Jeremie Calais

68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning

Target volume delineations for prostate cancer (PCa) salvage radiotherapy (SRT) after radical prostatectomy are usually drawn in the absence of visibly recurrent disease. 68Ga-labeled prostate-specific membrane antigen (PSMA-11) PET/CT detects recurrent PCa with sensitivity superior to standard-of-care imaging at serum prostate-specific antigen (PSA) values low enough to affect target volume delineations for routine SRT. Our objective was to map the recurrence pattern of PCa early biochemical recurrence (BCR) after radical prostatectomy with 68Ga-PSMA-11 PET/CT in patients with serum PSA levels of less than 1 ng/mL, determine how often consensus clinical target volumes (CTVs) based on the Radiation Therapy Oncology Group (RTOG) guidelines cover 68Ga-PSMA-11 PET/CT-defined disease, and assess the potential impact of 68Ga-PSMA-11 PET/CT on SRT. Methods: This was a post hoc analysis of an intention-to-treat population of 270 patients who underwent 68Ga-PSMA-11 PET/CT at 4 institutions for BCR after prostatectomy without prior radiotherapy at a PSA level of less than 1 ng/mL. RTOG consensus CTVs that included both the prostate bed and the pelvic lymph nodes were contoured on the CT dataset of the PET/CT image by a radiation oncologist masked to the PET component. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11–positive lesions not covered by planning volumes based on the consensus CTVs were considered to have a potential major impact on treatment planning. Results: The median PSA level at the time of 68Ga-PSMA-11 PET/CT was 0.48 ng/mL (range, 0.03–1 ng/mL). One hundred thirty-two of 270 patients (49%) had a positive 68Ga-PSMA-11 PET/CT result. Fifty-two of 270 (19%) had at least one PSMA-11–positive lesion not covered by the consensus CTVs. Thirty-three of 270 (12%) had extrapelvic PSMA-11–positive lesions, and 19 of 270 (7%) had PSMA-11–positive lesions within the pelvis but not covered by the consensus CTVs. The 2 most common 68Ga-PSMA-11–positive lesion locations outside the consensus CTVs were bone (23/52, 44%) and perirectal lymph nodes (16/52, 31%). Conclusion: Post hoc analysis of 68Ga-PSMA-11 PET/CT implied a major impact on SRT planning in 52 of 270 patients (19%) with PCa early BCR (PSA < 1.0 ng/mL). This finding justifies a randomized imaging trial of SRT with or without 68Ga-PSMA-11 PET/CT investigating its potential benefit on clinical outcome.

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy

The prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PC) cells. Therefore, the targeting of PSMA has become increasingly important over the last decade. Glu-urea–based PSMA ligands used for both imaging and radioligand therapy are the mainstays of the current success. For PET imaging, both 68Ga- and 18F-labeled agents have been successfully translated to clinical applications. Mainly retrospective cohort studies have shown a high value in the setting of biochemical recurrence, with high detection rates even in the presence of low prostate-specific antigen levels. Preliminary data indicated that radioguided surgery with PSMA ligands may help to further improve patient outcomes because it facilitates the removal of small tumor deposits that are otherwise difficult to detect. For primary PC, PSMA ligand PET imaging has been shown to be superior to cross-sectional imaging for the detection of metastatic lymph nodes. In addition, it promises to also provide intraprostatic tumor localization, especially when used in combination with multiparametric MRI. Increasing numbers of studies have reported considerable changes in management resulting from PSMA ligand PET imaging for both biochemical recurrence and primary disease. The use of 177Lu-PSMA–based radioligand therapy has demonstrated a reasonable response, mainly as defined by a prostate-specific antigen response of more than 50%, comparable to other recently introduced agents. Especially given the high level of safety of 177Lu-PSMA radioligand therapy, with only minimal grade 3 and 4 toxicities reported so far, it has the potential to expand options for metastatic castration-resistant PC. This review is intended to provide a comprehensive overview of the current literature on low-molecular-weight PSMA ligands for both PET imaging and therapeutic approaches, with a focus on agents that have been clinically adopted.

Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT

Prostate-specific membrane antigen (PSMA)–ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.

Most of the Intended Management Changes After68Ga-DOTATATE PET/CT Are Implemented

In this prospective referring-physician–based survey, we investigated the definite clinical impact of 68Ga-DOTATATE PET/CT on managing patients with neuroendocrine tumors (NETs). Methods: We prospectively studied 130 patients with 68Ga-DOTATATE PET/CT referred for initial or subsequent management decisions (NCT02174679). Referring physicians completed one questionnaire before the scan (Q1) to indicate the treatment plan without PET/CT information, one immediately after review of the imaging report to denote intended management changes (Q2), and one 6 mo later (Q3) to verify whether intended changes were in fact implemented. To further validate the Q3 responses, a systematic electronic chart review was conducted. Results: All 3 questionnaires were completed by referring physicians for 96 of 130 patients (74%). 68Ga-DOTATATE PET/CT resulted in intended management changes (Q2) in 48 of 96 patients (50%). These changes were finally implemented (Q3) in 36 of 48 patients (75%). Q3 responses were confirmed in all patients with an available electronic chart (36/96; 38%). Conclusion: This prospective study confirmed a significant impact of 68Ga-DOTATATE PET/CT on the intended management of patients with NETs (50% of changes) and notably demonstrated a high implementation rate (75%) of these intended management changes.

