The concept of fluorodeoxyglucose positron emission tomography (FDG PET) was conceived in the early 1970s by a number of researchers. In August 1976, the first brain and whole-body images were acquired successfully using the initial type of PET scanner optimized for in vivo imaging with positron-emitting radionuclides in humans [1]. This demonstrated the feasibility of the methodology, but it was still far from clinical study.

During most of the 1980s, FDG PET imaging was used to determine alterations in the brain function associated with a multitude of neuropsychiatric disorders. In the late 1980s, imaging of the entire body became a reality on the basis of refinement of the PET scanner. Under these circumstances, FDG PET was expected to play a major role in treating malignant disorders in the near future.

By the late 1990s, it became apparent that FDG PET imaging was substantially superior to conventional techniques in diagnosing, staging, treatment response monitoring, and detecting recurrence in a variety of cancer types. Although FDG PET was proved to be clinically useful in malignant disorders, there were few PET centers worldwide, which were focused predominantly on the research aspects of PET. Smaller institutions, which were interested in clinical usage of FDG PET, could not consider installing a PET system because of budget limitations.

By the 2000s, the introduction of PET/CT was a turning point, bringing great changes in the sociomedical status of FDG PET. FDG PET and PET/computed tomography (CT) have become popular clinical medical imaging tools, and recently have been accepted as the most important and innovative methods for cancer imaging. For instance, the striking increase of the number of FDG PET-related medical articles reflect the fact that FDG PET has had much attention brought to it by clinicians. Between 1995 and 1999, during the early stage of clinical usage, only 553 FDG PET-related articles were published, according to a PubMed search (National Center for Biotechnology Information, U.S. National Library of Medicine, and National Institutes of Health), whereas 1,374 and 2,981 articles were published between 2000–2004, and 2005–2009, respectively (Fig. 11.1).

Fig. 11.1
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Number of articles published annually in which the title contains fluorodeoxyglucose positron emission tomography (FDG PET)

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Resolution of Technical Barrier to Popularization

Because the installation and management of a PET center is considerably more difficult than other medical imaging systems (e.g., magnetic resonance image [MRI] or CT), PET could not advance as quickly as MRI or CT in the beginning. Because positron-emitting radionuclide has a short half-life, cyclotron and radiosynthesis equipment need to be installed near the PET scanner. As a result of these shortcomings, PET systems were not easily assessable and not many clinicians had the opportunity to familiarize themselves with FDG PET. Therefore, only few obvious clinical roles and indications for FDG PET were originated. This resulted in less use of FDG PET, leading to a vicious cycle. The high installation cost and complexity of the system was still a barrier for further installation and administration.

In the 1990s, manufacturers began to build clinically relevant PET scanners for whole-body imaging, beyond the brain and the heart, which could acquire whole-body images within a 1-h time period. In parallel, small-sized relatively cost-effective cyclotrons were built, and automated radiopharmaceutical synthesis systems came to the market. FDG could be produced at an acceptable cost and companies began to make infrastructures for FDG distribution to several satellite PET sites within 3-h (or less) travel distances. Thus, from the late 1990s to the present, the initial technical barrier to PET spread was resolved and the PET scanner could become a clinical modality rather than only an investigational means.

Advent of PET/CT

Another important advancement has been attributed to the popularization of PET−the development of PET/CT. In most clinical settings, PET imaging is more beneficial when viewed with data from other imaging techniques, mainly CT and MRI, which have attained a high level of clinical relevance. For such clinical needs, PET was combined with CT into a single scanner (PET/CT), which further enhanced the utility of the methodology in daily practice. The integration of PET and CT images allows precise localization of the diseased sites for optimal management of patients with cancer and other disorders, which is essential for accurate planning of surgical and biopsy procedures. PET/CT imaging is becoming a standard of care in radiation oncology where utilizing conventional imaging techniques results in either over- or undertreating cancer patients.

PET/CT imaging is more clinically relevant than PET alone, and after its advent into the clinical world, has been replacing PET scans. It was presented at the European Association of Nuclear Medicine (EANM) Congress in 2005 that use of PET was heading toward a considerable decline, and was being rapidly overtaken by PET/CT throughout Europe. Sales figures for PET/CT scanners have surpassed those of “stand alone” PET systems, and it is predicted that greater than 90% of PET scanners would be substituted for PET/CT in the near future. At the same Congress meeting, von Schulthess highlighted the fact that the use of PET/CT was growing by 60%, whereas PET use was declining at a rate of 20%. In 2001, 91% of all PET scanners were stand-alone PET systems, whereas in 2004, 67% were PET/CT systems.

