PET imaging of urothelial bladder cancer: addressing an unmet need

Objectives: Urothelial Bladder Cancer (UBC) affects >80,000 new patients annually. Treatment is stage dependent, thus accurate staging with conventional imaging and biopsy are crucial, but are often inaccurate. To improve visualization of primary disease, the extent of loco-regional disease and the presence or absence of metastatic lesions, a large number of PET biomarkers have been developed. However serious limitations, including urinary excretion of radioactivity, compromises their ability to accurately assess the bladder lumen and invasive tumors. This ongoing investigation is aimed to validate a hypothesis that VPAC (combined for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP)) receptors expressed in high density on UBC cells can be targeted to PET image UBC, its loco-regional disease and metastatic lesions. Materials and Methods: ⁶⁴Cu-TP3805, shown in our laboratory to have high affinity (3.1 x 10^-9 M) for VPAC was the imaging agent. Patients (M, N=15, 44-80 yrs.) diagnosed with invasive UBC scheduled for radical cystectomy were enrolled. Chemotherapy eligible patients were treated with standard of care cisplatin regimens. All subjects were administered 148±10% MBq ⁶⁴Cu-TP3805 (20 µg) intravenously. Urine and blood samples were collected at predetermined time points. Patients then underwent PET/CT imaging 90 minutes later. Images were read independently by two nuclear medicine physicians. Radical cystoprostatectomy and lymphadenectomy was performed 1 to 4 weeks later, and VPAC PET images were correlated with final surgical pathology.

Results: There were no adverse events. Blood clearance, t½ (∝), was 22.3 ± 2.7 min (> 85%) and t½ (β) was 118.2 ± 4.9 min (< 15%). Urinary excretion of radioactivity was negligible. As confirmed by post cystectomy histology, PET images were true positive in the bladder for UBC in 10 patients and true negative in 4. There was one false negative image. When examining the prostate, there was PET uptake in 12 patients. Of these, 5 patients had incidental prostate cancer or HGPIN; 2 patients had UCB involving the prostate; and 5 patients had negative histology in the prostate. PET image was true positive for one lymph node, true negative for 11 and false negative in 3. In one patient several bone lesions in iliac crest and spine were seen by PET imaging. Biopsy of iliac crest confirmed metastasis. These pilot data demonstrate ⁶⁴Cu-TP3805 VPAC targeting for imaging UBC has 91% sensitivity (95% CI 59%-100%), 100% specificity (95% CI 40%-100%) , and has positive predictive and negative predictive values 100% (95% CI 69%-100) and 80% (95% CI 38%-96%), respectively.

Conclusions: The results of this first-in-human study to image UBC by targeting VPAC receptor are encouraging. Further investigation continues. Acknowledgement: Supported in part by NIH, NCI R01 157372 (MLT) Dean’s Translational Science Award (MLT) and Sidney Kimmel Cancer Center Award (MLT).

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