PET/CT in Prostate Cancer: An Unmet Clinical Need

OncologyOncology Vol 28 No 12
Volume 28
Issue 12

Molecular imaging in prostate cancer can play the additional critical role of an early biomarker for response to therapy, similar to how 18F-FDG is used in other malignancies.

Drs. Koo and Crawford should be commended for their concise, clinically relevant overview of some recent developments in prostate cancer imaging.[1] While the vast majority of cancer patients have benefited from the technological advancement of positron emission tomography/computed tomography (PET/CT) using 18F-fluorodeoxyglucose (FDG), this modality has largely been excluded from standard clinical practice in patients with prostate cancer, owing to the lack of consistent FDG uptake in prostate cancer. Therefore, FDG currently has a very limited role in prostate cancer imaging,[2,3] with perhaps the exception of detecting castration-resistant metastatic disease.[4] To exploit the sensitivity of disease detection by PET/CT, additional radiotracers need to become part of the standard of care. As mentioned by Koo and Crawford, the emergence of 18F-sodium fluoride (NaF) PET/CT as a viable replacement for traditional bone scans provides a glimpse of the potential of PET/CT in the setting of prostate cancer. However, 18F-NaF has limitations similar to those of bone scans in that it detects only bone disease. The lack of a radiotracer with clinical utility analogous to FDG for the detection of both soft-tissue and bone disease in other malignancies makes the current availability of 18F-NaF an attractive imaging proposition for referring physicians. This is especially so in patients with lower levels of prostate-specific antigen, in whom conventional bone scans have limited sensitivity.[5] However, if one or more of the promising agents become a de facto standard of care in the setting of prostate cancer, this may decrease the need for a bone-restricted imaging test, similar to the decrease in bone scans in patients with FDG-avid malignancies who undergo FDG-PET scans.

The development of additional radiotracers beyond 18F-FDG and 18F-NaF has been stymied for a number of reasons, including new regulatory requirements, production limitations, and lack of consensus. These issues have led to a fragmented tracer development pipeline that includes anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC), 18F/11C-choline, and prostate-specific membrane antigen (PMSA)-targeted tracers. Therefore, the current selection of a PET radiotracer in prostate cancer has to do with which, if any, is available in a particular region or institution.

Regulatory issues

The first reported dose of 18F-FDG was administered at the University of Pennsylvania in 1976 to examine brain metabolism.[6] Of great importance to the development of this nascent technology, there was no strict FDA regulation on nuclear medicine tracer production for routine clinical use: manufacturing sites were not required to submit amended new drug applications. Therefore, over the next 3 decades, a number of academic centers and companies began operating cyclotrons to produce 18F-FDG for use in patients with cancer and dementia. During this period, sufficient evidence was produced in regard to the safety and efficacy of FDG-PET to allow routine clinical use and reimbursement for FDG-PET scans by the Centers for Medicare and Medicaid Services (CMS) and other third-party payers. This led to the advancement of PET and hybrid PET/CT technologies and the emergence of PET scanners as standard imaging equipment in community imaging centers. Similarly, 18F-NaF was first used in humans because of its bone-seeking properties, before the advent of the standard nuclear medicine 99mTc-based methylene diphosphonate (MDP) bone scan. The absence of advanced PET technology in that era led to its replacement by 99mTc-based bone scan tracers. However, as the authors point out, 18F-NaF is making a comeback now that PET scanners are commonplace in the community setting due to the success of 18F- FDG as a standard of care in other malignancies. However, the high cost of obtaining a new drug application for new tracers like 11C-choline limits the number of production sites and consequently inhibits their widespread use and convergence into standard clinical practice, as we saw happen in the early years of 18F-FDG and 18F-NaF.

Production issues

Another factor holding back the widespread use of 11C-choline and other new agents is that the current PET radiopharmacy production network is set up for the 110-minute half-life of 18F. Radiopharmacies can manufacture a single large batch of 18F-based tracer and distribute approximately 20 patient doses to sites within a 2- to 3-hour distance. In contrast, due to the short half-life of 11C-based agents, each cyclotron production run typically produces a dose for a single patient who will be scanned in close proximity to the cyclotron. This is not practical for many clinical sites. In addition to the cost and availability constraints resulting from these production issues, radiopharmacies are currently facing a saturation issue because of their need to produce 18F-FDG, 18F-NaF, and newer 18F-based proprietary amyloid agents. Furthermore, in contrast to the uncomplicated production of 18F-NaF that makes it easily produced by sites already producing 18F-FDG, other radiopharmaceuticals, such as 11C-choline, need to undergo a complex radiosynthesis process that will put further stress on the current radiopharmacy manufacturing network. Therefore, as the authors point out, production limitations will probably limit the use of 11C-choline to a very small number of academic sites, such as the Mayo Clinic, with the resources to satisfy current regulatory requirements and to operate cyclotrons. However, the authors’ clinical algorithms may not be limited to 11C-choline and could be applicable to other emerging tracers.

Intellectual property issues

Because of the limitations mentioned, in order to become accepted in clinical practice, tracers will likely need a strong corporate sponsor willing to invest in overcoming these substantial obstacles. Industry sponsorship is possible in this era because academic inventors now routinely secure strong intellectual property rights on new tracers. If strong intellectual property rights are secured and industry makes a large investment, the cost per scan will be substantially higher than scans using 18F-FDG and 18F-NaF, which are not proprietary agents. For example, the current cost of proprietary amyloid agents is 10- to 20-fold higher than the cost of 18F-FDG. High cost leads to few early adapters and little enthusiasm from third-party payers, as is seen for the amyloid agents that were FDA-approved but are generally not yet reimbursed by Medicare and others.

While the limitations mentioned above may hinder the role of 11C-choline for use in prostate cancer in the United States, the clinical algorithm presented by Koo and Crawford may also be applicable to other agents that are currently under development. The presentation of these clinical scenarios highlights the need for developing new molecular imaging/PET tracers to fill this unmet clinical need. Molecular imaging can play the additional critical role of an early biomarker for response to therapy, similar to how 18F-FDG is used in other malignancies.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Koo PJ, Crawford ED. 18F-NaF PET/CT and 11C-choline PET/CT for the initial detection of metastatic disease in prostate cancer: overview and potential utilization. Oncology (Williston Park). 2014;28:1057-65.

2. Yeh SD, Imbriaco M, Larson SM, et al. Detection of bony metastases of androgen-independent prostate cancer by PET-FDG. Nucl Med Biol. 1996;23:693-7.

3. Salminen E, Hogg A, Binns D, et al. Investigations with FDG-PET scanning in prostate cancer show limited value for clinical practice. Acta Oncol. 2002;41:425-9.

4. Schoder H, Larson SM. Positron emission tomography for prostate, bladder, and renal cancer. Semin Nucl Med. 2004;34:274-92.

5. Segall GM. PET/CT with sodium 18F-fluoride for management of patients with prostate cancer. J Nucl Med. 2014;55:531-3.

6. Hess S, Hoilund-Carlsen PF, Alavi A. Historic images in nuclear medicine: 1976: the first issue of Clinical Nuclear Medicine and the first human FDG study. Clin Nucl Med. 2014;39:701-3.

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