesions. Results: 68Ga-RM2 PET was positive in 35 and negative in 15 of the 50 patients. 68Ga-PSMA11/18F-DCFPyL PET was positive in 37 and negative in 13 of the 50 patients. Both scans detected 70 lesions in 32 patients. Forty-three lesions in 18 patients were identified on only 1 scan: 68Ga-RM2 detected 7 more lesions in 4 patients, whereas 68Ga-PSMA11/18F-DCFPyL detected 36 more lesions in 13 patients. Conclusion: 68Ga-RM2 remains a valuable radiopharmaceutical even when compared with the more widely used 68Ga-PSMA11/18F-DCFPyL in the evaluation of BCR of PC. Larger studies are needed to verify that identifying patients for whom these 2 classes of radiopharmaceuticals are complementary may ultimately allow for personalized medicine.
Prostate cancer (PC) is the most common noncutaneous cancer diagnosed in the United States, accounting for an estimated 191,930 new cases and 33,330 deaths (second only to lung cancer) in 2020 (1). Biochemical recurrence (BCR) within 10 y after primary treatment occurs in 20%–40% of cases after radical prostatectomy and 30%–50% of cases after radiation therapy (2,3). Despite a lack of consensus, the prostate-specific antigen (PSA) remains the biomarker of disease after primary treatment. BCR is characterized by heterogeneity; therefore, a single biologic target is unlikely to allow for complete understanding and accurate treatment.
Prostate-specific membrane antigen (PSMA) is currently the most evaluated PET molecular target for PC (4), showing better sensitivity and specificity than standard imaging for the detection of metastatic disease even at low PSA values (5). Commonly used radiopharmaceuticals targeting PSMA include 68Ga-PSMA-HBED-CC (68Ga-PSMA11) (6) and 18F-DCFPyL (7). Another class of radiopharmaceuticals used for the assessment of PC patients is the gastrin-releasing peptide analogs. Among them, 68Ga-BAY86-7548 (68Ga-RM2) has been reported in clinical studies (8,9). Our group showed that the PC detection rate was higher for 68Ga-RM2 PET than for MRI in a cohort of 32 patients (9).
Here, we compared 68Ga-RM2 with 68Ga-PSMA11 and 18F-DCFPyL. In the age of personalized medicine and theranostics, it is important to identify which patients will benefit from one class of radiopharmaceutical or the other. To our knowledge, this cohort has not been previously reported.
MATERIALS AND METHODS
Patient Population
Participants with suspected BCR of PC after primary treatment were prospectively enrolled in 3 clinical trials evaluating the performance of 68Ga-RM2 (NCT 02624518), 68Ga-PSMA11 (NCT02673151), and 18F-DCFPyL (NCT03501940). Twenty-three patients underwent both 68Ga-RM2 PET/MRI and 68Ga-PSMA11 PET/CT, whereas another 27 patients underwent both 68Ga-RM2 PET/MRI and 18F-DCFPyL PET/CT. BCR was diagnosed after prostatectomy with or without adjuvant radiotherapy at a PSA level of 0.2 ng/mL or greater, with a second confirmatory PSA level of at least 0.2 ng/mL (10). For patients after radiation therapy, BCR was diagnosed as a rise in PSA measurement of 2 ng/mL or more over the nadir (11). All participants gave written informed consent, and the protocols were approved by the local institutional review board. Data collected in these 3 trials were retrospectively analyzed for this comparison.
Clinical parameters, including stage of disease, Gleason score, PSA nadir, PSA within 30 d of the scan, PSA velocity, and primary and subsequent treatments, were obtained from the electronic medical records.
Scanning Protocols
All 68Ga-PSMA11 and 18F-DCFPyL scans were acquired using a silicon photomultiplier–based PET/CT system (Discovery Molecular Insights; GE Healthcare). The scans were performed according to PSMA PET guidelines (12) and as previously described (7).
All 68Ga-RM2 scans were acquired using a time-of-flight–enabled simultaneous PET/MRI scanner (Signa; GE Healthcare), as previously described (9).
