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Is whole-body FDG-PET valuable for health screening?

Michiru Ide1 Contact Information and Yutaka Suzuki1

(1) HIMEDIC Imaging Center at Lake Yamanaka, Hirano 562-12, Yamanakako-mura, Minamitsuru-gun, Yamanashi 401-0502, Japan

Published online: 22 February 2005

The survival of patients with various cancers, such as colorectal, breast and prostate carcinomas, has improved significantly since the 1970s [1], but unfortunately cancer remains the first or second most common cause of death among both men and women in developed countries. Present-day medical practice generally assumes that early detection of cancer offers the best chance of a good outcome. Finding a cancer in an asymptomatic person provides more treatment options, offers a better prognosis and cuts down on expenses compared with the cost incurred when cancers are detected at later stages. To detect cancers at an early stage, self-referral for mammography, routine or virtual colonoscopy, sigmoidoscopy, Pap smear screening, prostate-specific antigen testing and measurements of other tumour-specific markers have been actively recommended by consensual medical opinion, despite some continuing debate as to the value of these measures. With improvements in the standard of living and ready access to medical information via the internet and other mass media, more and more healthy lay persons are willing to undergo cancer screening. In Far Eastern countries (especially Japan), this tendency is strongly evident.

Tumour screening can be defined as the application of diagnostic tests or procedures to asymptomatic people for the purpose of dividing them into two groups: those who have a condition that would benefit from early intervention and those who do not. The intention of traditional or conventional cancer screening has been the early detection of cancer in a target organ, but an ideal cancer screening test would be a non-invasive and painless procedure that can (a) [COLOR=blue]simultaneously detect various cancers, regardless of the organ or site involved at a time when they are curable, [/COLOR],and (b) yield a high sensitivity and specificity [2].

不晓得作者的筛检是跟谁学的，总之蓝字部分在我见过的中英文教科书里都没有这种牺牲特异性的筛检策略。恰恰相反，在原文给出的引用文献里恰恰在Screening Test Detects Little Pseudodisease一节里强调了特异性的重要性。引文［2］为 Obuchowski NA, Grham RJ, Baker ME, Powell KA. Ten criteria for effective screening for pulmonary and colon cancers. Am J Roentgenol 2001;176:1357–62. 日本这位作者在这里完全是想当然了。

Whole-body FDG-PET

Warburg first reported that tumours are characterised by abnormally increased glucose metabolism, with increased production of lactate (caused by glycolysis) [3]. This is a basic principle underlying cancer detection by the glucose analogue 18F-fluoro-2-deoxy-d-glucose (FDG). Increased FDG accumulation in neoplastic tissues is a function of increased expression and activity of glucose transporter proteins and the glucose phosphorylating enzyme hexokinase, which result from increased anaerobic metabolism in cancer cells, as well as metabolic trapping of FDG within tumour cells due to the lack of further metabolic pathways for FDG [4]. FDG positron emission tomography (PET) is currently widely used as a way of examining virtually any part of the body in order to detect tumours, e.g. lung, breast, colorectal, pancreatic and head and neck cancer, malignant lymphoma and malignant melanoma [5, 6]. It can also be used successfully in patients with unknown primary tumours [7].

引文5 Hustinx R, Benard F, Alavi A. Whole-body PET imaging in the management of patients with cancer. Semin Nucl Med 2002;32:35–46.

6. Rohren EM, Turkington TG, Coleman RE. Clinical application of PET in oncology. Radiology 2004;231:305–32.

7. Rades D, Kuhnel G, Wildfang A, Borner AR, Chmoll HJ, Knapp W. Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol 2001;12:1605–9.

全部都是在肿瘤病人里进行疾病病程控制的文章。完全不涉及一般人群。

The advantage of whole-body FDG-PET in comparison with other imaging modalities is that it allows the entire body to be surveyed seamlessly within a reasonably short period ; furthermore, most metabolically active cancers can be detected at an early stage. State-of-the-art dedicated PET cameras offer high sensitivity and spatial resolution [8]. Using a contemporary PET camera, whole-body images can be obtained within 10 min with an administered dose of 185 MBq.可以跟德国人的那篇文章里提到的辐射潜在致癌剂量向比较一下

The characteristics of whole-body FDG-PET seem to satisfy the requirements for cancer screening [9, 10]. Whole-body FDG-PET comes close to being an ideal modality for the purpose of cancer screening in that it achieves high sensitivity without any apparent hazard. 非常重要的两点，1，高敏感度，没有提及特异度（很快就要提了）2，作者认为“无害”，显然我并不同意，大家可以自己查一下辐射剂量方面的资料。It also provides information on the extension of the cancer, because the primary tumour and metastatic foci can be detected simultaneously. Whole-body FDG-PET appeals to many people who are concerned about possibly harbouring a threat to their health and can afford the cost. Further development of PET hardware and software will lead to further reductions in the administered dose and scanning times, and will improve the throughput of the examination.

The most crucial limitation of whole-body FDG-PET is the possible[COLOR=red]low specificity in the diagnosis of cancer.[/COLOR] A number of benign processes, particularly inflammation, show higher uptake of FDG than background tissues. There is also physiological uptake. Recognition of physiological uptake of FDG and unusual patterns of FDG biodistribution is important in order to avoid misinterpretation of PET [11, 12]. False positive interpretations that lead to unnecessary biopsy or surgery can be largely avoided if the potential sites and characteristics of non-malignant lesions and physiological accumulation are recognised when evaluating the PET images. We nuclear physicians should be familiar with patterns of FDG uptake due to factors other than malignant tumours. 还是要主观判断啊Delayed images have been reported to be useful for differentiation between tumoural and non-tumoural uptake: in cases of non-tumoural uptake, the activity decreases in the delayed images [13, 14]. Recently, PET/CT has been advocated as a tool for improvement of diagnosis by FDG-PET [15]. Hybrid imaging can precisely localise and improve the characterisation of foci of increased FDG uptake, with the consequence that false positive rates will decrease. PET/CT has not been adopted for the purpose of cancer screening. If it were to be used for cancer screening, the radiation dose due to CT would have to be taken in consideration.