Potential impact of 68Ga-PSMA-11 PET/CT on prostate cancer definitive radiation therapy planning

Standard-of-care imaging for initial staging of prostate cancer (PCa) underestimates disease burden. Prostate-specific membrane antigen (PSMA) PET/CT detects PCa metastasis with superior accuracy, having a potential impact on the planning of definitive radiation therapy (RT) for nonmetastatic PCa. Our objectives were to determine how often definitive RT planning based on standard target volumes covers 68Ga-PSMA-11 PET/CT–defined disease and to assess the potential impact of 68Ga-PSMA-11 PET/CT on definitive RT planning. Methods: This was a post hoc analysis of an intention-to-treat population of 73 patients with localized PCa without prior local therapy who underwent 68Ga-PSMA PET/CT for initial staging as part of an investigational new drug trial. Eleven of the 73 were intermediate-risk (15%), 33 were high-risk (45%), 22 were very-high-risk (30%), and 7 were N1 (9.5%). Clinical target volumes (CTVs), which included the prostate, seminal vesicles, and (in accord with the Radiation Therapy Oncology Group consensus guidelines) pelvic lymph nodes (LNs), were contoured on the CT portion of the PET/CT images by a radiation oncologist masked to the PET findings. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11–positive lesions not covered by planning volumes based on the CTVs were considered to have a major potential impact on treatment planning. Results: All patients had one or more 68Ga-PSMA-11–positive primary prostate lesions. Twenty-five (34%) and 7 (9.5%) of the 73 patients had 68Ga-PSMA-11–positive pelvic LN and distant metastases, respectively. The sites of LN metastases in decreasing order of frequency were external iliac (20.5%), common iliac (13.5%), internal iliac (12.5%) obturator (12.5%), perirectal (4%), abdominal (4%), upper diaphragm (4%), and presacral (1.5%). The median size of the LN lesions was 6 mm (range, 4–24 mm). RT planning based on the CTVs covered 69 (94.5%) of the 73 primary lesions and 20 (80%) of the 25 pelvic LN lesions, on a per-patient analysis. Conclusion: 68Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 12 (16.5%) of the 73 patients whose RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 25 (37%) of the 66 patients whose RT fields covered the prostate and seminal vesicles but not the pelvic LNs.

Head-to-head comparison of 68Ga-PSMA-11 PET/CT and 18F-Fluciclovine PET/CT in a case series of 10 patients with prostate cancer recurrence

This was a head-to-head comparison between 68Ga-labeled prostate-specific membrane antigen (PSMA)-11 and 18F-fluciclovine PET/CT in a series of 10 patients with prostate cancer (PCa) recurrence. Methods: In total, 288 patients with PCa recurrence were enrolled in a prospective study of 68Ga-PSMA-11 PET/CT imaging for recurrent disease localization (ClinicalTrials.gov identifier NCT02940262). We retrospectively identified 10 patients who underwent clinically indicated 18F-fluciclovine PET/CT prior to enrollment. Results: The median time between the 2 scans was 2.2 mo (range, 0.2–4.2 mo). The median prostate-specific antigen (PSA) value was 1.0 ng/mL (mean, 4.7 ng/mL; range, 0.13–18.1 ng/mL) and 1.1 ng/mL (mean, 6.2 ng/mL; range, 0.24–31.3 ng/mL) at the time of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT, respectively. Five of 10 patients (50%) were negative with 18F-fluciclovine but positive with 68Ga-PSMA-11 PET/CT. Two of 10 patients (20%) were positive with both 18F-fluciclovine and 68Ga-PSMA-11 PET/CT, but 68Ga-PSMA-11 PET/CT showed additional lymph nodes metastasis. Three of 10 patients (30%) were negative with both 18F-fluciclovine and 68Ga-PSMA-11 PET/CT. Conclusion: This case series suggests improved detection rates for 68Ga-PSMA-11 PET/CT when compared with 18F-fluciclovine PET/CT in patients with recurrent PCa. Prospective trials designed to directly compare the two should be initiated.

Solitary Mucinous Prostate Adenocarcinoma Lung Metastasis Detected by 68Ga-PSMA-11 PET/CT

Mucinous adenocarcinoma of the prostate is a rare subtype of prostate cancer characterized by the presence of at least 25% of the tumor composed of glands with intracellular mucin. Lung is the second most common extranodal site of metastases after bone. However, solitary lung metastasis fromprostatecancer,withoutosseousor lymphatic involvement, is considered as a rare condition. Locating one single site of recurrence in the early phase of biochemical recurrence is important in order to select the most appropriate therapeutic approach with curative intent, such as metastasis-directed therapy. 68-Gallium prostate-specific membrane antigen (68GaPSMA-11) positron emission tomography/computed tomography (PET/CT) has a high sensitivity for detecting small site of recurrent prostate cancer at low prostatespecific antigen (PSA) levels. In this case report, 68-Ga-PSMA-11 PET/CT detected a solitary mucinous lung metastasis from prostate cancer (negative with 18F-fluorodeoxyglucose PET/ CT and 18F-fluciclovine PET/CT) in a patient with biochemical recurrence after prostatectomy at low PSA levels, leading to metastasis-directed therapy with curative intent.

Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer

To improve prostate-specific membrane antigen (PSMA)–targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging—that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT—have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA−; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein–positive, and luciferase-positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10–23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23–27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (≤22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models.

The Utility of PET/CT in the Planning of External Radiation Therapy for Prostate Cancer

Radiotherapy and radical prostatectomy are the definitive treatment options for patients with localized prostate cancer. A rising level of prostate-specific antigen after radical prostatectomy indicates prostate cancer recurrence, and these patients may still be cured with salvage radiotherapy. To maximize chance for cure, the irradiated volumes should completely encompass the extent of disease. Therefore, accurate estimation of the location of disease is critical for radiotherapy planning in both the definitive and the salvage settings. Current first-line imaging for prostate cancer has limited sensitivity for detection of disease both at initial staging and at biochemical recurrence. Integration of PET into routine evaluation of prostate cancer patients may improve both staging accuracy and radiotherapy planning. 18F-FDG PET/CT is now routinely used in radiation planning for several cancer types. However, 18F-FDG PET/CT has low sensitivity for prostate cancer. Additional PET probes evaluated in prostate cancer include 18F-sodium fluoride, 11C-acetate, 11C- or 18F-choline, 18F-fluciclovine, and 68Ga- or 18F-labeled ligands that bind prostate-specific membrane antigen (PSMA). PSMA ligands appear to be the most sensitive and specific but have not yet received Food and Drug Administration New Drug Application approval for use in the United States. Retrospective and prospective investigations suggest a potential major impact of PET/CT on prostate radiation treatment planning. Prospective trials randomizing patients to routine radiotherapy planning versus PET/CT-aided planning may show meaningful clinical outcomes. Prospective clinical trials evaluating the addition of 18F-fluciclovine PET/CT for planning of salvage radiotherapy with clinical endpoints are under way. Prospective trials evaluating the clinical impact of PSMA PET/CT on prostate radiation planning are indicated.

Reply: Comparison of 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a Case Series of 10 Patients with Prostate Cancer Recurrence: Prospective Trial Is on Its Way

REPLY: We thank Bela Denes and Peter Gardiner from BlueEarth Diagnostics, Inc., for their interest in our case series (1) and their relevant letter. BlueEarth Diagnostics, Inc., showed recently with great success how to get a PET probe approved by the Food and Drug Administration (2). We agree with each of their comments and concerns. We clearly highlighted the limitations throughout the article and, in particular, in the discussion section (1). Nevertheless, we are convinced that the cases may be informative even after considering the limitations that they and we highlighted. Except for 1 patient (patient 3), the difference in prostate-specific antigen (PSA) levels between the 2 scans was minimal: median, 0.11 ng/mL; mean, 0.24; range, 0.03–0.86 (1). Prostate-specific membrane antigen (PSMA) signals were entirely unambiguous, and we did not rely on CT to call findings positive or negative. We also agree that false-positive PSMA PET/CT findings can occur. However, the reported specificity and positive predictive values of PSMA PET/CT, especially for local and nodal disease, are reported to be very high (i.e., .95%) (3–6). The findings of the 2 imaging tests were so strikingly different that we felt a brief report would be prudent because no direct comparisons between these 2 tests have been published thus far. These differences are not surprising as amino acid transport and PSMA expression reflect fundamentally different biologic processes. We believe that lesion phenotypes such as concordant and discordant findings by these 2 imaging tests may give rise to future important research by, for instance, correlating these patterns with patient outcomes. We strongly support the notion that 18F-fluciclovine PET/CT has significantly improved the management of prostate cancer patients as documented in well-designed clinical trials (NCT01666808, NCT02578940). We acknowledge with great enthusiasm that the inclusion of 18F-fluciclovine PET/CT in the American College of Radiology Appropriateness Criteria guidelines, as well as most recently in the National Comprehensive Cancer Network guidelines, is a major milestone for improving the care of prostate cancer patients. We simply reported that 7 of 10 patients who underwent 18Ffluciclovine PET/CT before enrollment in our ongoing prospective trial (NCT02940262) exhibited more positive findings on 68GaPSMA-11 PET/CT scans. Although far from definitive evidence of superiority, these unexpected findings encouraged us to initiate a prospective single-center trial to compare 68Ga-PSMA-11 and 18Ffluciclovine PET/CT for restaging prostate cancer patients with biochemical recurrence after radical prostatectomy at low PSA values (UCLA IRB# 17-001885, NCI identifier 2018-00546).