The choice of PET/CT or PET/MRI was dictated by the funding available to support the clinical trials. The PET/CT and PET/MRI use the same silicon photomultiplier–based detectors, and we previously reported their clinical evaluation (13,14).
Image Analysis
Two nuclear medicine physicians reviewed and analyzed all images using MIMvista, version 6.9.2 (MIM Software Inc.). One of these physicians subsequently recorded semiquantitative measurements (SUVmax). All areas of increased radiotracer uptake in sites not expected to show a physiologic accumulation were reported as abnormal. Increased uptake was defined as focal tracer uptake higher than the adjacent background level. 68Ga-RM2 uptake was considered physiologic in the following tissues: gastrointestinal tract, liver, spleen, pancreas, kidneys, ureters, and bladder (15). This approach is similar to guidelines for standard image interpretation for 68Ga-PSMA11 PET (16). The PET Edge tool (MIM Software Inc.) was used for evaluation of focal uptake outside the expected biodistribution. The diameters of anatomic structures corresponding to focal uptake were measured on T1-weighted MR images for 68Ga-RM2 and on CT images for 68Ga-PSMA11 and 18F-DCFPyL.
Most patients with a positive scan (68Ga-RM2 PET/MRI or 68Ga-PSMA11/18F-DCFPyL) started therapy after the examination; therefore, follow-up comparison with other imaging modalities was not possible. The findings were pathologically confirmed in 5 participants.
Statistical Analyses
Statistical analysis was performed with SPSS, version 26 (SPSS Inc.). Continuous data are presented as mean ± SD, range, and frequency (%). The Welch test was used to compare PSA and PSA velocity between positive and negative scans. The paired Wilcoxon signed-rank test was used to compare differences in lesion SUVmax between the radiopharmaceuticals. The Fisher exact test was used to correlate clinical parameters with positivity versus negativity of the 2 radiopharmaceuticals. A P value of less than 0.05 was considered significant.
RESULTS
Patients’ Characteristics
Fifty patients, 52–81 y old (mean ± SD, 69.4 ± 7 y), underwent both 68Ga-RM2 PET/MRI and either 68Ga-PSMA11 PET/CT (n = 23) or 18F-DCFPyL PET/CT (n = 27). Thirty-six of the 50 had radical prostatectomy as the primary treatment, and 14 had radiation therapy. Fifteen patients were treated with androgen deprivation therapy (ADT) before the scans, whereas 23 started ADT after the scans. The PSA level at the time of the scans ranged from 0.1 to 21.5 ng/mL (4.2 ± 5 ng/mL). Supplemental Tables 1 and 2 summarize clinical and imaging characteristics of this cohort of patients (supplemental materials are available at http://jnm.snmjournals.org).
The injected dose ranged from 111 to 155.4 MBq (114.3 ± 7.4 MBq) for 68Ga-RM2, from 129.5 to 199.8 MBq (151.7 ± 14.8 MBq) for 68Ga-PSMA11, and from 270.1 to 366.3 MBq ( 333 ± 25.9 MBq) for 18F-DCFPyL.
The uptake time ranged from 39 to 100 min (52.7 ± 11 min) for 68Ga-RM2 PET/MRI, from 45 to 107.9 min (66.3 ± 15 min) for 68Ga-PSMA11 PET/CT, and from 60 to 120 min (81.2 ± 17 min) for 18F-DCFPyL. The interval between the 68Ga-RM2 and 68Ga-PSMA11/18F-DCFPyL scans ranged from 1 to 60 d (15.8 ± 17.7 d).
PSMA (68Ga-PSMA11 and 18F-DCFPyL) Versus 68Ga-RM2 Findings
68Ga-RM2 PET was positive in 35 (70%) and negative in 15 (30%) of the 50 patients. PSMA PET was positive in 37 (74%) and negative in 13 (26%) of the 50 patients. Both scans detected 70 lesions in 32 patients (42 in lymph nodes, 7 in the prostate bed, 6 in the seminal vesicles, 6 in the liver, and 9 in bone). The SUVmax for these 70 lesions ranged from 1.7 to 52.5 (8.1 ± 9.4) for 68Ga-RM2 and from 1.6 to 79.3 (16.7 ± 17.4) for PSMA. The difference in SUVmax was statistically significant (P < 0.001).
