Diagnostic performance of 18F-fluciclovine PET/CT for regional lymph node metastases in patients with primary prostate cancer: a multicenter phase II clinical trial

Diagnostic performance of 18F-fluciclovine PET/CT for regional lymph node metastases in patients... Abstract Objective This multicenter, phase II clinical trial evaluated the diagnostic performance of 18F-fluciclovine, a novel amino acid for positron-emission tomography (PET), for detection of small lymph node metastases with short-axis diameters of 5–10 mm in patients with prostate cancer. Methods Patients with prostate cancer were eligible after screening of laboratory tests and pelvic contrast-enhanced computed tomography (CT). Pelvic region 18F-fluciclovine PET/CT was then acquired within 28 days and dissection of regional lymph nodes was performed within 60 days of pelvic contrast-enhanced CT. Diagnostic performance of 18F-fluciclovine-PET/CT was evaluated by comparison with standard histopathology of lymph nodes. Results In a total of 28 patients, 40 regional lymph nodes with short-axis diameters of 5–10 mm were eligible for efficacy evaluation; seven of these showed metastases confirmed by histopathology. The sensitivity of 18F-fluciclovine PET/CT was 57.1% (4/7). All four true positive lymph nodes detected by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm and a high proportion of cancer volume (60–100%) according to pathology evaluation. The specificity, diagnostic accuracy, positive predictive value, and negative predictive value of 18F-fluciclovine PET/CT in lymph node-based analysis were 84.8% (28/33), 80.0% (32/40), 44.4% (4/9), and 90.3% (28/31), respectively. No clinically significant adverse events occurred. Conclusions 18F-fluciclovine PET/CT detected small lymph node metastases; however it also showed positive findings in benign lymph nodes. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT for small lymph node metastases in patients with prostate cancer. clinical trial, fluciclovine F-18, lymphatic metastasis, positron-emission tomography, prostate cancer Introduction The prevalence and associated mortality of prostate cancer is increasing in Japan, as well as in the USA and Europe. More specifically, the prevalence of prostate cancer in Japan is expected to increase from about 65 400 in 2010 to about 105,800 in 2020, with an increase in the associated mortality from 11 600 to 14 700 (1). The main management options for prostate cancer include surgery, radiation therapy, drug therapy (endocrine therapy), and active surveillance. The guidelines for prostate cancer treatment, such as those developed by the National Comprehensive Cancer Network (NCCN) (2) and the Japanese Urological Association (3), recommend selecting a treatment option most appropriate for the cancer stage. Specifically, radical treatment, such as total prostatectomy and radiation therapy, or active surveillance are recommended in patients with no lymph node or bone metastases, while endocrine therapy is indicated when the cancer is metastatic (2,3). Lymph node metastases are usually detected by computed tomography (CT) or magnetic resonance imaging (MRI), with both diagnostic methods using morphological change in lymph nodes (size and shape) as the diagnostic criterion. However, the reported performance of CT and MRI in diagnosing lymph node metastases is inconsistent because the size of the lymph node does not necessarily correlate with the presence or absence of prostate cancer metastases (4) and the criteria for interpreting test results (e.g., threshold of positive lymph node size) differ between institutions (5). 18F-fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), is a new positron-emission tomography (PET) tracer developed by Shoup and Goodman, which consists of a synthetic amino acid (1-aminocyclobutane carbonate [ACBC]) labeled with 18F (6). It accumulates in the tumor in response to an increase in amino acid metabolism (7,8). The background radioactivity in the pelvis is low because 18F-fluciclovine is slowly excreted into the bladder. Therefore, 18F-fluciclovine allows for clear visualization of the primary prostate cancer and lymph node metastases, while 18F-fludeoxyglucose (18F-FDG) does not, as it is excreted via the bladder in patients with primary or recurrent prostate cancer (9). Promising data have been reported on the use of 18F-fluciclovine in the detection of recurrent prostate cancer (10–12), and it was recently approved in both the USA and Europe for this indication. 18F-fluciclovine is also expected to be useful for initial staging of prostate cancer, and its performance in this indication has been evaluated in clinical trials conducted in Japan (13,14). Visualization of the primary prostate cancer lesions, lymph node metastases, bone metastases, and lung metastases was reported in an early clinical trial (13). No serious adverse events have been reported in association with 18F-fluciclovine and the level of radiation exposure was within acceptable limits (15–17). Results of a previous clinical study conducted in Japan suggest that 18F-fluciclovine may allow visualization of regional lymph node metastases of prostate cancer with a short-axis diameter of ≥5 mm but <10 mm, which are hard to diagnose using CT (14). However, pathology evaluation did not confirm the accumulation of 18F-fluciclovine in regional lymph node metastases. To address this issue, a phase II clinical study (NMK36-PC-P203) was conducted to evaluate the performance of 18F-fluciclovine in the diagnosis of regional lymph node metastases with a short-axis diameter of ≥5 mm to <10 mm in patients with primary prostate cancer confirmed by pathology. Patients and methods Study design This single-dose, multicenter, uncontrolled, open-label, phase II study was conducted at 21 institutions in Japan (Table 1) from December 2014 to April 2016. The patients were thoroughly informed of the study in writing and gave written consent to participate prior to enrollment. This study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was reviewed and approved by the institutional review boards of the study institutions prior to study commencement. The registration ID of this study is JapicCTI-142 707. Table 1. Study institutions Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Table 1. Study institutions Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Participants Patients aged ≥20 years with untreated prostate cancer confirmed by prostate needle biopsy and a regional lymph node with a short-axis diameter of ≥5 mm to <10 mm detected by pelvic contrast-enhanced CT, who were scheduled for regional lymph node dissection, were included in this study. Patients who satisfied all the inclusion criteria and to whom none of the exclusion criteria applied were eligible to participate in the study. Inclusion criteria Patients aged ≥20 years as of the day of informed consent. Patients histopathologically diagnosed with prostate cancer by prostate needle biopsy performed within 90 days of informed consent. Patients with a regional lymph node area that included one regional prostate cancer lymph node (left and right obturator nodes, internal iliac node and/or external iliac node) with a short-axis diameter of ≥5 mm to <10 mm on pelvic contrast-enhanced CT screening (presence of multiple regional lymph node areas acceptable). Patients scheduled for regional lymph node dissection (total prostatectomy not mandatory). Patients who gave written consent. Exclusion criteria Patients who had received treatment for prostate cancer (e.g., surgery, radiation therapy, hormone therapy, or chemotherapy). Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of ≤5 years). Patients with a performance status of grade 3 or higher. Patients with a documented history of serious drug sensitivity. Patients who had received 18F-fluciclovine prior to participation in this study or other investigational drugs within 180 days of informed consent. Patients with bone marrow/hepatic/renal dysfunction diagnosed by screening of laboratory tests . Patients considered by the investigator to be otherwise ineligible to participate. Methods Screening After providing informed consent, patients were screened for eligibility using laboratory tests and pelvic contrast-enhanced CT to confirm the presence of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm. Pelvic contrast-enhanced CT was performed using a multi-slice (≥16 slice) CT device. CT images were taken at ≤2 mm of reconstruction slice thickness after injection of the contrast medium. The regional lymph node area including only one regional lymph node with a short-axis diameter of ≥5 mm to <10 mm (left and right obturator nodes, internal iliac node, or external iliac node) was identified in the transverse pelvic contrast-enhanced CT image. CT image data acquired in prior to informed consent was allowed to use for screening on condition that imaging conditions were consistent with those described above and 18F-fluciclovine PET/CT was acquired within 28 days after pelvic contrast-enhanced CT. Laboratory test data was allowed to use for screening on condition that it was obtained within 28 days in prior to informed consent. 