Francesco Ceci

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.

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.

New aspects of molecular imaging in prostate cancer

Nowadays several new imaging modalities are available for investigating prostate cancer (PCa) such as magnet resonance imaging (MRI) in the form of whole body MRI and pelvic multiparametric MRI and positron emission tomography (PET) using choline as radiotracers. Nevertheless, these modalities proved sub-optimal accuracy for detecting PCa metastases, particularly in the recurrence setting. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been recently developed for PET imaging. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallo-peptidase over-expressed in PCa cells. It has been shown that PSMA based imaging offers higher tumor detection rate compared to choline PET/CT and radiological conventional imaging, especially at very low PSA levels during biochemical recurrence. In addition PSMA, as theranostics agent, allows both radiolabeling with diagnostic (e.g. 68Ga, 18F) or therapeutic nuclides (e.g. 177Lu, 225Ac). Initial results show that PSMA-targeted radioligand therapy can potentially delay disease progression in metastatic castrate-resistant PCa. Despite still investigational, the bombesin-based radiotracers and antagonist of gastrin releasing-peptide receptor (GRP) (RM2) and anti1-amino-3-18Ffluorocyclobutane-1-carboxylic acid (18F-FACBC) are emerging as possible alternatives for investigating PCa. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68Ga-PSMA-11, 18F-FACBC, 68Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy.

68Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy and PSA <0.5 ng/ml. Efficacy and impact on treatment strategy

PurposeThe primary aim of this retrospective, single-centre analysis was to assess the performance of 68Ga-PSMA-11 PET/CT in prostate cancer (PCa) patients in early PSA failure after radical prostatectomy (RP). The secondary aim was to assess the potential impact of 68Ga-PSMA-11 PET/CT on treatment strategy.Methods68Ga-PSMA-11 PET/CT is performed in our institution within an investigational new drug (IND) trial in PCa patients with biochemical recurrence (BCR). The records of all patients enrolled between March 2016 and July 2017 were evaluated. These records were retrospectively analysed according to the following inclusion criteria: (a) RP as primary therapy, (b) proven BCR, ©) PSA levels in the range 0.2–0.5xa0ng/ml at the time of the 68Ga-PSMA-11 PET/CT investigation, and (d) no salvage radiotherapy (S-RT) performed after recurrence. The performance of 68Ga-PSMA-11 PET/CT was evaluated in terms of detection rate on a per-patient and a per-region basis (local vs. distant lesions). We further performed an intention-to-treat (ITT) analysis. The patient cohort was grouped into three subpopulations, blinded to the 68Ga-PSMA-11 PET/CT results, according to the patients’ characteristics and different patterns of treatment: (1) S-RT (with or without systemic treatment), (2) stereotactic body radiotherapy (SBRT) (with or without systemic treatment), and (3) systemic treatment. The treatment strategy was re-evaluated for each patient taking into consideration the 68Ga-PSMA-11 PET/CT images.ResultsWe enrolled 119 PCa patients (mean age 66xa0years, range 44–78xa0years) with a mean PSA level at the time of 68Ga-PSMA-11 PET/CT of 0.34xa0ng/ml (median 0.32xa0ng/ml, SD ±0.09, range 0.20–0.50xa0ng/ml). 68Ga-PSMA-1 1 PET/CT was positive in 41 of the 119 patients, resulting in an overall detection rate of 34.4%. 68Ga-PSMA-11 uptake was observed in the prostate bed (3 patients, 2.5%), in the pelvic lymph nodes (21, 17.6%), in the retroperitoneal lymph nodes (4, 3.4%) and in the skeleton (21, 17.6%). Regarding ITT, 81 patients (68.1%) were considered possible candidates for S-RT only in the prostate bed and none of the patients (0%) for SBRT. According to the 68Ga-PSMA-11 PET/CT results, the intended treatment was changed in 36 patients (30.2%). According to the PET/CT results, S-RT was recommended in 70 patients (58.8%), only to the prostate bed in 58 (48.7%) and SBRT in 29 (24.4%). The intended RT planning was modified in 36 (87.8%) of 41 patients with a positive 68Ga-PSMA-11 PET/CT result.ConclusionIn our patient series with PSA levels <0.5xa0ng/ml, 68Ga-PSMA-11 PET/CT had a detection rate of 34.4%. In the ITT analysis, 30.2% of patients had a change in the intended treatment. These data support the hypothesis that 68Ga-PSMA-11 PET/CT is a useful procedure in the management of PCa patients showing early recurrence after RP, and should be implemented in routine clinical practice.