PSA ranged from 0.3 to 21.5 ng/mL (4.4 ± 4.8 ng/mL) and from 0.1 to 19.2 ng/mL (3.6 ± 5.7 ng/mL) for 68Ga-RM2–positive versus –negative scans, respectively, and the difference was not significant (P = 0.775). PSA ranged from 0.2 to 21.5 ng/mL (4.2 ± 4.7 ng/mL) and from 0.1 to 19.2 ng/mL (3.6 ± 6.1 ng/mL) for PSMA-positive versus -negative scans, respectively, and the difference was not significant (P = 0.739).
PSA velocity ranged from 0.1 to 42 ng/mL/y (5.7 ± 9.8 ng/mL/y) and from 0.1 to 21.3 ng/mL/y (3.5 ± 5.5 ng/mL/y) for 68Ga-RM2–positive versus –negative scans, respectively, and the difference was not significant (P = 0.320). PSA velocity ranged from 0.1 to 42 ng/mL/y (5.6 ± 9.8 ng/mL/y) and from 0.1 to 12.2 ng/mL/y (2.9 ± 3.9 ng/mL/y) for PSMA-positive versus -negative scans, respectively, and the difference was not significant (P = 0.174).
The positivity rate for PSA ≤0.5, <0.5 to ≤1, <1 to ≤2, <2 to ≤5, and >5 ng/mL was 38% (n = 3/8), 90% (n = 9/11), 50% (n = 4/8), 89% (n = 8/9), and 79% (n = 11/14), respectively, for 68Ga-RM2 and 22% (n = 2/9), 91% (n = 10/11), 75% (n = 6/8), 100% (n = 9/9), and 77% (n = 10/13), respectively, for PSMA.
68Ga-RM2 detected 7 more lesions in 4 patients than did PSMA (3 lymph node lesions, 3 bone lesions, and 1 adrenal gland lesion). The average SUVmax of these lesions was 5.8, and 6 of the 7 had a diameter of less than 1 cm. The mean PSA in these patients was 5 ng/mL, and 3 of them had negative findings on the PSMA scan.
PSMA detected 36 more lesions in 13 patients than did 68Ga-RM2 (27 lymph node lesions, 1 lung lesion, and 8 bone lesions). The average SUVmax of these lesions was 14.8, and 23 of the 36 measured less than 1 cm. The mean PSA value of these patients was 4.6 ng/mL, and 5 of them had negative findings on the 68Ga-RM2 scan.
Ten participants had both negative 68Ga-RM2 scans and negative PSMA scans. Their PSA at the time of the scans ranged from 0.1 to 19.2 ng/mL (3.1 ± 6.1 ng/mL). This subgroup included 6 participants with a PSA of 0.5 ng/mL or less, 1 with 1.2 ng/mL, 1 with 1.4 ng/mL, 1 with 8.2 ng/mL, and 1 with 19.2 ng/mL.
We did not identify any significant correlation between radiologic findings (positive vs. negative 68Ga-RM2 and PSMA scans) and clinical parameters such as Gleason score (≤3 + 4; ≤4 + 3), primary treatment (radical prostatectomy vs. radiation therapy), or ADT before imaging.
Figures 1 and 2 and Supplemental Figures 1 and 2 show pairs of 68Ga-RM2 and 18F-DCFPyL findings in different participants. We previously published images comparing 68Ga-RM2 and 68Ga-PSMA11 (8).
A 63-y-old man previously treated with radical prostatectomy, followed by salvage RT + ADT, presenting with BCR of PC (PSA, 0.4 ng/mL; PSA velocity, 1.6 ng/mL/y). Maximum-intensity-projection 68Ga-RM2 (A) and 18F-DCFPyL (B) PET images, axial 68Ga-RM2 (C) and 18F-DCFPyL (E) PET images, axial 68Ga-RM2 PET/MR image (D), and axial 18F-DCFPyL PET/CT image (F) are shown. Arrows mark left perirectal lymph nodes with significantly lower 68Ga-RM2 uptake than 18F-DCFPyL uptake.