18F-fluciclovine PET/CT A phantom study was conducted at all study institutions prior to this study to standardize PET image quality, establish imaging conditions for the PET/CT camera, and to fulfill the requirements of the Japanese Society of Nuclear Medicine (18). 18F-fluciclovine PET/CT was performed within 28 days of pelvic contrast-enhanced CT. Patients fasted for 4 hours before receiving 18F-fluciclovine. On the day of the examination, an entire vial of 18F-fluciclovine (2 mL; 185 MBq/2 mL) was intravenously injected as a single dose and then the site was flushed with normal saline. PET/CT was started within 10 minutes of 18F-fluciclovine injection, and images of the pelvis were taken by moving the device from the proximal femur towards the head at 2–5 min/bed. The investigational drug 18F-fluciclovine was manufactured in compliance with Good Manufacturing Practice for investigational drugs in the previously reported manufacturing process (19) and provided by Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). Regional lymph node dissection Left and right obturator, internal iliac, and external iliac nodes were dissected separately, and a lymph node with a short-axis diameter of ≥5 mm to <10 mm identified by pelvic contrast-enhanced CT was removed within 60 days of pelvic contrast-enhanced CT. The removed lymph node was sliced in 2-mm strips parallel to the short axis. Formalin-fixed, paraffin-embedded, hematoxylin and eosin (HE)-stained samples were prepared at the study institutions. Image analysis Two central image readers blind to patient information visually evaluated 18F-fluciclovine PET/CT-positive regional lymph nodes and reached a consensus result. Maximum standardized uptake value (SUVmax) of 1.5 to ≤2.0 was used as the criterion for positive evaluation when visual assessment was difficult. The confirmed 18F-fluciclovine PET/CT findings were compared with the pelvic contrast-enhanced CT image taken at the study institution to determine if the lymph node with a short-axis diameter of ≥5 mm to <10 mm was identified as positive or negative by 18F-fluciclovine PET/CT. Pathology One central pathologist blind to the patient information evaluated HE-stained samples submitted by the study institutions. Safety assessment Subjective and objective symptoms and vital signs were documented, and 12-lead electrocardiogram (ECG) and laboratory tests (hematologic, blood biochemistry, and urine tests) were performed at baseline and within 6 days of 18F-fluciclovine injection. Pre- and post-injection findings were compared to evaluate the safety of 18F-fluciclovine. Data analysis The primary endpoint of this study was the sensitivity of 18F-fluciclovine PET/CT in diagnosing regional prostate cancer lymph nodes with a short-axis diameter of ≥5 mm to <10 mm detected by pelvic contrast-enhanced CT. The secondary endpoints included specificity, diagnostic accuracy, positive predictive value (PPV), and negative predictive value (NPV). Subjective and objective symptoms, signs, ECG, vital signs, and laboratory tests (hematologic, blood biochemistry, and urine tests) were evaluated before and within 6 days after injection of 18F-fluciclovine, and adverse event information was collected for safety assessment. The target sample size was calculated as follows. The expected sensitivity to detect regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm (the primary endpoint) was hypothesized to be 55% based on the results of the aforementioned phase II study (14). On this basis, 12 positive lymph nodes would be needed to ensure the lower limit of sensitivity exceeded 20%. Based on the pathological assessment of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, 24 regional lymph nodes would need to be evaluated for metastases to produce 50% positive results. The target sample size was determined to be 27 based on a hypothesized drop-out rate of 10% and the assumption that each patient would have at least one involved regional lymph node. The sensitivity, specificity, PPV, NPV, and 95% confidence interval (CI) were calculated for metastasis diagnosis with 18F-fluciclovine PET/CT in regional prostate cancer lymph nodes with a short-axis diameter of ≥5 mm to <10 mm found in pelvic contrast-enhanced CT images. The 95% CI for sensitivity (primary endpoint) was calculated using the normal approximation and the Clopper-Pearson methods. A normal approximation test was performed with a population rate of 0.2 based on the null hypothesis to ascertain if the sensitivity of 18F-fluciclovine PET/CT statistically exceeded the lower limit of diagnostic accuracy (20%) used to determine the number of lymph nodes needed for evaluation. Adverse events were classified using MedDRA/J Version 19.0. The total number and proportion of patients with adverse events were calculated. The number of patients with each event and the total number and incidence of each event were calculated to evaluate the severity, seriousness, and causal relationship with 18F-fluciclovine. A one-sided significance level of 2.5% was used for efficacy evaluation, unless otherwise noted. A two-sided significance level of 5.0% was used for safety assessment, unless otherwise noted. Two-sided interval estimation was performed, unless otherwise noted. A confidence coefficient of 95% was used with the Clopper-Pearson method. SAS Version 9.3 was used for statistical processing. Results Patient flow and demographics Of the 38 patients who provided informed consent to participate in this study, 29 eligible patients received 18F-fluciclovine and underwent total prostatectomy with regional lymph node dissection. The study was discontinued in one patient because target lymph node could not be dissected. Twenty-eight patients completed the study (Fig. 1). Figure 1. View largeDownload slide Patient flow through study. Figure 1. View largeDownload slide Patient flow through study. Patient demographics are shown in Table 2. The mean age of the 29 patients was 67.9 years. The mean prostate-specific antigen (PSA) level was 17.9 mg/mL. Gleason score was 7 in 12 patients (41.4%) and 8 or higher in 16 patients (55.2%). T-stage classification was T2c or lower (localized cancer) in 18 patients (62.1%) and T3a or higher (invasive cancer) in 11 patients (37.9%). All 29 patients received the entire vial of 18F-fluciclovine. The administered activity was 105.2 to 266.6 MBq. Table 2. Baseline patient demographics N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 PSA, prostate-specific antigen; SD, standard deviation. Table 2. Baseline patient demographics N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 PSA, prostate-specific antigen; SD, standard deviation. Efficacy Primary endpoint Accuracy of 18F-fluciclovine PET/CT to diagnose the regional lymph nodes of 28 prostate cancer patients included in the efficacy evaluation is shown in Table 3. The sensitivity in diagnosing metastases in the regional lymph nodes (n = 40) was 57.1% (4/7 nodes; Clopper-Pearson method 95% CI: 18.4, 90.1; normal approximation method 95% CI: 20.5, 93.8). The normal approximation test showed that the diagnostic sensitivity of 18F-fluciclovine PET/CT was significantly higher than the lower limit of diagnostic sensitivity (20%) used to determine the number of lymph nodes needed (P = 0.024). The patient-based analysis showed a sensitivity of 66.7% (4/6 patients; Clopper-Pearson method 95% CI: 22.3, 95.7). The results of 18F-fluciclovine PET/CT of seven lymph nodes reported as positive for metastasis by central pathology are shown in Table 4. All four lymph nodes determined to be true positive by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm according to pathology. At 60%, 70%, 95%, and 100%, the approximate proportion of cancer volume in these lymph nodes was high. A typical image of 18F-fluciclovine PET/CT is shown in Fig. 2. The left obturator lymph node (arrow) had a high uptake of 18F-fluciclovine (SUVmax = 3.03), resulting in a true positive finding. However, the high uptake of 18F-fluciclovine (SUVmax = 4.85) in the right obturator region (arrow head) was incorrectly determined to be the uptake in the digestive tract, resulting in a false negative finding. The other two false-negative lymph nodes had a metastatic lesion with a long-axis diameter of 5.0 mm and 4.7 mm, according to pathology. The approximate proportion of cancer volume in these lymph nodes was lower, at 50% and 10%. Table 3. Precision of 18F-fluciclovine PET/CT in the diagnosis of regional lymph node metastasis in patients with prostate cancer 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 CI, confidence interval; CT, computed tomography; NPV, negative predictive value; PET, positron emission tomography; PPV, positive predictive value. Table 3. Precision of 18F-fluciclovine PET/CT in the diagnosis of regional lymph node metastasis in patients with prostate cancer 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 CI, confidence interval; CT, computed tomography; NPV, negative predictive value; PET, positron emission tomography; PPV, positive predictive value. Table 4. Diagnosis of pathology-positive lymph node by 18F-fluciclovine PET/CT. No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative aDeviation: the pathological sample was prepared by slicing in parallel to the long axial direction as opposed to the short axial direction specified in