Frederik A. Verburg

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide–labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy. Methods: 68Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68Ga-PSMA-11 PET/CT. Results: Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. Conclusion: Targeted α-therapy with 225Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.

Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement

BACKGROUNDnEven though the presence of antithyroglobulin antibodies (TgAbs) represents a significant problem in the follow-up of patients with differentiated thyroid cancer (DTC), the current guidelines on the management of DTC that have been published in recent years contain no text concerning the methods to be used for detecting such antibody-related interference in thyroglobulin (Tg) measurement or how to manage TgAb-positive patients in whom Tg cannot be used reliably as a tumor marker.nnnAIMnAn international group of experts from the European Thyroid Association Cancer Research Network who are involved in the care of DTC patients met twice to form a consensus opinion on how to proceed with treatment and follow-up in TgAb-positive DTC patients based on the available evidence in the literature. Here we will report on the consensus opinions that were reached regarding technical and clinical issues.nnnRESULTSnThis clinical opinion article provides an overview of the available evidence and the resulting consensus recommendations. The current literature does not provide sufficient data for giving evidence-based answers to many questions arising in the care of TgAb-positive DTC patients. Where insufficient evidence was available, a thorough discussion by a group of physician-scientists, all of whom have a distinguished track record in thyroid cancer care, was held to arrive at a consensus expert opinion. The questions and answers discussed were then summarized into an algorithm for the management of TgAb-positive patients.nnnCONCLUSIONnWe were able to define 26 consensus expert recommendations and a resulting algorithm for the care of TgAb-positive DTC patients.

Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score.

PurposeTo examine the relationship between the extent of disease determined by [68Ga]PSMA-HBED-CC-PET/CT and the important clinical measures prostate-specific antigen (PSA), PSA doubling time (PSAdt) and Gleason score.MethodsWe retrospectively studied the first 155 patients with recurrent prostate cancer (PCA) referred to our university hospital for [68Ga]PSMA-HBED-CC PET/CT.ResultsPET/CT was positive in 44xa0%, 79xa0% and 89xa0% of patients with PSA levels of ≤1, 1xa0–xa02 and ≥2 ng/ml, respectively. Patients with high PSA levels showed higher rates of local prostate tumours (pu2009<u20090.001), and extrapelvic lymph node (pu2009=u20090.037) and bone metastases (pu2009=u20090.013). A shorter PSAdt was significantly associated with pelvic lymph node (pu2009=u20090.026), extrapelvic lymph node (pu2009=u20090.001), bone (pu2009<u20090.001) and visceral (pu2009=u20090.041) metastases. A high Gleason score was associated with more frequent pelvic lymph node metastases (pu2009=u20090.039). In multivariate analysis, both PSA and PSAdt were independent determinants of scan positivity and of extrapelvic lymph node metastases. PSAdt was the only independent marker of bone metastases (pu2009=u20090.001). Of 20 patients with a PSAdt <6xa0months and a PSA ≥2 ng/ml, 19 (95xa0%) had a positive scan and 12 (60xa0%) had M1a disease. Of 14 patients with PSA <1 ng/ml and PSAdt >6xa0months, only 5 (36xa0%) had a positive scan and 1 (7xa0%) had M1a disease.Conclusion[68Ga]PSMA-HBED-CC PET/CT will identify PCA lesions even in patients with very low PSA levels. Higher PSA levels and shorter PSAdt are independently associated with scan positivity and extrapelvic metastases, and can be used for patient selection for [68Ga]PSMA-HBED-CC PET/CT.

[ 68 Ga]PSMA-HBED uptake mimicking lymph node metastasis in coeliac ganglia: an important pitfall in clinical practice