A 66-y-old man previously treated with RT + ADT, presenting with BCR of PC (PSA, 11.6 ng/mL; PSA velocity, 12.2 ng/mL/y). Maximum-intensity-projection 68Ga-RM2 (A) and 18F-DCFPyL (B) PET images, axial 68Ga-RM2 (C) and 18F-DCFPyL (E) PET images, axial 68Ga-RM2 PET/MR image (D), and axial 18F-DCFPyL PET/CT image (F) are shown. Red arrows mark right adrenal lesion clearly seen on 68Ga-RM2 but not prospectively identified on 18F-DCFPyL, given similar uptake in adrenal gland and liver parenchyma. Blue arrows mark physiologic 68Ga-RM2 uptake in pancreas.
Lesion analysis for 68Ga-RM2 versus PSMA is shown in Table 1.
Analysis of Lesions from 68Ga-RM2 vs. 68Ga-PSMA11/18F-DCFPyL
DISCUSSION
Our study evaluated gastrin-releasing peptide receptor and PSMA PET radiopharmaceuticals in patients with BCR of PC. The 68Ga-RM2 positivity rate was similar to our prior published reports (8,9). The overall semiquantitative analysis showed that SUVmax measurements were higher for PSMA radiopharmaceuticals than for 68Ga-RM2, and the difference was statistically significant. However, there were differences between 68Ga-PSMA11 and 18F-DCFPyL measurements against 68Ga-RM2, with higher and statistically significant values only for 18F-DCFPyL. This finding may be due to differences between 68Ga- and 18F-labeled radiopharmaceuticals. Prior work by Dietlein et al. showed that the same lesions have higher uptake measured on 18F-DCFPyL than on 68Ga-PSMA11 PET (17). PSA velocity for patients with positive versus negative scans was not statistically significant for either gastrin-releasing peptide receptor or PSMA PET in this cohort.
We previously reported the first comparison of 68Ga-RM2 and 68Ga-PSMA11 in a small pilot study (8). Here, we expanded with a new cohort of patients and 2 different PSMA-targeting radiopharmaceuticals. Hoberück et al. reported data from 16 patients with mostly advanced PC who underwent both and 68Ga-RM2 PET/CT and either 68Ga-PSMA11 PET/CT or 68Ga-PSMA11 PET/MRI (18). 68Ga-RM2 PET/CT showed 2 osseous lesions not seen by 68Ga-PSMA11, whereas the latter showed avid uptake in several locations not visible with 68Ga-RM2. To our knowledge, no previous studies compared 18F-DCFPyL and 68Ga-RM2.
PSMA ligands have a high positivity rate even at low PSA values (5). One study showed 50% positivity when PSA was less than 0.5 ng/mL in a cohort of 319 participants (19). In our cohort, the positivity rate was similar for PSMA and 68Ga-RM2 (2/9 and 3/8, respectively) at a PSA level of less than 0.5 ng/mL. Larger studies are needed to confirm these preliminary observations.
Gastrin-releasing peptide receptor is not highly expressed in advanced states of androgen-independent PC, especially in osseous metastases (20). Here, 68Ga-RM2 identified 3 bone lesions in 1 patient that were not conspicuous on PSMA. This patient was previously treated with radical prostatectomy and ADT, subsequently becoming androgen-independent. On the other hand, 68Ga-RM2 PET did not identify 8 osseous lesions seen by PSMA in other patients. These findings require further evaluation.
Some of the patients in this cohort received ADT before the scans, and this may have influenced the uptake of the 2 radiopharmaceuticals. PSMA uptake is regulated by androgen hormones, and ADT may considerably increase PSMA-ligand uptake (21–23). A single study suggested that ADT induces gastrin-releasing peptide activity, activation of nuclear factor κ-light-chain enhancer of activated B cells, and increased levels of androgen receptor splice variant 7 expression, resulting in progression to CRPC (24).