the protocol. CT, computed tomography; PET, positron emission tomography Table 4. Diagnosis of pathology-positive lymph node by 18F-fluciclovine PET/CT. No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative aDeviation: the pathological sample was prepared by slicing in parallel to the long axial direction as opposed to the short axial direction specified in the protocol. CT, computed tomography; PET, positron emission tomography Figure 2. View largeDownload slide Axial images of (a) CT, (b) 18F-fluciclovine PET, and (c) 18F-fluciclovine PET/CT in a patient with lymph node metastases. The patient was a 68-year old man with an initial PSA of 35.9 ng/mL, a Gleason score of 4 + 5, and T2c. High uptake of 18F-fluciclovine was detected in the left obturator lymph node (arrow) with an SUVmax of 3.03. There was also high uptake in right obturator region (arrow head) with an SUVmax of 4.86; however, central image readers concluded that this was uptake in the intestine. Lymph node dissection and pathology evaluation revealed that both the left and the right obturator lymph nodes contained metastases, concluding that the assessment of the left lymph node (arrow) was a true positive, while the assessment of the right lymph node (arrow head) was a false negative. Figure 2. View largeDownload slide Axial images of (a) CT, (b) 18F-fluciclovine PET, and (c) 18F-fluciclovine PET/CT in a patient with lymph node metastases. The patient was a 68-year old man with an initial PSA of 35.9 ng/mL, a Gleason score of 4 + 5, and T2c. High uptake of 18F-fluciclovine was detected in the left obturator lymph node (arrow) with an SUVmax of 3.03. There was also high uptake in right obturator region (arrow head) with an SUVmax of 4.86; however, central image readers concluded that this was uptake in the intestine. Lymph node dissection and pathology evaluation revealed that both the left and the right obturator lymph nodes contained metastases, concluding that the assessment of the left lymph node (arrow) was a true positive, while the assessment of the right lymph node (arrow head) was a false negative. Secondary endpoints The specificity, diagnostic accuracy, PPV, and NPV of lymph node-based metastasis diagnosis was 84.8% (28/33 nodes), 80.0% (32/40 nodes), 44.4% (4/9 nodes), and 90.3% (28/31 nodes), respectively (Table 3). The patient-based analysis yielded a specificity of 86.4% (19/22 patients), diagnostic accuracy of 82.1% (23/28 patients), PPV of 57.1% (4/7 patients), and NPV of 90.5% (19/21 patients). Safety assessment Three adverse events were reported in 2 of the 29 patients (6.9%). Specifically, headache and vessel puncture site erythema due to blood sample collection occurred in one patient on day 2, while postural dizziness occurred in one patient on day 3 (3.4% each). None of the events were serious and all resolved without treatment. A causal relationship with 18F-fluciclovine was not found for these events. No clinically significant adverse events were reported in this study. Discussion This study evaluated the performance of 18F-fluciclovine PET/CT in the diagnosis of metastasis to regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, using pathology results as the gold standard. Of the 40 lymph nodes evaluated, the presence of metastases was confirmed by pathology in seven nodes, and four of these nodes were found to be positive for metastases by 18F-fluciclovine. The diagnostic sensitivity of 18F-fluciclovine PET/CT was, therefore, 57.1%. This was the first study conducted in Japan to report pathologically confirmed accumulation of 18F-fluciclovine in the lymph node metastases of prostate cancer. Use of new PET tracers such as 11C-choline, 18F-choline, and prostate-specific membrane antigen (PSMA) ligands to diagnose lymph node metastases of prostate cancer has been evaluated previously. Although a direct comparison would be impractical, the reported sensitivity of lymph node-based diagnosis of regional lymph node metastases of primary prostate cancer with 11C-choline and 18F-choline was 41–66% (20–23), which is comparable to the sensitivity of 18F-fluciclovine PET/CT reported in this study. These studies reported that metastasis to small lymph nodes with a short-axis diameter of <5 mm could not be detected by PET/CT, as reported with 18F-fluciclovine (14). In contrast, 68Ga-PSMA has been shown to have better diagnostic performance, detecting metastasis to lymph nodes with a short-axis diameter of <5 mm in some patients (24–26). However, further studies are needed, because PSMA is non-uniformly expressed in prostate cancer and may not be overexpressed in all patients (27,28). In traditional diagnosis with CT or MRI, a short-axis diameter of ≥10 mm is generally considered to indicate the presence of lymph node metastases, while <10 mm is considered to indicate that metastases are absent. This study suggests that about half of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, that would be overlooked in the traditional contrast-enhanced CT examination, may be detected by 18F-fluciclovine PET/CT. Diagnosing lymph node metastases with 18F-fluciclovine PET/CT in place of CT or MRI may be useful for more complete patient management, given that the presence or absence of lymph node metastasis is an important factor for choosing optimal treatment and establishing a prognosis. In the present study, all four lymph nodes evaluated and determined to be true positives by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm according to pathology. At 60–100%, the approximate proportion of cancer volume in the lymph node was high. Of the three lymph nodes evaluated and determined to be false negatives by 18F-fluciclovine PET/CT, lymph node accumulation could not be distinguished from gastrointestinal accumulation in one lymph node, leading to the incorrect diagnosis. The remaining two lymph nodes both had a metastatic lesion with a long-axis diameter of ≤5.0 mm according to pathology, with approximate cancer volumes of 50% and 10%. Lymph node metastases with a long-axis diameter of ≤5 mm could not be detected by 18F-fluciclovine PET/CT in patients who had undergone total prostatectomy in the aforementioned phase II study (14), suggesting a limitation of PET resolution. Thus, 18F-fluciclovine PET/CT may only be able to detect a certain size of regional lymph node metastasis. Further research is needed to confirm this finding. In one instance, the reason for a false-negative assessment was the high 18F-fluciclovine accumulation in the lymph node that appeared to be continuous with the faint 18F-fluciclovine signal in the digestive tract (Fig. 2). Careful assessment that includes checking the gastrointestinal continuum in triaxial (cross-sectional, coronal, and sagittal) images is therefore necessary when a lymph node is hard to distinguish from the digestive tract, despite high nodular accumulation of 18F-fluciclovine. The current criteria for diagnostic imaging need to be reviewed to improve the diagnostic performance of 18F-fluciclovine PET/CT. While the lymph node-based metastasis diagnosis had good specificity and NPV, PPV was 44.4% (4/9 nodes). Five lymph nodes from three patients were false-positive for metastases, according to 18F-fluciclovine PET/CT. The false-positive assessment may have been caused by accumulation of 18F-fluciclovine in the inflammatory lymph node. An animal study suggested that the accumulation of 18F-fluciclovine in inflammatory tissues was low compared with those in tumor tissue (29); however, accumulation was relatively high in chronic inflammation compared with acute inflammation (30). Therefore, the false-positive findings of 18F-fluciclovine reported in this study may have been due to its accumulation in the mildly enlarged lymph nodes associated with chronic inflammation. During the pathological examination, lymph nodes were assessed for primary follicular hyperplasia, secondary follicular hyperplasia, marginal sinus hyperplasia, lymphatic sinus hyperplasia, sinus histiocytosis, hyalinization, and fibrosis in the evaluated lymph nodes; and no apparent differences between the false-positive lymph nodes and other lymph nodes were observed. Additional research is necessary to explore the cause of false-positive findings. In the present study, diagnostic performance of 18F-fluciclovine PET/CT for bone metastasis was not evaluated, however the previous study (14) suggested the possibility of 18F-fluciclovine PET/CT for early detection of bone metastasis compared to conventional bone scan. Amzat et al. (31) also reported the case that 18F-fluciclovine PET/CT visualized osteolytic bone metastasis which was not detected by bone scintigraphy. 