CONVENTIONAL TYPES OF IMAGING
Ultrasound has a role in doing prostate biopsies and the placement of radioactive seeds in primary prostate cancer. It is also for evaluating local recurrence after surgery in patients with an increasing PSA. CT Scans are commonly used for staging men with newly-diagnosed disease, looking for enlarged lymph nodes in the pelvis. However, it is inaccurate for detecting cancer in the lymph nodes. If cancer is present in the nodes, a CT scan only finds it 35% of the time. Prostate MRI is used for staging, biopsy guidance, surgical planning, radiation planning, and restaging after PSA relapse. Multi-parametric MRI is being found to be very helpful for detection and local staging of untreated prostate cancer, to reveal features such as extra-capsular extension or seminal vesicle invasion, thus helping to confirm local (organ confined) disease. Additionally, multi-parametric MRI is a useful imaging tool for following changes in the prostate gland for men on active surveillance.
Prostate cancer frequently metastasizes to the bone, therefore the mainstay of imaging for advanced prostate cancer has been technetium-labeled bisphosphonate bone scintigraphy. T-99 bone scans are used for initial staging of intermediate-to-high-risk disease and for restaging after PSA relapse. Unfortunately, it is not sensitive enough to detect small skeletal metastases. False positives are common due to interference from non-cancerous arthritic changes and/or prior trauma.
SODIUM FLUORIDE (NAF) PET/CT SCANS
NaF PET is similar to standard bone scans, but uses PET imaging which is significantly more sensitive and specific than T-99. Another advantage of NaF PET is the shorter scan time, typically less than one hour, compared to 4 hours.
11C CHOLINE AND ACETATE PET SCANS
Prostate cancer cells rely on fatty acid metabolism as their energy source. 11C-choline and 11C-acetate are lipid- metabolism PET agents. Both of these agents are useful for detecting recurrent disease after a PSA relapse. 11C-choline has been approved for use at Mayo Clinic. 11C-acetate is available under expanded access clinical trials at multiple institutions. Small direct comparison studies of 11C-acetate and 11C-choline have revealed no clear clinical differences between these agents, although a few studies have suggested a slightly higher detection rate of local recurrences and small pelvic lymph node metastases with 11C-acetate. In a large-scale study of 11C-acetate PET/CT imaging in 887 patients with relapsing PSA (at Phoenix Molecular Imaging), the overall detection rate of recurrent prostate cancer was 88%. A PSA threshold of 1.09 ng/mL was established for optimal imaging. However, if the PSA was less than 1.0 ng/mL but the PSA doubling rate was brisk (less than 3 months), the detection rate was better than 90%. The reported detection rate for 11C-choline generally ranges from 42-82% with a PSA threshold of 2.0 recommended for optimal imaging. However, at least one study in 102 patients has demonstrated a significant influence of the PSA doubling time on 11C-choline with a 93% detection rate noted in a PSA range of 0.67-1.1 ng/ mL if the PSA doubling rate was under seven months.
AXUMIN PET SCANNING (18F-FACBC)
Amino acids, such as leucine, methionine, and glutamine, are absorbed into the cancer cells because of the increased metabolic demands of the growing cancer cells. The FDA recently approved Axumin (Fluciclovine or 18F-FACBC), which is a fluorine-18 radiolabeled synthetic leucine amino acid. The FDA approved Axumin for the detection of recurrent cancer in men with rising PSA after previous surgery or radiation.
CLINICAL TRIALS OF AXUMIN
Scans were performed in 105 patients. The results were checked for accuracy with biopsy or surgery after the scan. Three independent reviewers analyzed the scan results. For men who had biopsy confirmation of cancer in the prostate bed, the true-positive rate ranged from 49-58%. The false positive rates ranged from 16-30%. For patients who had positive biopsies outside of the prostate bed, the results were much better, with a true-positive rate of 88-93% and a false-positive rate of only 7-8%. Optimal detection rates were seen when the PSA was above 1.78.