Recently, interest in metastasis-directed therapies in patients with minimal metastatic tumor burden (oligometastatic disease) has increased (25); in these patients, for whom the exact number and localization of the lesions is of great importance, having access to different classes of radiopharmaceuticals may be useful. Whether the PSA rise reflects a locoregional recurrence or distant metastatic disease still remains an important question in BCR of PC, because treatment planning would change accordingly from a potentially curative local therapy to watchful waiting or palliative systemic treatment. In this setting and considering how heterogeneous PC is, identifying patients for whom different classes of radiopharmaceuticals are complementary may ultimately allow for personalized medicine. The use of combination therapies with nonoverlapping toxicities may allow delivery of greater doses to lesions, as well as possibly less adverse events.
Our study had limitations, including the relatively small number of patients analyzed (albeit the largest dataset of gastrin-releasing peptide receptor vs. PSMA PET imaging results at BCR of PC) and the different methods used for scanning patients, dictated by available research funding. However, both PET/CT and PET/MRI used the same silicon photomultiplier–based detectors, which provide similar performance in both modalities. Magnetic resonance– based attenuation correction is not ideal for the skeleton; it is known that improperly accounting for bone may lead to underestimation of PET signal in tissues near bone (26), and this factor may have impacted the results of 68Ga-RM2. Lastly, pathologic confirmation of the identified lesions was limited to a small number of participants (10%) because of a bias from the referring physicians who accepted putative sites of disease on imaging after initial biopsies had returned no false-positive 68Ga-RM2 findings; in addition, PSMA findings are now widely accepted by treating physicians.
To determine whether there is a correlation between clinical features and gastrin-releasing peptide receptor versus PSMA-positive or -negative lesions, we ran the Fisher exact test but did not observe any significant associations. The cause may be the small cohort of patients enrolled. Furthermore, 20% of our participants had negative PSMA and 68Ga-RM2 findings, including at a PSA level of more than 5 ng/mL. These issues underline the complexity of the PC biology and should be evaluated in larger prospective studies.
CONCLUSION
68Ga-RM2 remains a valuable radiopharmaceutical even when compared with the more widely used 18F-DCFPyL/68Ga-PSMA11 in the evaluation of BCR of PC. Larger studies are needed to verify that identifying patients for whom these 2 classes of radiopharmaceuticals are complementary may ultimately allow for personalized medicine.
DISCLOSURE
The Clinicaltrials.gov identifiers for this work are NCT 02624518 (68Ga-RM2), NCT02673151 (68Ga-PSMA11), and NCT03501940 (18F-DCFPyL). NCT 02624518 (68Ga-RM2) was supported by Department of Defense Impact Award (W81XWH-16-1-0604). NCT02673151 (68Ga-PSMA11) was partially supported by institutional support from GE Healthcare and by Department of Radiology discretionary funds. NCT03501940 (18F-DCFPyL) was partially supported by Department of Radiology discretionary funds. Life MI provided the RM2 precursor. Progenics Pharmaceuticals provided 18F-DCFPyL as part of a research access program. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Is there a benefit to using gastrin-releasing peptide receptor PET in addition to PSMA PET in patients with BCR of PC?
PERTINENT FINDINGS: Of the 50 patients, 68Ga-RM2 PET was positive in 35 (70%) and negative in 15 (30%), whereas PSMA PET was positive in 37 (74%) and negative in 13 (26%). Both scans detected 70 lesions in 32 patients (42 in lymph nodes, 7 in the prostate bed, 6 in the seminal vesicles, 6 in the liver, and 9 in bone). Forty-three lesions in 18 patients were shown by only 1 class of radiopharmaceutical: 68Ga-RM2 detected 7 more lesions in 4 patients, whereas PSMA detected 36 more lesions in 14 patients (9 lesions were identified by 68Ga-PSMA11 and 27 by 18F-DCFPyL).
IMPLICATIONS FOR PATIENT CARE: 68Ga-RM2 remains a valuable radiopharmaceutical even when compared with the more widely used 68Ga-PSMA11/18F-DCFPyL in the evaluation of BCR of PC. Larger studies are needed to verify that identifying patients for whom these 2 classes of radiopharmaceuticals are complementary may ultimately allow for personalized medicine.
Footnotes
Published online March 5, 2021.
- © 2021 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication October 31, 2020.
- Accepted for publication March 1, 2021.
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