18F-fluciclovine PET/CT may be useful for not only N-staging but also for M-staging, however further study is necessary to assess the usefulness of 18F-fluciclovine PET/CT for NM staging. No clinically significant adverse events were reported in this study. Neither the previous 18F-fluciclovine study, nor an overseas study of a diagnostic radiopharmaceutical containing the same active ingredient as that in 18F-fluciclovine, reported any serious adverse reactions. Therefore, it is likely that there will not be any safety issues associated with the use of 18F-fluciclovine. This study had a number of limitations. Firstly, although the study protocol hypothesized that the positive rate for metastases in regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm would be 50%, only 7 of the 40 nodes (17.5%) were actually positive for metastases. The sample size used in this study was, therefore, too small for the evaluation of sensitivity and PPV. A future study should use a larger sample size. Secondly, the current criteria for diagnostic imaging have not been adequately reviewed because only limited data are available for 18F-fluciclovine in patients with primary prostate cancer. Reviewing the criteria for diagnostic imaging may improve the diagnostic performance of 18F-fluciclovine PET/CT. Conclusion Four out of seven regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm were determined to be true positive for prostate cancer metastases by 18F-fluciclovine PET/CT. The diagnostic sensitivity of 18F-fluciclovine PET/CT was 57.1%. However, 18F-fluciclovine PET/CT produced a false-positive result in five lymph nodes, which resulted in a low PPV of 44%. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT in detecting small lymph node metastases in patients with prostate cancer. Acknowledgments We would like to thank the following doctors who helped us to plan, implement and evaluate this study, as well as providing support and giving suggestions: Dr. Keiichi Ishihara (deceased) (Department of Radiology, Nippon Medical School), Dr. Yasushi Takagi (School of Medicine, Showa University), Dr. Keiichi Matsumoto (Faculty of Radiology, Kyoto College of Medical Science), Dr. Shin Egawa (Department of Urology, The Jikei University), Dr. Youichi Ito (Department of Biostatics, Hokkaido University Graduate School of Medicine), Dr. Junji Yonese (Department of Urology, Cancer Institute Hospital), Dr. Kazunari Tanabe (Department of Urology, Tokyo Women’s Medical University), Dr. Masafumi Oyama (Department of Urologic Oncology, Saitama Medical University International Medical Center), Dr. Masashi Niwakawa (Department of Urology, Shizuoka Cancer Center) and Dr. Ryoichi Shiroki (Department of Urology, Fujita Health University School of Medicine). We also thank the sub-investigators at the study institutions and the study coordinators, including clinical research coordinators (CRCs), and radiological technologists. Springer Healthcare Business Unit of Springer Japan KK assisted with the preparation of this manuscript. We would also like to thank Marie Cheeseman, who edited and styled the manuscript before submission on behalf of Springer Healthcare Communications. This medical writing support was supported by Nihon Medi-Physics Co., Ltd. Funding This study was sponsored by Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). Nihon Medi-Physics covered the expenses for the preparation of the study report. Conflict of interest statement Hiroyoshi Suzuki received an honorarium from Nihon Medi-Physics for serving as the medical specialist. Hiroyoshi Suzuki also received honoraria and/or research fundings from Astellas Pharma Inc., Takeda pharmaceutical company Ltd., Astra Zeneca, Novartis Pharma, Daiichi-Sankyo, Bayer and Janssen Pharmaceutical. Seishi Jinnouchi received an honorarium from Nihon Medi-Physics for serving as the medical specialist and lectures. Yoshiyuki Kakehi received an honorarium from Nihon Medi-Physics for serving as the coordinating investigator. Yoshiyuki Kakehi also received honoraria and/or research fundings from Astellas Pharma Inc., Takeda pharmaceutical company Ltd., Astra Zeneca, Bayer and Janssen Pharmaceutical. Yasushi Kaji received an honorarium for serving as the coordinating investigator and research funding from Nihon Medi-Physics. Koji Murakami received honoraria serving as members of the Central Imaging Evaluation Committee and for lectures and research funding from Nihon Medi-Physics. Kazuhiro Yoshimura, Yasushi Yoshino, Junya Furukawa, and Hisashi Hasumi received research fundings from Nihon Medi-Physics. Mutsushi Kawakita received honoraria and/or research fundings from Astra Zeneca and Medicaroid. Takeshi Kishida, Hidefumi Kinoshita, Seiji Yamaguchi, Toyofusa Tobe, Takehiko Okamura, Satoshi Fukasawa, Hiroyuki Fujimoto, Ryoei Hara, Junichi Ota, Yukio Kageyama, Masahiro Yashi and Hiroyuki Takahashi have no conflict of interest to declare. Akiharu Otaka is an employee of Nihon Medi-Physics. Authors’ contributions Hiroyoshi Suzuki and Seishi Jinnouchi were the medical experts in this study, involved in the study planning and design, as well as interpretation of the study results. Yoshiyuki Kakehi and Yasushi Kaji were the coordinating investigators and were involved in the study implementation and interpretation of the study results. Takeshi Kishida, Hidefumi Kinoshita, Seiji Yamaguchi, Toyofusa Tobe, Takehiko Okamura, Mutsushi Kawakita, Junya Furukawa, Satoshi Fukasawa, Hiroyuki Fujimoto, Kazuhiro Yoshimura, Ryoei Hara, Yasushi Yoshino, Hisashi Hasumi, Junichi Ota, Yukio Kageyama, and Masahiro Yashi were the investigators and were involved in the study implementation and interpretation of the study results. Koji Murakami was the central image reader, Hiroyuki Takahashi was the central pathologist, and both were involved in the study implementation. Akiharu Otaka is an employee of the sponsor company and was involved in the study planning and design, study management, data analysis, and interpretation of study results. All the authors were involved in the preparation of this study report and approved the final draft. References 1 Sobue T , Saika K , Matsuda A , et al. Future Estimation of Cancer Incidence in Japan . 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Google Scholar PubMed 10 Bach-Gansmo T , Nanni C , Nieh PT , et al. Multisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) positron emission tomography/computerized tomography imaging in the staging of biochemically recurrent prostate cancer . J Urol 2017 ; 197 : 676 – 83 . Google Scholar Crossref Search ADS PubMed 11 Nanni C , Zanoni L , Pultrone C , et al. 18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial . Eur J Nucl Med Mol Imaging 2016 ; 43 : 1601 – 10 . Google Scholar Crossref Search ADS PubMed 12 Schuster DM , Nieh PT , Jani AB , et al. Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial . J Urol 2014 ; 191 : 1446 – 53 . 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Google Scholar Crossref Search ADS PubMed 17 Wakabayashi T , Iuchi T , Tsuyuguchi N , et al. Diagnostic performance and safety of positron emission tomography using 18F-fluciclovine in patients with clinically suspected high- or low-grade gliomas: a multicenter phase IIb trial . Asia Ocean J Nucl Med Biol 2017 ; 5 : 10 – 21 . Google Scholar PubMed 18 Fukukita H , Senda M , Terauchi T , et al. Japanese guideline for the oncology FDG-PET/CT data acquisition protocol: synopsis of Version 1.0 . Ann Nucl Med 2010 ; 24 : 325 – 34 . Google Scholar Crossref Search ADS PubMed 19 McConathy J , Voll RJ , Yu W , Crowe RJ , Goodman MM . Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis . Appl Radiat Isot 2003 ; 58 : 657 – 66 . Google Scholar Crossref Search ADS PubMed 20 Contractor K , Challapalli A , Barwick T , et al. 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The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis . Eur Urol 2013 ; 64 : 106 – 17 . Google Scholar Crossref Search ADS PubMed 24 Herlemann A , Wenter V , Kretschmer A , et al. 68Ga-PSMA positron emission tomography/computed tomography provides accurate staging of lymph node regions prior to lymph node dissection in patients with prostate cancer . Eur Urol 2016 ; 70 : 553 – 7 . Google Scholar Crossref Search ADS PubMed 25 Hijazi S , Meller B , Leitsmann C , et al. Pelvic lymph node dissection for nodal oligometastatic prostate cancer detected by 68Ga-PSMA-positron emission tomography/computerized tomography . Prostate 2015 ; 75 : 1934 – 40 . Google Scholar Crossref Search ADS PubMed 26 Maurer T , Gschwend JE , Rauscher I , et al. Diagnostic efficacy of (68)gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer . J Urol 2016 ; 195 : 1436 – 43 . Google Scholar Crossref Search ADS PubMed 27 Mannweiler S , Amersdorfer P , Trajanoski S , Terrett JA , King D , Mehes G . Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis . Pathol Oncol Res 2009 ; 15 : 167 – 72 . Google Scholar Crossref Search ADS PubMed 28 Silver DA , Pellicer I , Fair WR , Heston WD , Cordon-Cardo C . Prostate-specific membrane antigen expression in normal and malignant human tissues . Clin Cancer Res 1997 ; 3 : 81 – 5 . Google Scholar PubMed 29 Oka S , Hattori R , Kurosaki F , et al. A preliminary study of anti-1-amino-3-18F-fluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer . J Nucl Med 2007 ; 48 : 46 – 55 . 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Google Scholar Crossref Search ADS PubMed Appendix The following authors have contributed equally to this study in addition to the authors listed on the title page: Satoshi Fukasawa (Prostate Center and Division of Urology, Chiba Cancer Center, Chiba, Japan), Hiroyuki Fujimoto (Department of Urology, National Cancer Center Hospital, Chuo-ku, Japan), Kazuhiro Yoshimura (Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan), Ryoei Hara (Department of Urology, Kawasaki Medical School, Kurashiki, Japan), Yasushi Yoshino (Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan), Hisashi Hasumi (Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan), Junichi Ota (Department of Urology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan), Yukio Kageyama (Department of Urology, Saitama Cancer Center, Kitaadachi-gun, Japan), Masahiro Yashi (Department of Urology, Dokkyo Medical University, Shimotsuga-gun, Japan), Koji Murakami (Department of Radiology, School of Medicine, Keio University, Shinjuku-ku, Japan), Hiroyuki Takahashi (Department of Pathology, The Jikei University School of Medicine, Minato-ku, Japan). © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Diagnostic performance of 18F-fluciclovine PET/CT for regional lymph node metastases in patients with primary prostate cancer: a multicenter phase II clinical trial

