1. Introduction. Cancer of the prostate (PCa) is currently the leading newly diagnosed cancer and the second most common cause of cancer deaths among men in the industrialized world . In Denmark alone more than 4000 men are yearly diagnosed with PCa . As PCa primarily affects elderly patients, one can assume that PCa will become one of the most important medical issues in the developed world due to the already high incidence combined with a growing population of elderly men.
The aetiology of the disease is not well understood. In its most common form PCa evolves from the glandular tissue of the prostate. Metastatic spread will most commonly happen as lymphogenous spread to the regional lymph nodes or as haematogenous spread to the red bone marrow .
Intended curative treatment of PCa is associated with considerable side effects, in particular incontinence, impotence and radiation damage to the surrounding tissues. Furthermore, over 30% of patients with organ-confined disease, which was treated with radical prostatectomy, will have biochemical relapse within 10 years . Relapse may be due to local recurrent disease suggesting poor surgical quality or poor initial staging with undetected metastases at the time of treatment.
At diagnosis patients are stratified as having low, intermediary or high risk of dissieminatio according to D'Amico. Patients with intermediate or high risk of dissemination will be examined further with whole-body bone scintigraphy (WBS) and pelvic lymph node dissection (PLND).
2. Background. 2.1. Current staging and limitations. WBS has been the examination of choice for evaluation of potential dissemination to bone. WBS utilizes 99mTc-labeled methylene diphosphonate (99mTc-MDP) that binds to the bone matrix formed by the osteoblasts. Gamma cameras detect the γ-radiation emitted by the decaying tracer thereby creating a 2-dimensional image depicting local osteoblast activity .
Several limitations apply to the use of WBS in staging of patients with PCa. Sensitivity has reported as low as 39% in lesion-based analysis in patients with a low number of lesions . This combines with a low sensitivity due to many equivocal lesions caused by other bone pathology than metastasis.
Sensitivity and specificity is improved by the use of single-photon emission computed tomography (SPECT), where the same tracer as with WBS is used to generate a three-dimensional image using a rotating gamma camera. This method also gives better anatomical information on the exact position of a potential metastasis.
The examination of choice for the evaluation of potential metastases to lymph nodes is extended PLND . This procedure is done either prior to radiotherapy or during prostatectomy in patients with intermediate or high risk of dissemination. The optimal extent of the dissection is debated. The extended PLND performed at our institution includes the nodes in the obturator fossa, the nodes over the external iliac artery and vein, the nodes around the internal iliac artery and the nodes along the common iliac artery up to the crossing of the ureter. This dissection is assumed to include approximately 75% of lymph nodes known to harbor primary prostatic lymph node metastases . Extended PLND is surgically demanding with risk of lymphocele formation, infectious complications and severe bleeding due the lymph nodes' close proximity to the large vessels in the pelvis. All in all extended PLND is perhaps the best option for lymph node staging of PCa but it cannot be considered as optimal due to the above-mentioned issues.
2.2 Positron Emission Tomography (PET). Positron Emission Tomography combined with Computerized Tomography (PET/CT) is a well-established tool in diagnosing and staging of several types of cancer . PET is an imaging technique where pairs of gamma rays emitted by positron-emitting radionuclide tracer are detected, producing a three-dimensional image of tracer concentration based on the amount of gamma rays emitted. The radioactive tracer is coupled to a biologically active molecule depending on the organ or metabolic process of interest . These images can then be fused with CT to create a combined functional and high-resolution anatomical image. Several tracers have been developed for use in cancer diagnostics and staging. As of now, PET/CT has no generally accepted role in the diagnosing or staging of PCa neither in Europe nor in the US .
2.2.1 Choline. Choline is a precursor for phosphatidylcholine, a phospholipid that is integrated in the cell membrane making it a marker for cell membrane turnover and metabolism . 11C-Choline was first used as a PET tracer in 1997 . Since then many studies have been performed with 11C-Choline and later 18F-Choline (FCH) having approximately the same properties as 11C-Choline, but with a longer half-life (110 min vs. 20 min) making it more versatile in every-day use. A recent study from our department tested the use of FCH-PET/CT in detecting lymph node metastasis in 210 patients with PCa . The study concluded that FCH-PET/CT was not ideally suited for lymph node staging but could give additional information about bone metastasis. Several other investigators have also implied this , . A likely reason for the better detection of metastasis to the bone is that bone metastasis in an early stage is actually bone-marrow metastases rather than bone matrix metastasis and that it most likely that bone-marrow metastases proceed to bone matrix metastases. These will not be detectable by WBS (and probably not by CT and MRI either). Larger prospective series on the use of FCH-PET/CT for imaging of bone metastasis in PCa-patients have not yet been produced.
2.2.2 FDG. 18F-fluorodeoxyglucose (FDG) is the most common PET-tracer used in more than 95% of oncologic PET studies. FDG is a metabolic tracer depicting cellular glucose uptake, which is increased in cancer, inflammation and other conditions with a rapid cellular turnover. It is trapped inside the cells depending on the presence and activity of the enzyme glucose-6-phosphatase, which appear to be decreased in proportion to the aggressiveness of the individual malignancy. Increased cellular FDG accumulation is, therefore, not specific for malignancies, but at the same time an indicator of the degree of malignancy, which may cover the entire spectrum ranging from insignificant and non-aggressive to highly aggressive and rapidly metastasizing PCa FDG-PET imaging for PCa has been intensively investigated, but so far without convincing success. The reasons are several. Well-differentiated PCa's utilizes less glucose than other tumors in general and thus may give rise to results considered false negative. Moreover, since surplus radioactive FDG is excreted through the kidneys, intense accumulation in the ureteres and urine bladder may hamper interpretation of the prostate gland and nearby regional lymph nodes .
However, this does not necessarily mean that FDG is a poor tracer for imaging PCa. In fact, it may be a very useful one, if considering several factors not taken into account in the past. The traditional acquisition time point one hour after administration of tracer may not be the ideal one. This time point is entirely arbitrary. The increase in FDG accumulation seems to take place for several hours after administration in malignant tissue, whereas FDG accumulation in normal or inflamed tissue may reach a maximal uptake at an earlier time point . Thus, late imaging may result in increased FDG accumulation and decreased blood and urine background and, therefore, a much better signal-to-noise ratio and subsequently better results. A recent review on the use of dual-point acquisition demonstrated an increased specificity and sensitivity for the detection of several malignancies . The use of dual time point FDG-PET/CT in staging of PCa has not been investigated.
3. Trial objective. To evaluate the diagnostic value of Dual time point-PET/CT in detecting bone and lymph node metastases in 30 patients with newly diagnosed PCa
4. Method. Patients included in this study will have Choline PET/CT perfomed as part of another study. In addition a dual time point FDG-PET/CT will be performed. The FDP-PET/CT will be performed with acquisition 1 and 3 hours after administration of tracer. All scans are performed in random order within three weeks and the images interpreted by a specialist in nuclear medicine and a specialist in radiology.
Images are interpreted based on visual evaluation with supplementary measurements of SUV. Activity in lymph nodes will be recorded according to their location - external iliac vein, obturator fossa and internal iliac artery and vein.
During extended PLND the tissue from the above mentioned stations will be removed and placed in separate containers marked as followed - "Iliaca externa dxt", "Iliaca externa sin", "Fossa obturatorius dxt", "Fossa obturatorius sin", "Iliaca interna dxt" and "Iliaca interna sin" Experts in pathology will examine the tissue samples. Results of PET/CT will not be available to the pathologist.