In another clinical trial of 96 patients, a comparison was made between Axumin and 11C-choline PET. The scans showed equivalent findings 61-77% of the time. However, this study did not include biopsy confirmation. In a third study performed in Italy, 89 patients with a rising PSA were studied. The overall cancer detection rate was 37%. In those patients with a PSA of less than 1.0 ng/mL, the detection rate was 21%, with a PSA of 1.0- 2.0 ng/mL detection was 29%, and when the PSA was higher than 3.0 the detection rate was 59%. Direct comparison to 11C-choline indicated better performance for Axumin. However, the detection rates they achieved with 11C-choline were far below that seen in nearly all previously published studies. Hopefully, the performance of Axumin will improve as time goes by and investigators learn how to use this new tool in an optimal way.
PSMA PET SCANS
The prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that occurs much more commonly in prostate cancer cells compared to benign prostate tissue. The clinically approved imaging method using PSMA was ProstaScint. ProstaScint, however, has several limitations. The technique uses an intact antibody which targets the internal portion of the cell membrane glycoprotein (PSMA) which requires long circulating times. There is pro- longed blood-pool retention leading to high background signals, low detection rates, and much lower spatial resolution compared to PET.
Better agents for detecting PSMA have been developed, such as 68gallium-PSMA-11. Several retrospective studies have indicated a higher diagnostic efficiency of 68Ga-PSMA PET/CT compared to 11C-choline PET. In one study, for example, with 319 patients with PSA relapse, an overall 82.8% detection rate was seen. As would be expected, the probability of detecting lesions was correlated with PSA level. A 50% detection was seen when the PSA was 0.2-0.5, 58.3% detection with a PSA of 0.5-1.0, 71.8% detection with a PSA of 1.0-2.0, and 93% detection when the PSA was over 2.0. 68Ga-PSMA is under clinical trial investigation in multiple U.S. institutions (e.g. UCSF, UCLA, and Stanford University).
A few limitations of PSMA-targeting agents are important to understand. Not all prostate cancers exhibit PSMA overexpression. In one study, about 8% of patients with prostate cancer did not show PSMA overexpression. Additionally, PSMA ligands are not completely specific for prostate cancer and several benign lesions such as thyroid adenoma, Paget’s disease, schwannoma, adrenal adenomas, and several types of vascular tumors (colon, breast, renal, liver, thyroid) may also exhibit increased PSMA expression. False positive celiac lymph nodes frequently have been noted in the upper abdomen. Finally, the PSMA-targeting agents to date are significantly excreted in the urinary tract and urinary bladder, which often obscures the prostate bed, making detection of small locally recurrent lesions and lymph nodes in the lower pelvis challenging.
In summary, the excitement surrounding the current and emerging PET agents is appropriately exuberant. Despite the radical breakthroughs that are occurring in the area of imaging, a fair amount of confusion also exists. There is still no “perfect” imaging methodology with 100% accuracy. The recent FDA approval of Axumin is cause for celebration. In addition, our experience at Phoenix Molecular has shown 11C-acetate PET to be a very valuable tool. But 11C-acetate PET is unlikely to become widely available due to the requirement for an on-site cyclotron. PSMA-targeted agents are becoming the major focus for future attention and development. Despite some limitations, PSMA-targeted imaging appears to provide high sensitivity and specificity, and is likely to become part of the routine evaluation and management of men with prostate cancer in the near future.
Fabio Almeida, MD is the Medical Director of Phoenix Molecular Imaging and Southwest PET/CT Institute in Phoenix, Arizona, providing his extensive clinical expertise in PET/CT imaging. He research is focused on applied medical informatics with emphasis on imaging and networking systems, optimization of fusion technology and volumetric tumor assessment for radiation therapy planning. He actively participates in several oncology and neurologic clinical trials and is the principal investigator for a novel Carbon-11 PET agent for prostate cancer imaging. He is one of the pioneers in the development and implementation of cross modality fusion for cancer imaging (SPECT, PET, CT and MRI) and PET/CT. He has authored and participated in several publications in radiology, oncology and information science.