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Abstract

Abstract Objective This multicenter, phase II clinical trial evaluated the diagnostic performance of 18F-fluciclovine, a novel amino acid for positron-emission tomography (PET), for detection of small lymph node metastases with short-axis diameters of 5–10 mm in patients with prostate cancer. Methods Patients with prostate cancer were eligible after screening of laboratory tests and pelvic contrast-enhanced computed tomography (CT). Pelvic region 18F-fluciclovine PET/CT was then acquired within 28 days and dissection of regional lymph nodes was performed within 60 days of pelvic contrast-enhanced CT. Diagnostic performance of 18F-fluciclovine-PET/CT was evaluated by comparison with standard histopathology of lymph nodes. Results In a total of 28 patients, 40 regional lymph nodes with short-axis diameters of 5–10 mm were eligible for efficacy evaluation; seven of these showed metastases confirmed by histopathology. The sensitivity of 18F-fluciclovine PET/CT was 57.1% (4/7). All four true positive lymph nodes detected by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm and a high proportion of cancer volume (60–100%) according to pathology evaluation. The specificity, diagnostic accuracy, positive predictive value, and negative predictive value of 18F-fluciclovine PET/CT in lymph node-based analysis were 84.8% (28/33), 80.0% (32/40), 44.4% (4/9), and 90.3% (28/31), respectively. No clinically significant adverse events occurred. Conclusions 18F-fluciclovine PET/CT detected small lymph node metastases; however it also showed positive findings in benign lymph nodes. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT for small lymph node metastases in patients with prostate cancer. clinical trial, fluciclovine F-18, lymphatic metastasis, positron-emission tomography, prostate cancer Introduction The prevalence and associated mortality of prostate cancer is increasing in Japan, as well as in the USA and Europe. More specifically, the prevalence of prostate cancer in Japan is expected to increase from about 65 400 in 2010 to about 105,800 in 2020, with an increase in the associated mortality from 11 600 to 14 700 (1). The main management options for prostate cancer include surgery, radiation therapy, drug therapy (endocrine therapy), and active surveillance. The guidelines for prostate cancer treatment, such as those developed by the National Comprehensive Cancer Network (NCCN) (2) and the Japanese Urological Association (3), recommend selecting a treatment option most appropriate for the cancer stage. Specifically, radical treatment, such as total prostatectomy and radiation therapy, or active surveillance are recommended in patients with no lymph node or bone metastases, while endocrine therapy is indicated when the cancer is metastatic (2,3). Lymph node metastases are usually detected by computed tomography (CT) or magnetic resonance imaging (MRI), with both diagnostic methods using morphological change in lymph nodes (size and shape) as the diagnostic criterion. However, the reported performance of CT and MRI in diagnosing lymph node metastases is inconsistent because the size of the lymph node does not necessarily correlate with the presence or absence of prostate cancer metastases (4) and the criteria for interpreting test results (e.g., threshold of positive lymph node size) differ between institutions (5). 18F-fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), is a new positron-emission tomography (PET) tracer developed by Shoup and Goodman, which consists of a synthetic amino acid (1-aminocyclobutane carbonate [ACBC]) labeled with 18F (6). It accumulates in the tumor in response to an increase in amino acid metabolism (7,8). The background radioactivity in the pelvis is low because 18F-fluciclovine is slowly excreted into the bladder. Therefore, 18F-fluciclovine allows for clear visualization of the primary prostate cancer and lymph node metastases, while 18F-fludeoxyglucose (18F-FDG) does not, as it is excreted via the bladder in patients with primary or recurrent prostate cancer (9). Promising data have been reported on the use of 18F-fluciclovine in the detection of recurrent prostate cancer (10–12), and it was recently approved in both the USA and Europe for this indication. 18F-fluciclovine is also expected to be useful for initial staging of prostate cancer, and its performance in this indication has been evaluated in clinical trials conducted in Japan (13,14). Visualization of the primary prostate cancer lesions, lymph node metastases, bone metastases, and lung metastases was reported in an early clinical trial (13). No serious adverse events have been reported in association with 18F-fluciclovine and the level of radiation exposure was within acceptable limits (15–17). Results of a previous clinical study conducted in Japan suggest that 18F-fluciclovine may allow visualization of regional lymph node metastases of prostate cancer with a short-axis diameter of ≥5 mm but <10 mm, which are hard to diagnose using CT (14). However, pathology evaluation did not confirm the accumulation of 18F-fluciclovine in regional lymph node metastases. To address this issue, a phase II clinical study (NMK36-PC-P203) was conducted to evaluate the performance of 18F-fluciclovine in the diagnosis of regional lymph node metastases with a short-axis diameter of ≥5 mm to <10 mm in patients with primary prostate cancer confirmed by pathology. Patients and methods Study design This single-dose, multicenter, uncontrolled, open-label, phase II study was conducted at 21 institutions in Japan (Table 1) from December 2014 to April 2016. The patients were thoroughly informed of the study in writing and gave written consent to participate prior to enrollment. This study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was reviewed and approved by the institutional review boards of the study institutions prior to study commencement. The registration ID of this study is JapicCTI-142 707. Table 1. Study institutions Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Table 1. Study institutions Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Study institutions Chiba Cancer Center Saiseikai Utsunomiya Hospital Cancer Institute Hospital National Cancer Center Hospital Tokyo Women’s Medical University Hospital Kanagawa Cancer Center Saitama Medical University International Medical Center Shizuoka Cancer Center Anjo Kosei Hospital Fujita Health University Hospital Kansai Medical University Hospital Kindai University Hospital Osaka General Medical Center Kobe City Medical Center General Hospital Kawasaki Medical School Hospital Nagoya University Hospital Kobe University Hospital Yokohama City University Hospital Yokohama Municipal Citizen’s Hospital Saitama Cancer Center Dokkyo Medical University Hospital Participants Patients aged ≥20 years with untreated prostate cancer confirmed by prostate needle biopsy and a regional lymph node with a short-axis diameter of ≥5 mm to <10 mm detected by pelvic contrast-enhanced CT, who were scheduled for regional lymph node dissection, were included in this study. Patients who satisfied all the inclusion criteria and to whom none of the exclusion criteria applied were eligible to participate in the study. Inclusion criteria Patients aged ≥20 years as of the day of informed consent. Patients histopathologically diagnosed with prostate cancer by prostate needle biopsy performed within 90 days of informed consent. Patients with a regional lymph node area that included one regional prostate cancer lymph node (left and right obturator nodes, internal iliac node and/or external iliac node) with a short-axis diameter of ≥5 mm to <10 mm on pelvic contrast-enhanced CT screening (presence of multiple regional lymph node areas acceptable). Patients scheduled for regional lymph node dissection (total prostatectomy not mandatory). Patients who gave written consent. Exclusion criteria Patients who had received treatment for prostate cancer (e.g., surgery, radiation therapy, hormone therapy, or chemotherapy). Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of ≤5 years). Patients with a performance status of grade 3 or higher. Patients with a documented history of serious drug sensitivity. Patients who had received 18F-fluciclovine prior to participation in this study or other investigational drugs within 180 days of informed consent. Patients with bone marrow/hepatic/renal dysfunction diagnosed by screening of laboratory tests . Patients considered by the investigator to be otherwise ineligible to participate. Methods Screening After providing informed consent, patients were screened for eligibility using laboratory tests and pelvic contrast-enhanced CT to confirm the presence of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm. Pelvic contrast-enhanced CT was performed using a multi-slice (≥16 slice) CT device. CT images were taken at ≤2 mm of reconstruction slice thickness after injection of the contrast medium. The regional lymph node area including only one regional lymph node with a short-axis diameter of ≥5 mm to <10 mm (left and right obturator nodes, internal iliac node, or external iliac node) was identified in the transverse pelvic contrast-enhanced CT image. CT image data acquired in prior to informed consent was allowed to use for screening on condition that imaging conditions were consistent with those described above and 18F-fluciclovine PET/CT was acquired within 28 days after pelvic contrast-enhanced CT. Laboratory test data was allowed to use for screening on condition that it was obtained within 28 days in prior to informed consent. 18F-fluciclovine PET/CT A phantom study was conducted at all study institutions prior to this study to standardize PET image quality, establish imaging conditions for the PET/CT camera, and to fulfill the requirements of the Japanese Society of Nuclear Medicine (18). 18F-fluciclovine PET/CT was performed within 28 days of pelvic contrast-enhanced CT. Patients fasted for 4 hours before receiving 18F-fluciclovine. On the day of the examination, an entire vial of 18F-fluciclovine (2 mL; 185 MBq/2 mL) was intravenously injected as a single dose and then the site was flushed with normal saline. PET/CT was started within 10 minutes of 18F-fluciclovine injection, and images of the pelvis were taken by moving the device from the proximal femur towards the head at 2–5 min/bed. The investigational drug 18F-fluciclovine was manufactured in compliance with Good Manufacturing Practice for investigational drugs in the previously reported manufacturing process (19) and provided by Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). Regional lymph node dissection Left and right obturator, internal iliac, and external iliac nodes were dissected separately, and a lymph node with a short-axis diameter of ≥5 mm to <10 mm identified by pelvic contrast-enhanced CT was removed within 60 days of pelvic contrast-enhanced CT. The removed lymph node was sliced in 2-mm strips parallel to the short axis. Formalin-fixed, paraffin-embedded, hematoxylin and eosin (HE)-stained samples were prepared at the study institutions. Image analysis Two central image readers blind to patient information visually evaluated 18F-fluciclovine PET/CT-positive regional lymph nodes and reached a consensus result. Maximum standardized uptake value (SUVmax) of 1.5 to ≤2.0 was used as the criterion for positive evaluation when visual assessment was difficult. The confirmed 18F-fluciclovine PET/CT findings were compared with the pelvic contrast-enhanced CT image taken at the study institution to determine if the lymph node with a short-axis diameter of ≥5 mm to <10 mm was identified as positive or negative by 18F-fluciclovine PET/CT. Pathology One central pathologist blind to the patient information evaluated HE-stained samples submitted by the study institutions. Safety assessment Subjective and objective symptoms and vital signs were documented, and 12-lead electrocardiogram (ECG) and laboratory tests (hematologic, blood biochemistry, and urine tests) were performed at baseline and within 6 days of 18F-fluciclovine injection. Pre- and post-injection findings were compared to evaluate the safety of 18F-fluciclovine. Data analysis The primary endpoint of this study was the sensitivity of 18F-fluciclovine PET/CT in diagnosing regional prostate cancer lymph nodes with a short-axis diameter of ≥5 mm to <10 mm detected by pelvic contrast-enhanced CT. The secondary endpoints included specificity, diagnostic accuracy, positive predictive value (PPV), and negative predictive value (NPV). Subjective and objective symptoms, signs, ECG, vital signs, and laboratory tests (hematologic, blood biochemistry, and urine tests) were evaluated before and within 6 days after injection of 18F-fluciclovine, and adverse event information was collected for safety assessment. The target sample size was calculated as follows. The expected sensitivity to detect regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm (the primary endpoint) was hypothesized to be 55% based on the results of the aforementioned phase II study (14). On this basis, 12 positive lymph nodes would be needed to ensure the lower limit of sensitivity exceeded 20%. Based on the pathological assessment of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, 24 regional lymph nodes would need to be evaluated for metastases to produce 50% positive results. The target sample size was determined to be 27 based on a hypothesized drop-out rate of 10% and the assumption that each patient would have at least one involved regional lymph node. The sensitivity, specificity, PPV, NPV, and 95% confidence interval (CI) were calculated for metastasis diagnosis with 18F-fluciclovine PET/CT in regional prostate cancer lymph nodes with a short-axis diameter of ≥5 mm to <10 mm found in pelvic contrast-enhanced CT images. The 95% CI for sensitivity (primary endpoint) was calculated using the normal approximation and the Clopper-Pearson methods. A normal approximation test was performed with a population rate of 0.2 based on the null hypothesis to ascertain if the sensitivity of 18F-fluciclovine PET/CT statistically exceeded the lower limit of diagnostic accuracy (20%) used to determine the number of lymph nodes needed for evaluation. Adverse events were classified using MedDRA/J Version 19.0. The total number and proportion of patients with adverse events were calculated. The number of patients with each event and the total number and incidence of each event were calculated to evaluate the severity, seriousness, and causal relationship with 18F-fluciclovine. A one-sided significance level of 2.5% was used for efficacy evaluation, unless otherwise noted. A two-sided significance level of 5.0% was used for safety assessment, unless otherwise noted. Two-sided interval estimation was performed, unless otherwise noted. A confidence coefficient of 95% was used with the Clopper-Pearson method. SAS Version 9.3 was used for statistical processing. Results Patient flow and demographics Of the 38 patients who provided informed consent to participate in this study, 29 eligible patients received 18F-fluciclovine and underwent total prostatectomy with regional lymph node dissection. The study was discontinued in one patient because target lymph node could not be dissected. Twenty-eight patients completed the study (Fig. 1). Figure 1. View largeDownload slide Patient flow through study. Figure 1. View largeDownload slide Patient flow through study. Patient demographics are shown in Table 2. The mean age of the 29 patients was 67.9 years. The mean prostate-specific antigen (PSA) level was 17.9 mg/mL. Gleason score was 7 in 12 patients (41.4%) and 8 or higher in 16 patients (55.2%). T-stage classification was T2c or lower (localized cancer) in 18 patients (62.1%) and T3a or higher (invasive cancer) in 11 patients (37.9%). All 29 patients received the entire vial of 18F-fluciclovine. The administered activity was 105.2 to 266.6 MBq. Table 2. Baseline patient demographics N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 PSA, prostate-specific antigen; SD, standard deviation. Table 2. Baseline patient demographics N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 N = 29 Age (year)  Mean ± SD 67.9 ± 5.4  Median [range] 69 [57, 77] PSA (ng/mL)  Mean ± SD 17.94 ± 16.81  Median [range] 12.84 [1.20, 82.38] Gleason score; n (%)  ≤6 1 (3.4)  7 12 (41.4)  8 8 (27.6)  9 8 (27.6)  10 0 T-stage classification; n (%)  T1c 4 (13.8)  T2a 8 (27.6)  T2b 0  T2c 6 (20.7)  T3a 7 (24.1)  T3b 4 (13.8)  T4 0 PSA, prostate-specific antigen; SD, standard deviation. Efficacy Primary endpoint Accuracy of 18F-fluciclovine PET/CT to diagnose the regional lymph nodes of 28 prostate cancer patients included in the efficacy evaluation is shown in Table 3. The sensitivity in diagnosing metastases in the regional lymph nodes (n = 40) was 57.1% (4/7 nodes; Clopper-Pearson method 95% CI: 18.4, 90.1; normal approximation method 95% CI: 20.5, 93.8). The normal approximation test showed that the diagnostic sensitivity of 18F-fluciclovine PET/CT was significantly higher than the lower limit of diagnostic sensitivity (20%) used to determine the number of lymph nodes needed (P = 0.024). The patient-based analysis showed a sensitivity of 66.7% (4/6 patients; Clopper-Pearson method 95% CI: 22.3, 95.7). The results of 18F-fluciclovine PET/CT of seven lymph nodes reported as positive for metastasis by central pathology are shown in Table 4. All four lymph nodes determined to be true positive by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm according to pathology. At 60%, 70%, 95%, and 100%, the