Radioisotopes in PET imaging emit positrons during radioactive decay. After combining with an electron, the positron and electron are annihilated and their combined masses are converted into two gamma rays that travel in opposite directions (E = mc2). The gamma rays thus produced are detected by a PET camera, when opposite detectors register a gamma ray in coincidence (i.e., within a few nanoseconds) (13). The registered gamma rays are subsequently converted into 3D tomographic images. FDG-PET visualises the increased glycolytic metabolism in cancer cells compared to normal cells. FDG is transported across the cell membrane by glucose transporter proteins and is enzymatically phosphorylated by hexokinases. In contrast to glucose-6-phosphate, FDG-6-phosphate is not further metabolised and thus 'trapped' in the cell. The entrapment of FDG-6-phosphate can be detected with a PET camera. Under physiological conditions, FDG predominantly accumulates in tissues with high glucose metabolism, such as the brain. A lower grade uptake is seen in muscle, myocardium, liver, and kidneys.
In a pre-operative setting, high FDG tumour uptake was observed particularly in ductal carcinomas (14) of all stages. The quantity of FDG uptake in tumours was positively correlated with the pathologic grade, and the proliferation index (Ki-67) (14, 15). However, FDG uptake itself is not tumour-specific, and the distinction between malignant and benign breast cells can be difficult- particularly in situations of breast hypermetabolism (breast feeding, mastitis) (16, 17). Also, false positive results can be caused by the accumulation of FDG in activated inflammatory cells such as granulocytes and macrophages (4).
In early stage breast cancer, the value of FDG-PET detection of micrometastatic disease and small lymph nodes is limited by the spatial resolution of PET imaging systems (about 5 mm). For initial staging of breast cancer, FDG-PET has limited additional value compared to conventional imaging and especially sentinel node analysis which allows relatively easy detection of micrometastatic disease (18). With regard to the value of FDG-PET for detecting and staging metastatic breast cancer (Figure 1), a number of reports exist. Moon et al. (19) assessed the accuracy of FDG-PET detection in 57 patients. Sensitivity was 85%, and specificity was 79%, when compared with routine imaging follow-up and histology as standard reference. False negative results in bone were particularly due to osteoblastic bone lesions. When FDG-PET was compared with magnetic resonance imaging (MRI; with histology as standard reference) in 32 patients, sensitivity was 94% (versus 79% for MRI), and specificity was 72% (versus 94% for MRI). In recent, larger studies, specificity varied from 95% (n = 80 patients, 12 with metastatic breast cancer) (20) to as low as 38% (n = 200 patients, 33 with metastatic breast cancer) (18). In contrast, sensitivity was up to 100% (20). Therefore, while sensitivity of FDG-PET may vary with tumour biological characteristics (such as tumour type, proliferation index, as mentioned above), overall acceptable and generally superior sensitivity is reported compared to conventional imaging for metastatic breast cancer. Specificity is (highly) variable in different reports, and therefore histologic or cytologic confirmation of PET positive lesions is advised in breast cancer, similar as in other tumour types (21). For the detection of osseous metastases, particularly osteolytic or mixed type, FDG-PET may have a specificity advantage over the conventional bone scan (22). Limited anatomical information by FDG-PET alone is increasingly improved by integration of PET with CT imaging (23).
Assessment of therapeutic response can also be studied by means of FDG-PET. A relative decrease of the standardised (FDG) uptake value of 20% compared to baseline, is considered to indicate a response (5). In one study in a neo-adjuvant setting, uptake of FDG was significantly decreased after one course of chemotherapy compared to baseline, in responding breast cancer patients (n = 51 patients) (24). Metabolic response determined with FDG-PET was more predictive of histopathological response than clinical examination or ultrasound imaging. Similar results were previously shown by Smith et al., in 30 patients with primary and metastatic breast cancer (25). However, in a recent report, histopathological tumour response could not be predicted in patients with low initial FDG uptake (in a large part of the patients: 57 out of 96) (26). Thus far, no studies have been performed in which treatment differentiation in breast cancer was based on tumour response assessment by means of FDG-PET. Therefore, the role of FDG-PET in this setting remains to be evaluated. Increased metabolic activity, or "metabolic flare", detected by FDG-PET in response to hormonal treatment was shown to be predictive for tumour response (11). However, differentiation of early tumour progression from metabolic flare in this setting may be difficult. Also in the setting of hormonal therapy, the usefulness of FDG-PET for therapeutic decision making has not yet been shown. Nonetheless, monitoring of response, as well as staging of recurrent or metastatic breast cancer is a reimbursable oncological application for PET scanning in for instance the USA.
One study has recently been published with regard to the prognostic role of FDG-PET in 47 metastatic breast cancer patients, treated with high-dose chemotherapy. Cachin et al. showed a significantly superior prognostic value of complete metabolic response measured with FDG-PET before- and one month after completion of chemotherapy, as compared with conventional imaging techniques. Mean survival was 10 months without metabolic response (n = 13), versus 24 months with response (n = 34 patients). In patients with response measured by conventional imaging (n = 31), median survival was 21 months, versus 10 months in non-responders. Although these differences appear small, in a multivariate analysis only metabolic response was an independent predictor of response (p < 0.0001) (27).
At present, FDG-PET imaging can be of value in selected cases for staging of recurrent and metastatic disease, in addition to conventional staging and imaging techniques. Sensitivity of this detection technique is generally reported to be superior to other techniques, but with varying specificity, histological confirmation appears necessary. In summary, FDG-PET is potentially useful for response monitoring and prognostic evaluation, however, future studies are required to confirm this.
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