The other important aspect which must be mentioned is the higher throughput of PET/CT than stand-alone PET. PET/CT scanner uses fast CT for attenuation correction, as opposed to conventional time-consuming transmission scans. CT-based attenuation correction accomplished whole-body examination in less than 30 min. Although PET/CT carries a higher cost than stand-alone PET, PET/CT could be more cost effective than stand-alone PET because of its high throughput and clinical usefulness. PET/CT requires short scanning time, has high throughput, provides more clinical information including functional and anatomic aspects, and is more convenient to patients and the operator. These features are encouraging for the continued exploration of new clinical indications of PET.

Reimbursement and Insurance

After the 1990s, when FDG PET had been accepted as a clinical imaging modality, some developed countries had considered reimbursement by national or private insurance systems. Eventually, based on data that had been collected in the literature, Medicare became convinced of the technique’s efficacy and granted reimbursement for this service by the late 1990s.

Although reimbursement for this service had been initiated in the US in the late 1990s, the reimbursement system was still in a transition state in the US and Europe until the early 2000s [2]. Public and private insurance systems are different among US and European countries. In the UK, both public and private insurance authorizes clinical PET to some extent. In Germany, private health insurance companies give authorization but public insurance does not. In Belgium, private health insurance companies do not exist but public insurance authorizes clinical PET.

Reimbursement seems to be one of the most important factors influencing the development of PET. Serious intervention or regulation by insurance systems could restrict the expensive modality, whereas reimbursement by public insurance systems may have a positive effect on the popularization of PET. Korea began reimbursement by public insurance systems in June of 2006. Between 2006 and 2007, there was a 45% increase in PET studies nationwide. The market share of PET in the imaging branch of nuclear medicine was 45% in 2006 (Table 11.1).

Table 11.1 Market share of PET in nuclear medicine departments in Korea
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According to a survey conducted in 2006 by the World Federation of Nuclear Medicine and Biology (WFNMB), in 2005, 67% of developed countries in Europe initiated reimbursement for PET along with 31% of developing countries. At that time, Luxembourg, Belgium, The Netherlands, France, UK, Italy, Denmark, Finland, Czech Republic, Cyprus, Germany, Switzerland, Ireland, Israel, Japan, Spain, Indonesia, Poland, Taiwan, and Hungary had already initiated reimbursement. However, Mongolia, Pakistan, Vietnam, Singapore, United Arab Emirates, Slovenia, Bulgaria, Chile, Paraguay, Peru, Philippines, Romania, Serbia and Montenegro, South Africa, Thailand, Argentina, and Algeria had not. The reimbursement fee for PET varies considerably throughout Europe. For example, in Great Britain, reimbursement is €222; Belgium, €825; France, €1,050; Switzerland, €1,230; and Czech Republic, €2,050 [2]. In Korea, reimbursement is about 710,000 KRW (764 US dollar).

The spectrum of reimbursement indications was different among countries. A relatively broad spectrum of indications was accepted in Europe (Belgium, The Netherlands, France, Great Britain, Italy, Finland, Switzerland, and Spain) and the US. In 2006, Korea also adopted broad indications. Reimbursement spectrums vary by the economic needs, cost-effectiveness of societies, and the recommendations of health professional groups.

Although reimbursement systems began in major leading countries, cost-effectiveness analysis of FDG PET had not yet been carried out. Until then, some researchers had reported that ovarian cancer, recurrent laryngeal cancer, locally advanced head and neck cancer, recurrent nasopharyngeal cancer, and suspected lung cancer are cost-effective indications for FDG PET [3–7]. It seemed that the more cost-effective data would accumulate, more indications would be revealed.

Popularization of PET

Until the early 2000s we had witnessed a rise in the number of PET/CT installations. Most of the 1,000 PET/CT units worldwide were operational in the US, and notably less in Europe. Only 17 PET/CT installations existed in Germany. There are about 300 stand-alone PET scanners installed in Europe at the present time, most of them operating in clinical practice [8].

According to the survey by the WFNMB, the number of PET installation sites increased dramatically after 2000 (Table 11.2). The installation sites increased between 1996 and 2000 in the US, and other countries followed between 2000 and 2005. More are expected to be installed in 2010. The market share of PET in nuclear medicine increased (Table 11.1) and is probably be the leading most portion of market share of nuclear medicine at the present time.