PurposeTo determine the frequency of seemingly pathological retroperitoneal uptake in the location of the coeliac ganglia in patients undergoing [68Ga]PSMA-HBED PET/CT.MethodsThe study included 85 men with prostate cancer referred for [68Ga]PSMA-HBED PET/CT. The PET/CT scans were evaluated for the local finding in the prostate and the presence of lymph node metastases, distant metastases and coeliac ganglia. The corresponding standardized uptake values (SUV) were determined. SUVmax to background uptake (gluteal muscle SUVmean) ratios were calculated for the ganglia and lymph node metastases. Immunohistochemistry was performed on the ganglia.ResultsIn 76 of the 85 patients (89.4xa0%) at least one ganglion with tracer uptake was found. For the ganglia, SUVmax and SUVmax to background SUVmean ratios were 2.97xa0±xa00.88 and 7.98xa0±xa02.84 (range 1.57–6.38 and 2.83–30.6), respectively, and 82.8xa0% of all ganglia showed an uptake ratio of >5.0. For lymph node metastases, SUVmax and SUVmax to background SUVmean ratios were 8.5xa0±xa07.0 and 23.31xa0±xa022.23 (range 2.06–35.9 and 5.25–115.8), respectively. In 35 patients (41.2xa0%), no lymph node metastases were found but tracer uptake was seen in the ganglia. Immunohistochemistry confirmed strong PSMA expression in the ganglia.ConclusionCoeliac ganglia show a relevant [68Ga]PSMA-HBED uptake in most patients and may mimic lymph node metastases.

Detection of recurrent prostate cancer lesions before salvage lymphadenectomy is more accurate with (68)Ga-PSMA-HBED-CC than with (18)F-Fluoroethylcholine PET/CT.

Aim[68Ga]PSMA-HBED-CC (68Ga-PSMA) is a novel and promising tracer for highly sensitive combined integrated positron emission tomography and X-ray computed tomography (PET/CT) diagnosis of recurrent prostate cancer (PCA). Our aim was to assess the sensitivity, specificity, positive and negative predictive value (PPV/NPV), and accuracy per lesion, as well as the positive predictive value per patient of 68Ga-PSMA PET/CT using post-lymphadenectomy histology as a standard, and to compare these values to those obtained in a patient collective scanned using 18F-Fluoroethylcholine (18FEC) PET/CT.MethodsThirty eight patients had 18FEC and 28 patients had 68Ga-PSMA. We performed a pelvic and/or retroperitoneal lymphadenectomy, if necessary supplemented by resection of locally recurrent lesions in accordance with imaging results.ResultsIn 30/38 18FEC and 23/28 68Ga-PSMA patients ≥1 focus of PCA was identified in postsurgical histology, leading to a per-patient PPV of 78.9xa0% for 18FEC and 82.1xa0% for 68Ga-PSMA. In 18FEC and 68Ga-PSMA patients, a total of 378 and 308 lymph nodes and local lesions were removed, respectively. For 18FEC and 68for Ga-PSMA, the respective sensitivity (95xa0% confidence interval) was 71.2xa0% (64.5–79.6xa0%) and 86.9xa0% (75.8–94.2xa0%), specificity was 86.9xa0% (82.3–90.6xa0% ) and 93.1xa0% (89.2–95.9xa0%), PPV was 67.3xa0% (57.7–75.9xa0%) and 75.7xa0% (64.0–98.5xa0%), NPV was 88.8xa0% (84.4–92.3xa0%) and 96.6xa0% (93.5–98.5xa0%), and accuracy was 82.5xa0% (78.3–86.8xa0%) and 91.9xa0% (88.7xa0%–95.1xa0%).ConclusionIn the present series Ga-PSMA PET/CT shows a better performance than FEC PET/CT with a significantly higher NPV and accuracy for the detection of locoregional recurrent and/or metastatic lesions prior to salvage lymphadenectomy.

First evidence of PSMA expression in differentiated thyroid cancer using [68Ga]PSMA-HBED-CC PET/CT

The prostate-specific membrane antigen (PSMA) has recently emerged as a target for radionuclide imaging and therapy of prostate cancer [1, 2]. However, PSMA expression was also shown on the cell membrane of endothelial cells of tumour neovasculature in a number of other cancers such as renal cell carcinoma [3, 4], colon carcinoma, neuroendocrine tumours, melanoma or breast cancer [3]. However, to our knowledge no study has yet investigated

Long-Term Survival in Differentiated Thyroid Cancer Is Worse After Low-Activity Initial Post-Surgical 131I Therapy in Both High- and Low-Risk Patients