Japanese experience in cancer screening

In Japan, we have 10 years experience in the performance of whole-body FDG-PET, in addition to conventional modalities, for the purpose of cancer screening [9, 10, 16]. In April 2004, a questionnaire survey不是病例报告，而是病例调查－追查由此引发的偏倚不是临床医生的专长了吧 on cancer screening with whole-body FDG-PET was carried out. At the 11 PET facilities, 39,785 applicants (23,431 male and 16,354 female, average age 53.6 years) participated in cancer screening. The screening modalities other than whole-body PET differed between the facilities. All participants were asymptomatic with regard to cancer. For cancer screening, the administered dose of FDG was 3.7 MBq/kg and whole-body PET scanning generally was performed 60 min after tracer injection, from the neck to the upper third of the thigh. Whole-body FDG-PET images were evaluated by visual inspection. The results are presented in Tables 1 and 2.

Table 1 Cancers detected by cancer screening with whole-body FDG-PET in Japan

没法贴数据表格。请查阅http://www.springerlink.com/content/l5butvbyj30qjl53/fulltext.html

表中给出了526例肿瘤患者，其中358例PET-CT阳性，168例PET－CT阴性。但是，作者没有给出假阳性和假阴性的数字，这在评估任何一种检测方法时都是必需的。可以这么说，缺少了这两个数字，本文所有结论都无法得到证明，PET－CT的敏感度、特异度、阴／阳性预测值无一能被计算出来

Overall, malignant tumours were discovered in 526 participants (1.35%). This discovery rate is much higher than that achieved with conventional cancer screening in Japan (0.10%). In descending order of frequency, the most commonly detected cancers were thyroid, lung, colon, prostate and breast cancers. All these cancers were found in the early stages. There were 358 PET-positive cases and 168 PET-negative cases. Most of the thyroid, lung, colon and breast cancers were PET positive, but the prostate, renal and bladder cancers were generally PET negative. PET-negative cancers were detected by the conventional methods: computed tomography, ultrasound, magnetic resonance imaging and tumour-specific markers. Overall, there were more PET-negative cases among males than females, because of the many PET-negative cases of prostate cancer (Table 1).

The PET-negative cases can be attributed to the following four reasons: (1) high urinary tract activity, (2) cancers of low cell density (signet ring cell cancer of the stomach and the scirrhous type of breast cancer), (3) hypometabolic or FDG-negative cancers (lung cancer and malignant hepatoma) and (4) small cancers. 这一段实际是在说PET－CT假阴性的可能原因Renal excretion of FDG may hamper the detection of urological cancers and lesions in the pelvic cavity [17]. Most well-differentiated lung adenocarcinomas have been reported to be PET negative [18]. Malignant hepatoma is also PET negative due to the high activity of glucose-6-phosphatase [19]. The spatial resolution of the PET camera is around 6 mm [8], and in tumours smaller than twice the resolution, the sensitivity is decreased due to partial volume effects. Tumours smaller than 10 mm in diameter are, therefore, difficult to detect, although detection of much smaller cancers by FDG-PET has been reported [10]. In order to minimise the number of false negative cases, it is important that conventional examinations are performed conjointly.

In the application of PET for cancer screening, radiation exposure should be taken seriously. Radiation absorbed doses have been measured and the effective dose equivalent of 18F-FDG was estimated at 2.1×10–2 mSv/MBq [20]. In cancer screening we administer 185 MBq, so the radiation dose is 3.9 mSv. If screening is limited to the older generation, the additional radiation dose at this level will not be a big issue.

Needless to say, the quality of screening should be kept to a high standard. To this end, the Clinical PET Promotion Council and the Japanese Society of Nuclear Medicine have worked hard together to produce guidelines for mass screening with whole-body FDG-PET. These guidelines were published last year [21] and are now available at http://www.jsnm.org/report/FDG-PET_gaidorain2004_part3.pdf 这应该就是某位河友贴出来的日文版的指南吧出处吧The guidelines describe the nature of an appropriate facility and offer an outline of cancer screening. Data acquisition and analysis methods are fully described, and the guidelines also refer to the other screening modalities that may be used in conjunction with whole-body FDG-PET. In addition it is explained which tumours are easy and which are difficult to detect by FDG-PET; in the latter cases, effective alternative modalities are recommended. A new edition will be published yearly. When whole-body FDG-PET cancer screening is performed on the basis of these guidelines, the quality of cancer screening will be much improved.

Conclusion

Cancer is still the leading cause of death in developing countries. The success of cancer treatment is highly dependent on early detection. There is a need for a highly accurate screening method that is easy to perform and non-invasive or minimally invasive. Whole-body FDG-PET may fulfil this need. Based on experience in Japan, we believe that it has the potential to detect a wide variety of cancers at potentially curable stages in asymptomatic individuals, provided the data are evaluated by radiologists or oncologists who are highly trained in the interpretation of PET images. Whole-body FDG-PET might be the most powerful tool for cancer detection when it is used in combination with tumour markers and other imaging modalities.

此文发表2年后，综合日本各地数据的文献发表，其阳性预测值仅3。3％，该文附后