Table 11.2 Number of facilities/sites in various countries where PET has been installed
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For example, in Korea, the number of PET applications did not increase during the 1990s, but the trend changed and began to increase exponentially since 2001 (Fig. 11.2). Profound distribution of PET or PET/CT scanners, on-site medical cyclotrons, and supporting delivery infrastructure of radiopharmaceuticals made the increase possible in Korea. Between 1994 and 2002, there were only seven PET centers in Korea and they distributed only around the area of the capital (Fig. 11.3). In 2008, the number of PET sites and PET scanners reached 78 sites with 127 scanners, and 113 of the 127 scanners were PET/CT. The PET sites were distributed regionally nationwide. There was a burst in the number of PET applications around 2006 as a result of reimbursement by public insurance systems. PET became an available technology for most Korean patients, geographically and financially.

Fig. 11.2
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Number of PET applications performed annually in Korea from 1997 to 2008

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Fig. 11.3
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Chronologic changes of regional distribution of PET scanners and medical cyclotrons in Korea

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The total number of scans per million head of population varied considerably from one country to another. The total number of scans per scanner or utilization rate also varied considerably from one European country to another. According to the EANM Congress of 2005, the Czech Republic performed about 3,400 scans per scanner, whereas Belgium performed 870 scans [8].

Infrastructures that deeply influence the popularity of PET, such as the delivery system, distribution of medical cyclotron, medical insurance coverage, medical care system, and economic status, are very different among countries. Although developed and developing countries have infrastructures and substantial PET sites, less developing countries do not. Moreover, the number of PET or PET/CT per capita is different between developed countries and developing countries. In Benelux, Austria, Switzerland, and Italy the number of PET studies per million inhabitants is more than 1,000; whereas in France, Iberia, and Scandinavia this number varies between 500 and 1,000; in Germany and the UK, it is less than 500 scans (Table 11.3).

Table 11.3 FDG PET studies per million population
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Prospects and Collaboration

As mentioned previously, the popularization of PET is not geographically homogenous. However, despite the rising number of PET installations, PET imaging accounts for only a small part of the total expense of diagnostic imaging. Developing countries and less developed countries do not have substantial infrastructure, and PET technology is not yet clinically relevant. Until 2006, a considerable number of countries had substantial numbers of PET and infrastructure to influence the national medical care system. A commercial transportation and distribution system for FDG has been already been initiated in almost every country in Europe and Asia-Oceania, whereas in Japan, a typical developed country, neither transportation of FDG nor full reimbursement of clinical PET has been started or has been delayed. The coverage by insurance and regulatory approval systems varies among nations. Obviously, the applicability and recognition of PET as an imaging modality in diagnostic oncology (and neurology) is affected by the recommendations of professional groups regarding the different levels of oncologic scanning. Based on these facts, it would be much easier for less-developed countries to facilitate PET centers by obtaining help and experience from the leading countries by international collaboration.

To overcome this unequal level of popularization, a new PET application and radiotracer, which cannot be replaced by other modality, should be developed, and PET should be more popularly used. A new array of promising new positron-emitting radiotracers, other than FDG, as well as new imaging instruments would make the future of PET brighter than its current success. FDG is only one of many radiopharmaceuticals, and others are now in production or under active investigation. These new radiotracers have characteristic roles and the indications of PET will be wider. Current PET scanners are rapidly evolving as well, with new crystal materials, PET/CT combination systems, and other technical innovations that are already in use. Technology, such as PET and MRI combinations as well as new tabletop medical cyclotrons, will strengthen the usefulness of PET.

The lack of a unified international or domestic system and excessive requirements for regulatory approval of radiopharmaceuticals are serious obstacles that need to be addressed prior to reimbursement. Currently, 18F-FDG manufacturers need to comply with more rigorous regulatory standards similar to those required for unlabelled drugs. Complying with such standards requires additional upfront costs for personnel, office space, and equipment. In addition, regulatory agencies have been increasingly moving toward a more stringent regulatory environment for manipulation and transport of radiopharmaceuticals [9].

Conclusion

The field of PET is relatively the newest, and will progress with many advantageous conditions. PET/CT was emerging as an investigational ­technology for four decades prior to maturing as a clinical medical imaging modality, especially for oncology. In the future, promising new tracers and new instruments will continue to drive the sustainable success of PET technology. International collaboration and the sharing of experience will be helpful for promoting clinical PET worldwide and abolishing regional unequal diffusion.