Oligorecurrent prostate cancer limited to lymph nodes: getting our ducks in a row

PurposeOligorecurrent prostate cancer with exclusive nodal involvement represents a common state of disease, amenable to local therapy. New radio-labeled tracers have enriched the possibility of cancer detection and treatment. In this review, we aim to illustrate the main nuclear medicine diagnostic options and the role of radiotherapy in this setting of patients.MethodsWe performed a PubMed search referring to the PRISMA guidelines to analyze the performance of PSMA- and choline-PET in detecting oligorecurrence limited to lymph nodes, and to review the main studies supporting either ablative stereotactic body radiotherapy or regional lymph node irradiation in this clinical setting.ResultsPSMA-PET has shown higher efficacy in the diagnosis of nodal lesions if compared with choline-PET. More specifically, for PSA ≤u20092xa0ng/ml, the median detection rate of choline-PET ranges from 19.5 to 44.5%, whereas PSMA ranges from 51.5 to 74%. SBRT achieves high local control rates positively affecting progression-free survival (PFS), with androgen deprivation therapy (ADT)-free survival ranging from 25 to 44xa0months and with low toxicity rates (0–15%). Prophylactic nodal irradiation shows 3-year PFS rates ranging from 62 to 75%, but with a potential higher risk of toxicity. However, the chosen treatment option needs to be tailored on the single patient.ConclusionsNewer PET/CT radio-labeled tracers have increased disease detection in oligorecurrent prostate cancer patients. Growing evidence of their impact on metastasis-directed therapy encourages the use of the most advanced radiotherapy techniques in the clinical management of such patients.

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).

Future Perspective of the Application of Positron Emission Tomography-Computed Tomography-MR Imaging in Musculoskeletal Disorders

Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is the imaging method of choice in sarcoma patients. PET may help in diagnosis, grading, staging, biopsy guidance, monitoring response to therapy, restaging for recurrence, and prognosis. 18F-FDG-PET/MRI combines the higher tissue contrast of MRI in the study of soft-tissue lesions and the peculiarities of PET imaging that allow the characterization of tissues. The use of 18F-FDG-PET/MRI in these patients has reduces the radiation dose, which is of great importance, particularly in children. Data support the routine use of 18F-FDG-PET either using CT or MRI in patients with sarcoma.

State‐of‐the‐art imaging techniques in the management of preoperative staging and re‐staging of prostate cancer

We aimed to review the current state‐of‐the‐art imaging methods used for primary and secondary staging of prostate cancer, mainly focusing on multiparametric magnetic resonance imaging and positron‐emission tomography/computed tomography with new radiotracers. An expert panel of urologists, radiologists and nuclear medicine physicians with wide experience in prostate cancer led a PubMed/MEDLINE search for prospective, retrospective original research, systematic review, meta‐analyses and clinical guidelines for local and systemic staging of the primary tumor and recurrence disease after treatment. Despite magnetic resonance imaging having low sensitivity for microscopic extracapsular extension, it is now a mainstay of prostate cancer diagnosis and local staging, and is becoming a crucial tool in treatment planning. Cross‐sectional imaging for nodal staging, such as computed tomography and magnetic resonance imaging, is clinically useless even in high‐risk patients, but is still suggested by current clinical guidelines. Positron‐emission tomography/computed tomography with newer tracers has some advantage over conventional images, but is not cost‐effective. Bone scan and computed tomography are often useless in early biochemical relapse, when salvage treatments are potentially curative. New imaging modalities, such as prostate‐specific membrane antigen positron‐emission tomography/computed tomography and whole‐body magnetic resonance imaging, are showing promising results for early local and systemic detection. Newer imaging techniques, such as multiparametric magnetic resonance imaging, whole‐body magnetic resonance imaging and positron‐emission tomography/computed tomography with prostate‐specific membrane antigen, have the potential to fill the historical limitations of conventional imaging methods in some clinical situations of primary and secondary staging of prostate cancer.