approximate proportion of cancer volume in these lymph nodes was high. A typical image of 18F-fluciclovine PET/CT is shown in Fig. 2. The left obturator lymph node (arrow) had a high uptake of 18F-fluciclovine (SUVmax = 3.03), resulting in a true positive finding. However, the high uptake of 18F-fluciclovine (SUVmax = 4.85) in the right obturator region (arrow head) was incorrectly determined to be the uptake in the digestive tract, resulting in a false negative finding. The other two false-negative lymph nodes had a metastatic lesion with a long-axis diameter of 5.0 mm and 4.7 mm, according to pathology. The approximate proportion of cancer volume in these lymph nodes was lower, at 50% and 10%. Table 3. Precision of 18F-fluciclovine PET/CT in the diagnosis of regional lymph node metastasis in patients with prostate cancer 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 CI, confidence interval; CT, computed tomography; NPV, negative predictive value; PET, positron emission tomography; PPV, positive predictive value. Table 3. Precision of 18F-fluciclovine PET/CT in the diagnosis of regional lymph node metastasis in patients with prostate cancer 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 18F-fluciclovine-PET/CT diagnostic imaging of lymph node metastasis Pathology of lymph node metastasis Sensitivity [95% CI] Specificity [95% CI] Diagnostic accuracy [95% CI] PPV [95% CI] NPV [95% CI] Positive Negative Total Lymph node based Positive 4 (10.0%) 5 (12.5%) 9 57.1% [18.4, 90.1] P = 0.024 84.8% [68.1, 94.9] 80.0% [64.4, 90.9] 44.4% [13.7, 78.8] 90.3% [74.2, 98.0] Negative 3 (7.5%) 28 (70.0%) 31 Total 7 33 40 Patient based Positive 4 (14.3%) 3 (10.7%) 7 66.7% [22.3, 95.7] 86.4% [65.1, 97.1] 82.1% [63.1, 93.9] 57.1% [18.4, 90.1] 90.5% [69.6, 98.8] Negative 2 (7.1%) 19 (67.9%) 21 Total 6 22 28 CI, confidence interval; CT, computed tomography; NPV, negative predictive value; PET, positron emission tomography; PPV, positive predictive value. Table 4. Diagnosis of pathology-positive lymph node by 18F-fluciclovine PET/CT. No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative aDeviation: the pathological sample was prepared by slicing in parallel to the long axial direction as opposed to the short axial direction specified in the protocol. CT, computed tomography; PET, positron emission tomography Table 4. Diagnosis of pathology-positive lymph node by 18F-fluciclovine PET/CT. No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative No. Region of lymph node Central pathology 18F-fluciclovine-PET/CT Standard diagnosis Gleason score Extranodal spread Approximate proportion of cancer volume in lymph node Metastasis Maximum diameter of metastatic lesion [mm] PET/CT findings Diagnosis 1 Left external iliac node Positive 22.0a 4 + 4 = 8 Positive 95% Positive True positive 2 Left obturator node Positive 7.5 3 + 4 = 7 Positive 60% Positive True positive 3 Right obturator node Positive 7.0 4 + 4 = 8 Negative 70% Positive True positive 4 Left obturator node Positive 16.0 4 + 5 = 9 Negative 100% Positive True positive 5 Right internal iliac node Positive 5.0 4 + 3 = 7 Negative 50% Negative False negative 6 Left external iliac node Positive 4.7 4 + 3 = 7 Negative 10% Negative False negative 7 Right obturator node Positive 13.0 4 + 5 = 9 Negative 100% Negative False negative aDeviation: the pathological sample was prepared by slicing in parallel to the long axial direction as opposed to the short axial direction specified in the protocol. CT, computed tomography; PET, positron emission tomography Figure 2. View largeDownload slide Axial images of (a) CT, (b) 18F-fluciclovine PET, and (c) 18F-fluciclovine PET/CT in a patient with lymph node metastases. The patient was a 68-year old man with an initial PSA of 35.9 ng/mL, a Gleason score of 4 + 5, and T2c. High uptake of 18F-fluciclovine was detected in the left obturator lymph node (arrow) with an SUVmax of 3.03. There was also high uptake in right obturator region (arrow head) with an SUVmax of 4.86; however, central image readers concluded that this was uptake in the intestine. Lymph node dissection and pathology evaluation revealed that both the left and the right obturator lymph nodes contained metastases, concluding that the assessment of the left lymph node (arrow) was a true positive, while the assessment of the right lymph node (arrow head) was a false negative. Figure 2. View largeDownload slide Axial images of (a) CT, (b) 18F-fluciclovine PET, and (c) 18F-fluciclovine PET/CT in a patient with lymph node metastases. The patient was a 68-year old man with an initial PSA of 35.9 ng/mL, a Gleason score of 4 + 5, and T2c. High uptake of 18F-fluciclovine was detected in the left obturator lymph node (arrow) with an SUVmax of 3.03. There was also high uptake in right obturator region (arrow head) with an SUVmax of 4.86; however, central image readers concluded that this was uptake in the intestine. Lymph node dissection and pathology evaluation revealed that both the left and the right obturator lymph nodes contained metastases, concluding that the assessment of the left lymph node (arrow) was a true positive, while the assessment of the right lymph node (arrow head) was a false negative. Secondary endpoints The specificity, diagnostic accuracy, PPV, and NPV of lymph node-based metastasis diagnosis was 84.8% (28/33 nodes), 80.0% (32/40 nodes), 44.4% (4/9 nodes), and 90.3% (28/31 nodes), respectively (Table 3). The patient-based analysis yielded a specificity of 86.4% (19/22 patients), diagnostic accuracy of 82.1% (23/28 patients), PPV of 57.1% (4/7 patients), and NPV of 90.5% (19/21 patients). Safety assessment Three adverse events were reported in 2 of the 29 patients (6.9%). Specifically, headache and vessel puncture site erythema due to blood sample collection occurred in one patient on day 2, while postural dizziness occurred in one patient on day 3 (3.4% each). None of the events were serious and all resolved without treatment. A causal relationship with 18F-fluciclovine was not found for these events. No clinically significant adverse events were reported in this study. Discussion This study evaluated the performance of 18F-fluciclovine PET/CT in the diagnosis of metastasis to regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, using pathology results as the gold standard. Of the 40 lymph nodes evaluated, the presence of metastases was confirmed by pathology in seven nodes, and four of these nodes were found to be positive for metastases by 18F-fluciclovine. The diagnostic sensitivity of 18F-fluciclovine PET/CT was, therefore, 57.1%. This was the first study conducted in Japan to report pathologically confirmed accumulation of 18F-fluciclovine in the lymph node metastases of prostate cancer. Use of new PET tracers such as 11C-choline, 18F-choline, and prostate-specific membrane antigen (PSMA) ligands to diagnose lymph node metastases of prostate cancer has been evaluated previously. Although a direct comparison would be impractical, the reported sensitivity of lymph node-based diagnosis of regional lymph node metastases of primary prostate cancer with 11C-choline and 18F-choline was 41–66% (20–23), which is comparable to the sensitivity of 18F-fluciclovine PET/CT reported in this study. These studies reported that metastasis to small lymph nodes with a short-axis diameter of <5 mm could not be detected by PET/CT, as reported with 18F-fluciclovine (14). In contrast, 68Ga-PSMA has been shown to have better diagnostic performance, detecting metastasis to lymph nodes with a short-axis diameter of <5 mm in some patients (24–26). However, further studies are needed, because PSMA is non-uniformly expressed in prostate cancer and may not be overexpressed in all patients (27,28). In traditional diagnosis with CT or MRI, a short-axis diameter of ≥10 mm is generally considered to indicate the presence of lymph node metastases, while <10 mm is considered to indicate that metastases are absent. This study suggests that about half of regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm, that would be overlooked in the traditional contrast-enhanced CT examination, may be detected by 18F-fluciclovine PET/CT. Diagnosing lymph node metastases with 18F-fluciclovine PET/CT in place of CT or MRI may be useful for more complete patient management, given that the presence or absence of lymph node metastasis is an important factor for choosing optimal treatment and establishing a prognosis. In the present study, all four lymph nodes evaluated and determined to be true positives by 18F-fluciclovine PET/CT had a metastatic lesion with a long-axis diameter of ≥7 mm according to pathology. At 60–100%, the approximate proportion of cancer volume in the lymph node was high. Of the three lymph nodes evaluated and determined to be false negatives by 18F-fluciclovine PET/CT, lymph node accumulation could not be distinguished from gastrointestinal accumulation in one lymph node, leading to the incorrect diagnosis. The remaining two lymph nodes both had a metastatic lesion with a long-axis diameter of ≤5.0 mm according to pathology, with approximate cancer volumes of 50% and 10%. Lymph node metastases with a long-axis diameter of ≤5 mm could not be detected by 18F-fluciclovine PET/CT in patients who had undergone total prostatectomy