CONTEXTnRecent trial results have revived interest in low-activity initial (131)I therapy (RIT) of differentiated thyroid cancer (DTC).nnnOBJECTIVEnThis study sought to compare different initial (131)I activities for outcome.nnnDESIGN AND SETTINGnA database study was performed in a University hospital.nnnPATIENTSn1298 DTC patients were included (698 low risk, 434 high risk M0, and 136 M1), grouped according to ablation activity (I, ≤ 2000 MBq [54 mCi]; II, 2000-3000 MBq [54-81 mCi]; and III, >3000 MBq [81 mCi]), subdivided by age (<45 and ≥ 45 y at diagnosis).nnnMAIN OUTCOME MEASURESnComplete remission (CR, defined as thyroglobulin [Tg] below functional sensitivity combined with visually negative (131)I diagnostic whole-body scintigraphy), recurrence, DTC-specific mortality, and relative survival rates were studied.nnnRESULTSnLow-risk patients: In patients <45 years, a lower median cumulative activity was required to achieve CR in group III (3590 MBq) than in groups I (8050 MBq) and II (6300 MBq). In patients at least 45 years of age, DTC-specific mortality was significantly higher in group I than in groups II and III (15-y: 16.1 ± 7.7%, 0.8 ± 0.8%, and 7.2 ± 5.5%, respectively; P = .004). High-risk M0 patients: In patients at least 45 years of age, the recurrence rate (15-y: 44.4 ± 16.6%, 24.1 ± 7.6%, and 8.6 ± 3.9%; P = .001) and DTC-specific mortality (15-y: 51.8 ± 15.8%, 13.2 ± 4.4%, and 9.5 ± 3.7%; P = .004) were significantly higher in group I than in groups II and III. M1 patients: There were no significant differences in survival results between different activity groups in either age category.nnnCONCLUSIONnBefore adopting low initial activity RIT for, especially older, low-risk patients, results of long-term followup should be regarded critically. Low-activity RIT in older, high-risk patients is not to be recommended.

Thyroglobulin levels and thyroglobulin doubling time independently predict a positive 18F-FDG PET/CT scan in patients with biochemical recurrence of differentiated thyroid carcinoma

PurposeTo assess the relationship between serum thyroglobulin (Tg) levels, Tg doubling time (Tg-DT) and the diagnostic performance of 18F-FDG PET/CT in detecting recurrences of 131I-negative differentiated thyroid carcinoma (DTC).MethodsIncluded in the present study were 102 patients with DTC. All patients were treated by thyroid ablation (e.g. thyroidectomy and 131I), and underwent 18F-FDG PET/CT due to detectable Tg levels and negative conventional imaging. Consecutive serum Tg measurements performed before the 18F-FDG PET/CT examination were used for Tg-DT calculation. The 18F-FDG PET/CT results were assessed as true or false after histological and/or clinical follow-up.ResultsSerum Tg levels were higher in patients with a positive 18F-FDG PET/CT scan (median 6.7xa0ng/mL, range 0.7–73.6xa0ng/mL) than in patients with a negative scan (median 1.8xa0ng/mL, range 0.5–4.9xa0ng/mL; Pu2009<u20090.001). In 43 (88xa0%) of 49 patients with a true-positive 18F-FDG PET/CT scan, the Tg levels were >5.5xa0ng/mL, and in 31 (74xa0%) of 42 patients with a true-negative 18F-FDG PET/CT scan, the Tg levels were ≤5.5xa0ng/mL. A Tg-DT of <1xa0year was found in 46 of 49 patients (94xa0%) with a true-positive 18F-FDG PET/CT scan, and 40 of 42 patients (95xa0%) with a true-negative scan had a stable or increased Tg-DT. Moreover, combining Tg levels and Tg-DT as selection criteria correctly distinguished between patients with a positive and a negative scan (P<0.0001).ConclusionThe accuracy of 18F-FDG PET/CT significantly improves when the serum Tg level is above 5.5xa0ng/mL during levothyroxine treatment or when the Tg-DT is less than 1xa0year, independent of the absolute value.

DIAGNOSIS OF ENDOCRINE DISEASE: Thyroglobulin measurement using highly sensitive assays in patients with differentiated thyroid cancer: a clinical position paper

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.

Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma

Objectivesu2002 To assess (i) the influence of Thyrotropin (TSH) suppression at a level of <0·1u2003mU/l and (ii) whether FT3 and FT4 levels have a prognostic significance independently of TSH values with regard to survival in patients with differentiated thyroid carcinoma (DTC) and distant metastases.