Koos Boeve

188 Chapter 9 In chapter 3 , 46% of the SLN positive patients had macrometastasis (>2 mm) which was the case in 40% of the SLN positive patients in nine other studies [75]. The question is, is it possible to detect occult metastases with a higher sensitivity preoperatively? Recently, a review with promising results was published for detecting small metastases using a Combidex-enhanced MRI (CEM) [97]. The CEM is based on the intravenously administration of a solution of ultra-small (20-50 nm) superparamagnetic iron oxides (USPIO) particles (Combidex). CEM was already reported in the nineties, however Combidex was not available for a long time after the manufacturer withdrew Combidex from the registration process in Europe. Recently, the Radboud University Medical Center obtained all rights and manufactured Combidex again. After Combidex is administered, the USPIOs are picked up by macrophages. These macrophages are accumulated in lymph nodes and as a result normal lymph nodes (metastasis negative) lose MR signal (black) while lymph nodes positive for metastases remain white or have a white spot because the macrophages cannot accumulated at the position of the metastases. The difference between black and white lymph nodes enables to distinct positive and negative lymph nodes with a normal size from each other [97]. Moreover, with the CEM it is also possible to detect (pathological) lymph nodes as small as 2 mm [97,98]. Before the withdrawal of Combidex, a very promising 82% sensitivity and 93% NPV for the detection of lymph node metastasis were reported in 375 patients with prostate cancer [99]. In a study with 28 HNSCC patients the sensitivity for the detection of lymph node metastases increased from 52% to 82% after USPIOs were added to the MRI protocol [100]. Although the current evidence with the CEM is mainly from prostate and bladder cancer, Heesakkers et al. stated that this technique might be useable in other cancers as well. With the knowledge that ~25% of the early stage patients are diagnosed with an occult metastasis of which 40% is more than 2 mm in size, it might be that CEM lowers the occult metastasis rate with 10%. As mentioned earlier, a hybrid tracer with fluorescence is one of the recommendations in the consensus guidelines to prevent false negatives in FOM tumours [16] as a result of the shine-through phenomenon. Besides that hybrid tracer, several experimental techniques are mentioned in the imaging consensus guidelines such as the use of portable gammacameras, freehand SPECT, opto-nuclear probe for acoustic gamma and virtual augmented reality [15]. These techniques are not validated yet, but might be used in the future. Also the use of another radiolabelled colloid tracer was reported [101]. 99mTc-Tilmanocept (Lymphoseek®) has the theoretically advantage of a rapid injection site clearance and a stable bindingwithin lymph nodes as a result of the small particle size (7 nm) and the binding to macrophages by the CD206 receptors [102]. These rapid clearance and stable lymph node accumulation might prevent false negatives caused by shine-through. A phase III trial with 101 included