in the aforementioned phase II study (14), suggesting a limitation of PET resolution. Thus, 18F-fluciclovine PET/CT may only be able to detect a certain size of regional lymph node metastasis. Further research is needed to confirm this finding. In one instance, the reason for a false-negative assessment was the high 18F-fluciclovine accumulation in the lymph node that appeared to be continuous with the faint 18F-fluciclovine signal in the digestive tract (Fig. 2). Careful assessment that includes checking the gastrointestinal continuum in triaxial (cross-sectional, coronal, and sagittal) images is therefore necessary when a lymph node is hard to distinguish from the digestive tract, despite high nodular accumulation of 18F-fluciclovine. The current criteria for diagnostic imaging need to be reviewed to improve the diagnostic performance of 18F-fluciclovine PET/CT. While the lymph node-based metastasis diagnosis had good specificity and NPV, PPV was 44.4% (4/9 nodes). Five lymph nodes from three patients were false-positive for metastases, according to 18F-fluciclovine PET/CT. The false-positive assessment may have been caused by accumulation of 18F-fluciclovine in the inflammatory lymph node. An animal study suggested that the accumulation of 18F-fluciclovine in inflammatory tissues was low compared with those in tumor tissue (29); however, accumulation was relatively high in chronic inflammation compared with acute inflammation (30). Therefore, the false-positive findings of 18F-fluciclovine reported in this study may have been due to its accumulation in the mildly enlarged lymph nodes associated with chronic inflammation. During the pathological examination, lymph nodes were assessed for primary follicular hyperplasia, secondary follicular hyperplasia, marginal sinus hyperplasia, lymphatic sinus hyperplasia, sinus histiocytosis, hyalinization, and fibrosis in the evaluated lymph nodes; and no apparent differences between the false-positive lymph nodes and other lymph nodes were observed. Additional research is necessary to explore the cause of false-positive findings. In the present study, diagnostic performance of 18F-fluciclovine PET/CT for bone metastasis was not evaluated, however the previous study (14) suggested the possibility of 18F-fluciclovine PET/CT for early detection of bone metastasis compared to conventional bone scan. Amzat et al. (31) also reported the case that 18F-fluciclovine PET/CT visualized osteolytic bone metastasis which was not detected by bone scintigraphy. 18F-fluciclovine PET/CT may be useful for not only N-staging but also for M-staging, however further study is necessary to assess the usefulness of 18F-fluciclovine PET/CT for NM staging. No clinically significant adverse events were reported in this study. Neither the previous 18F-fluciclovine study, nor an overseas study of a diagnostic radiopharmaceutical containing the same active ingredient as that in 18F-fluciclovine, reported any serious adverse reactions. Therefore, it is likely that there will not be any safety issues associated with the use of 18F-fluciclovine. This study had a number of limitations. Firstly, although the study protocol hypothesized that the positive rate for metastases in regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm would be 50%, only 7 of the 40 nodes (17.5%) were actually positive for metastases. The sample size used in this study was, therefore, too small for the evaluation of sensitivity and PPV. A future study should use a larger sample size. Secondly, the current criteria for diagnostic imaging have not been adequately reviewed because only limited data are available for 18F-fluciclovine in patients with primary prostate cancer. Reviewing the criteria for diagnostic imaging may improve the diagnostic performance of 18F-fluciclovine PET/CT. Conclusion Four out of seven regional lymph nodes with a short-axis diameter of ≥5 mm to <10 mm were determined to be true positive for prostate cancer metastases by 18F-fluciclovine PET/CT. The diagnostic sensitivity of 18F-fluciclovine PET/CT was 57.1%. However, 18F-fluciclovine PET/CT produced a false-positive result in five lymph nodes, which resulted in a low PPV of 44%. Refinement of the image assessment criteria may improve the diagnostic performance of 18F-fluciclovine PET/CT in detecting small lymph node metastases in patients with prostate cancer. Acknowledgments We would like to thank the following doctors who helped us to plan, implement and evaluate this study, as well as providing support and giving suggestions: Dr. Keiichi Ishihara (deceased) (Department of Radiology, Nippon Medical School), Dr. Yasushi Takagi (School of Medicine, Showa University), Dr. Keiichi Matsumoto (Faculty of Radiology, Kyoto College of Medical Science), Dr. Shin Egawa (Department of Urology, The Jikei University), Dr. Youichi Ito (Department of Biostatics, Hokkaido University Graduate School of Medicine), Dr. Junji Yonese (Department of Urology, Cancer Institute Hospital), Dr. Kazunari Tanabe (Department of Urology, Tokyo Women’s Medical University), Dr. Masafumi Oyama (Department of Urologic Oncology, Saitama Medical University International Medical Center), Dr. Masashi Niwakawa (Department of Urology, Shizuoka Cancer Center) and Dr. Ryoichi Shiroki (Department of Urology, Fujita Health University School of Medicine). We also thank the sub-investigators at the study institutions and the study coordinators, including clinical research coordinators (CRCs), and radiological technologists. Springer Healthcare Business Unit of Springer Japan KK assisted with the preparation of this manuscript. We would also like to thank Marie Cheeseman, who edited and styled the manuscript before submission on behalf of Springer Healthcare Communications. This medical writing support was supported by Nihon Medi-Physics Co., Ltd. Funding This study was sponsored by Nihon Medi-Physics Co., Ltd. (Tokyo, Japan). Nihon Medi-Physics covered the expenses for the preparation of the study report. Conflict of interest statement Hiroyoshi Suzuki received an honorarium from Nihon Medi-Physics for serving as the medical specialist. Hiroyoshi Suzuki also received honoraria and/or research fundings from Astellas Pharma Inc., Takeda pharmaceutical company Ltd., Astra Zeneca, Novartis Pharma, Daiichi-Sankyo, Bayer and Janssen Pharmaceutical. Seishi Jinnouchi received an honorarium from Nihon Medi-Physics for serving as the medical specialist and lectures. Yoshiyuki Kakehi received an honorarium from Nihon Medi-Physics for serving as the coordinating investigator. Yoshiyuki Kakehi also received honoraria and/or research fundings from Astellas Pharma Inc., Takeda pharmaceutical company Ltd., Astra Zeneca, Bayer and Janssen Pharmaceutical. Yasushi Kaji received an honorarium for serving as the coordinating investigator and research funding from Nihon Medi-Physics. Koji Murakami received honoraria serving as members of the Central Imaging Evaluation Committee and for lectures and research funding from Nihon Medi-Physics. Kazuhiro Yoshimura, Yasushi Yoshino, Junya Furukawa, and Hisashi Hasumi received research fundings from Nihon Medi-Physics. Mutsushi Kawakita received honoraria and/or research fundings from Astra Zeneca and Medicaroid. Takeshi Kishida, Hidefumi Kinoshita, Seiji Yamaguchi, Toyofusa Tobe, Takehiko Okamura, Satoshi Fukasawa, Hiroyuki Fujimoto, Ryoei Hara, Junichi Ota, Yukio Kageyama, Masahiro Yashi and Hiroyuki Takahashi have no conflict of interest to declare. Akiharu Otaka is an employee of Nihon Medi-Physics. Authors’ contributions Hiroyoshi Suzuki and Seishi Jinnouchi were the medical experts in this study, involved in the study planning and design, as well as interpretation of the study results. Yoshiyuki Kakehi and Yasushi Kaji were the coordinating investigators and were involved in the study implementation and interpretation of the study results. 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Google Scholar Crossref Search ADS PubMed Appendix The following authors have contributed equally to this study in addition to the authors listed on the title page: Satoshi Fukasawa (Prostate Center and Division of Urology, Chiba Cancer Center, Chiba, Japan), Hiroyuki Fujimoto (Department of Urology, National Cancer Center Hospital, Chuo-ku, Japan), Kazuhiro Yoshimura (Department of Urology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan), Ryoei Hara (Department of Urology, Kawasaki Medical School, Kurashiki, Japan), Yasushi Yoshino (Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan), Hisashi Hasumi (Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan), Junichi Ota (Department of Urology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan), Yukio Kageyama (Department of Urology, Saitama Cancer Center, Kitaadachi-gun, Japan), Masahiro Yashi (Department of Urology, Dokkyo Medical University, Shimotsuga-gun, Japan), Koji Murakami (Department of Radiology, School of Medicine, Keio University, Shinjuku-ku, Japan), Hiroyuki Takahashi (Department of Pathology, The Jikei University School of Medicine, Minato-ku, Japan). © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Japanese Journal of Clinical OncologyOxford University Press

Published: Nov 9, 21

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