The influence of PSA flare in mCRPC patients treated with alpha-emitting radiopharmaceuticals

In this issue of the European Journal of Nuclear Medicine, Castello et al. [1] performed a retrospective analysis in 168 metastatic castration-resistant prostate cancer (mCRPC) patients who underwent RaCl2. All patients presented bone metastases and 34% of these patients had concomitant visceral and/or nodal metastases. Authors evaluated the prognostic impact of PSA flare on overall survival (OS) and progression-free survival (PFS) in this cohort. This is the first study specifically designed to assess the presence and the influence of PSA flare in patients undergoing alpha-emitting radiopharmaceuticals. The PSA flare is a well-known phenomenon observed in several studies in the course of systemic therapies, including hormonal therapies (especially luteinizing hormone-releasing hormone (LHRH) agonist), new androgen receptor targeted therapies (abiraterone acetate or enzalutamide) and taxane-based chemotherapy (either docetaxel or cabazitaxel) [2]. A transient PSA rise followed by a decrease of PSA below the baseline can be considered a temporary flare-up. The cause of such flare has only been postulated. Many suggest that it could be caused by PSA release from lysed cells. However, the aberrant activation of the androgen receptor or the transactivation of the androgen receptor induced by corticosteroids have been suggested as the possible cause responsible for PSA flare-up during systemic therapy [3]. Other explanations are related to cellular heterogeneity and diversity in terms of drug sensitivity, cell cycle kinetics, and PSA expression [4]. The development of PSA flare does not influence diseasespecific outcomes. Its incidence is attested in 5–30% of patients receiving LHRH agonist and in 8–20% of patients receiving chemotherapy [2, 5]. As treatment of mCRPC becomes more complex, and definitions of progression on treatment continue to evolve, referring physicians must be aware of this laboratory pattern to avoid unnecessary discontinuation of these therapies based on early PSA change alone. Castello et al. [1] confirmed the presence of PSA flare-up also inmCRPC patients treatedwith alpha-emitting radiopharmaceuticals (RaCl2). Although there is no agreed definition on the extent of the following PSA decline to be considered as a flare after an initial rise in PSA, a flare followed by a decrease below the baseline is generally considered the most accepted definition. According to these criteria, authors observed PSA flare-up in 11.9% of their population. In the flare group, OS and PFS were considerably better than in the nonresponder group. These results are consistent with data obtained in mCRPC patients undergoing abiraterone or taxanebased chemotherapies [2, 3, 5, 6]. RaCl2 preferentially targets new bone growth surrounding bone metastases while emitting alpha particles within the tumour microenvironment. Whereas beta particles generate primarily single-stranded deoxyribonucleic acid breaks that may be overcome by cellular repair mechanisms, alpha particles have high linear energy transfer with enhanced ability to induce lethal double-stranded deoxyribonucleic acid breaks, thus eliciting greater cytotoxic effects on bone-metastatic tumour sites [7]. Accordingly, Castello et al. hypothesized that PSA flare during RaCl2 treatment is due to PSA release from tumour cell lysis, and may correspond to a high degree of tumour cell death. However, the concomitant administration of therapies, including hormonal therapy, can be responsible for the PSA flare-up in this patient-series, through the This Editorial Commentary refers to the article https://doi.org/10.1007/ s00259-018-4051-y