Igle J. de Jong

In vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer.

PurposeProstate cancer is the second leading cause of death from cancer among US men. Positron emission tomography (PET) with [11C]choline has been shown to be useful in the staging and detection of prostate cancer. The background of the increased uptake of choline in human prostate cancer is not completely understood. The aim of this study was to prospectively investigate the relationship between the [11C]choline uptake and the cell proliferation in human prostate cancer.MethodsProstate cancer tissue from 18 patients who had undergone a radical prostatectomy for histologically proven disease was studied. An [11C]choline PET scan was performed prior to surgery. Post-prostatectomy specimens were prepared and stained with the antibody MIB-1 for Ki-67, which depicts proliferation. Two independent observers counted the amount of stained nuclei per specimen. ResultsProstate cancer showed Ki-67 staining and high uptake of [11C]choline. Statistical analysis showed no significant correlation between [11C]choline uptake and Ki-67 staining (R=0.23; P=0.34). No significant relationships were found between the uptake of [11C]choline (SUV) and either preoperative PSA (R=0.14; P=0.55) or Gleason sum score (R=0.28; P=0.25).ConclusionIn vivo uptake of [11C]choline does not correlate with cell proliferation in human prostate cancer as depicted by Ki-67. Our results suggest that a process other than proliferation is responsible for the uptake of [11C]choline in prostate cancer.

Clinical Activity and Tolerability of Enzalutamide ( MDV3100) in Patients With Metastatic, Castration- Resistant Prostate Cancer Who Progress After Docetaxel and Abiraterone Treatment

Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration‐resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date.

Expression of the Gastrin-Releasing Peptide Receptor, the Prostate Stem Cell Antigen and the Prostate-Specific Membrane Antigen in Lymph Node and Bone Metastases of Prostate Cancer

Cell membrane antigens like the gastrin‐releasing peptide receptor (GRPR), the prostate stem cell antigen (PSCA), and the prostate‐specific membrane antigen (PSMA), expressed in prostate cancer, are attractive targets for new therapeutic and diagnostic applications. Therefore, we investigated in this study whether these antigens are expressed in metastasized prostate cancer.

Detection of Local, Regional, and Distant Recurrence in Patients With PSA Relapse After External-Beam Radiotherapy Using 11C-Choline Positron Emission Tomography

PURPOSE An elevated serum prostate-specific antigen (PSA) level cannot distinguish between local-regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study, the potential of (11)C-choline positron emission tomography (PET) to identify site of recurrence was investigated in patients with rising PSA after external-beam radiotherapy (EBRT). METHODS AND MATERIALS Seventy patients with histologically proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by American Society for Therapeutic Radiology and Oncology consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq (11)C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/or response to adjuvant therapy were used as comparative references. RESULTS None of the 10 patients without biochemical recurrence had a positive PET scan. Fifty-seven of 70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41 of 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/or distant in 16 of 57 patients (mean PSA 17.7 ng/mL). Overall the positive predictive value and negative predictive value for (11)C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%. CONCLUSIONS (11)C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer.

Cediranib monotherapy in patients with advanced renal cell carcinoma: Results of a randomised phase II study

BACKGROUND Cediranib is a highly potent vascular endothelial growth factor (VEGF) signalling inhibitor with activity against VEGF receptors 1, 2 and 3. This Phase II, randomised, double-blind, parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor. METHODS Patients were randomised (3:1) to cediranib 45 mg/day or placebo. The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy. Secondary objectives included response rate and duration, progression-free survival (PFS) and safety and tolerability. Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed. This study has been completed and is registered with ClinicalTrials.gov, number NCT00423332. FINDINGS Patients (n=71) were randomised to receive cediranib (n=53) or placebo (n=18). The primary study outcome revealed that, after 12weeks of therapy, there was a significant difference in mean percentage change from baseline in tumour size between the cediranib (-20%) and placebo (+20%) arms (p<0.0001). Eighteen patients (34%) on cediranib achieved a partial response and 25 (47%) experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo (hazard ratio (HR)=0.45, 90%confidence interval: 0.26-0.76, p=0.017; median PFS 12.1 versus 2.8 months). The most common adverse events in patients receiving cediranib were diarrhoea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%). INTERPRETATION Cediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma. The adverse event profile was consistent with previous studies of cediranib 45 mg.

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of 89Zr-bevacizumab, a VEGF-A–binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. Methods: Patients underwent 89Zr-bevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3–9 million IU 3 times/wk) (n = 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n = 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. Results: 89Zr-bevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUVmax (maximum standardized uptake value) of 6.9 (range, 2.3–46.9). Bevacizumab/interferon-α induced a mean change in tumor SUVmax of −47.0% (range, −84.7 to +20.0%; P < 0.0001) at 2 wk and an additional −9.7% (range, −44.8 to +38.9%; P = 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUVmax was −14.3% at 2 wk (range, −80.4 to +269.9; P = 0.006), but at 6 wk the mean change in tumor SUVmax was +72.6% (range, −46.4 to +236%; P < 0.0001) above baseline. SUVmax was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUVmax greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05–1.00). Conclusion: Tumor uptake of 89Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drug-free weeks. High baseline tumor SUVmax was associated with longer time to progression.

Prospective validation of a risk calculator which calculates the probability of a positive prostate biopsy in a contemporary clinical cohort

BACKGROUND Prediction models need validation to assess their value outside the development setting. OBJECTIVE To assess the external validity of the European Randomised study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC) in a contemporary clinical cohort. METHODS The RC calculates the probability of a positive sextant prostate biopsy (P(posb)) using serum prostate-specific antigen (PSA), results of digital rectal examination, transrectal ultrasound (TRUS) and ultrasound assessed prostate volume. We prospectively validated the RC in 320 biopsied men (55-75 years), with no previous prostate biopsy, included in five Dutch hospitals in 2008-2011. If the P(posb) was ≥ 20% a biopsy was recommended. The performance of the RC was tested by comparing the observed outcomes to predicted probabilities, using the area under the curve (AUC) and decision curves analyses. RESULTS Compared to the screening cohort, men in the clinical cohort differed. They had higher PSA levels (median 6.8 versus 4.3 ng/ml, p<0.01), less TRUS-lesions (27% versus 34%, p = 0.01) and more prostate cancer (PCa) at biopsy (43% versus 25%, p<0.01). Mainly eight biopsy cores were taken. Despite the differences between these cohorts, the mean observed probability agreed with the mean predicted probability (43% versus 40%). The RC predicted P(posb) better than a model with PSA and digital rectal examination, AUC 0.77 (95% confidence interval (CI) 0.72-0.83) and 0.71 (95%CI 0.65-0.76, p<0.01), respectively. This was confirmed by the decision curves analysis. Under the 20% threshold, 17% (11/63) of the biopsied men were diagnosed with PCa. Two of 11 men had an important cancer (Gleason 3+4). CONCLUSIONS The ERSPC RC performs well in a Dutch clinical cohort in men with previous PSA tests and contemporary biopsy schemes, and outperforms a PSA and DRE-based approach in the decision to perform a biopsy.

PSMA, EpCAM, VEGF and GRPR as Imaging Targets in Locally Recurrent Prostate Cancer after Radiotherapy

In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion molecule (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochemistry was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens’ stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy.

Effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer

Our study assessed whether rising age, socioeconomic status (SES) and the presence of serious comorbidity affected treatment choice and survival in a population‐based series of patients with muscle‐invasive bladder cancer (MIBC) in The Netherlands. Therefore, a consecutive series was studied, including all patients diagnosed with MIBC between 1995 and 2009 in the Eindhoven Cancer Registry, preceding centralization of cystectomy. The independent effects of age, SES and serious comorbidity on therapy choice and their effects on overall survival were estimated by multivariate logistic regression and multivariate Cox proportional hazard analyses, respectively. Out of the 2,445 patients, 38% were aged ≥75 years at diagnosis and 63% had at least one serious comorbid condition. Higher age and serious comorbidity were independent predictors for abstaining from cystectomy, where SES was not (61–74 vs. ≤60: odds ratio [OR], 0.8; 95% confidence interval [CI], 0.6–1.0; ≥75 vs. ≤60: OR, 0.1; 95% CI,0.1–0.2; one comorbid condition vs. none: OR, 0.7; 95% CI, 0.5–0.9; two vs. none: OR, 0.6; 95% CI, 0.5–0.8). Patients undergoing cystectomy, external beam radiotherapy or interstitial radiotherapy survived longer independent of age, SES and serious comorbidity (hazard ratio [HR]: 0.4; 95% CI: 0.4–0.5; HR: 0.8; 95% CI: 0.7–0.9; HR: 0.4; 95% CI: 0.3–0.5, respectively). Consequently, preceding centralization of cystectomy, higher age and serious comorbidity were independent predictors for abstaining from cystectomy owing to an expected high rate of short‐term medical problems. As cystectomy is associated with a better survival, independently of age, SES and serious comorbidity, it can be questioned whether cystectomy has been underutilised in elderly and in patients with serious comorbidity. Centralization might be a solution for this suggested underutilisation.

An Update of Radiolabeled Bombesin Analogs for Gastrin-Releasing Peptide Receptor Targeting

Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods which have been widely used for diagnosing diseases in the clinic. Lack of suitable radiotracers is the major issue for nuclear imaging of prostate cancer, although radiolabeled bombesin (BN) peptides targeting the Gastrin-Releasing Peptide Receptor (GRPR) on tumor cells are widely investigated. In this review we discuss the recent trends in the development of GRPR-targeted radiopharmaceuticals based on BN analogs with regard to their potential for imaging and therapy of GRPR-expressing malignancies. Following a brief introduction of GRPR and bombesin peptides, we summarize the properties of prostate cancer specific radiolabeled bombesins. New bombesin tracers published in the last five years are reviewed and compared according to their novelties in biomolecules, radionuclides, labeling methods, bifunctional chelators and linkers. Hot topics such as multimerization, application of agonists and antagonists are highlighted in the review. Lastly, a few clinical trials of cancer nuclear imaging with radiolabeled bombesin have been discussed.