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RADIO-NUCLIDE IMAGING OF PROSTATE CANCER : A New Approach
ADITYA PAREEK
Doma Hospital, Domat Al-Jandal, Al-Jowf, Saudi Arabia.
INTRODUCTION
There has been an appreciable increase in the number of radical prostatectomies (RP) performed for localized carcinoma of the prostate (Cap) worldwide through last decade. However, the complications of this method of treatment are still significant, which are mainly the incontinence, stricture, and erectile dysfunction. Considering planned radical nature of this operation, it is obviously important that only those patients who have organ-confined-disease (OCD), and are suitable candidates on other grounds, be offered this operation. Thus the preoperative staging of the Cap is of vital importance.
Despite the availability of various methods to assess the preoperative stage, under-staging is quite common. In fact, over 1/3 of the patients undergoing RP are shown to have advanced disease on pathological examination postoperatively. This is very disappointing since the RP is unlikely to eradicate the cancer in this group of the patients and the complications of this procedure are significant. If the disease can be shown to be advanced preoperatively, this group of the patients can be spared unnecessary trauma and potential complications of the operation. This may also reduce the burden on waiting lists. In addition, the preoperative detection of advanced disease may further stimulate the interest in specific screening programmes using tumour markers.
STAGING MODALITIES
Commonly used staging modalities are a combination of DRE, PSA (total value, free/total PSA ratio, PSA density, and the value of PSA adjusted to transition zone etc), CT/MRI and radionuclide bone scan. These techniques have certainly improved the accuracy of preoperative staging but we are still nowheer near perfection, which is obviously the ultimate goal. RT-PCR for PSA-mRNA of circulating Cap cells is also being investigated though it is likely that this may over stage the OCD because of circulating shed cells from localized Cap, thus denying curative treatment to those who may actually need it. Anyway, the significance of this finding is not yet known.
Of the imaging modalities, Grey scale TRUS is most widely used, primarily for targeted biopsies because, as a staging method for local disease, it is quite inaccurate.[1] CT and MRI have greatly added to the staging accuracy though, it is still far from perfect (see reviews by Engelbrecht et al[2], and Probert et al[3].) Power-Doppler-Ultrasonography (PDU), 3D contrast enhanced PDU, and colour Doppler US are under evaluation.[4-7] It should be noted that all these imaging modalities depend on altered physical characteristics of the given area of tissue (prostate, lymph nodes, bone marrow, etc) in identifying the presence and dimensions of the tumour. These physical characteristics, such as deformity, size, architecture, elasticity, echotexture and vascularity, etc are not cancer specific. Areas of the prostate altered by infection, infarction, and amyloid deposits, etc may confuse imaging interpretations. Of course, none of these modalities can detect microscopic local tumour extensions.
Radio-nuclide bone scan is sometimes used to detect osseous metastases though an appropriate level of PSA (< 20 ng/ml) may suggest that it may be unnecessary. The radio-nuclide bone scan detects changes caused by altered bone turn over, which are not cancer specific, and of course, the bone scan is of no use for local (prostatic) tumour staging. Other methods using radio-nuclides to stage local disease have been disappointing. Most widely investigated technique employs administration of radioactive fluorine (F18) tagged to deoxy-glucose followed by imaging with a PET scanner. Results are generally poor.[8-12] Use of FDG-PET is based on the assumption that most cancer cells are rapidly dividing and hence utilize greater amount of glucose than normal cells. Deoxy-glucose is used as a vehicle for F18. Since the deoxy-glucose is arrested in the glycolytic pathways leading to its accumulation, a high gamma-emission is expected from accompanying F18. Strategically positioned PET scanner detects annihilation radiation so produced.
Not only the FDG accumulates in all cells, though to a varying extent depending mainly upon the energy expenditure of the cells, its accumulation in Cap cells may not be significantly different since most of the Cap cells are slow growing. Hence the energy requirements and FDG accumulation in Cap cells is likely to be rather lower than expected of cancer cells giving very little gamma-emission over and above that from normal surrounding cells. This problem can be circumvented if the vehicle carrying a radio-isotope almost exclusively in the cancer.
Ehrlich’s Magic Bullet
Monoclonal antibodies (mAb) tagged to a variety of radio-isotopes have been used with varying success. The problem with most widely investigated mAb (7E 11C 5.3 against PSMA) tagged with In 111 or Te99m is that the corresponding epitopes of the PSMA are intracellular, and therefore, not easily accessible to the antibody in intact cells.[13] Investigations using radio-isotope labelled antibodies against PAP and PSA have been largely unsuccessful.
A NEW APPROACH
It is widely known that certain ions and radicals such as fluorides and phosphates are strong inhibitors of PAP activity probably by homing onto the strategic sites of the molecule. Radio-active fluoride (F18) appears to be suitable because of its energy emission characteristics, which can be conveniently detected by a PET scanner. Injected or ingested F18 (tagged to a suitable vehicle) would be taken up by a variety of tissues including particularly the bone. In the prostate, the epithelial cells would take up F18 and this amount would include the amount of F18 combining with intracellular acid-phosphatase (AP). Since the Cap cells contain less AP, a proportionately less F18 accumulation and corresponding gamma-emission would be expected from the areas containing Cap cells; higher the histological grade of the cancer, lesser the intracellular AP and correspondingly lesser would be the gamma-emission from such a focus. Thus grading of the tumour may be possible after suitable standardization and calibration done experimentally with sections of the prostates removed surgically at RP. FAP-PET (Fluoride Acid Phosphatase PET) imaging may thus show the area of cancer as a window or space occupying lesion in the midst of surrounding medium of intense gamma-emission (from normal prostate). Microscopic extensions may be detectable. Microscopic foci of cancer cells in lymph nodes, bone marrow and other tissues may be detected by suitable subtraction scans or combining this technique with other imaging modalities.
Three dimensional reconstructions of the images may give an idea of tumour volume. Thus, the histological grade, tumour volume and local extension may be shown by FAP-PET. Since the normal prostate epithelial cells are very rich in AP and since there are very few other kind of cells in prostate which lack AP, the false +ve rates should be low.
A suitable and acceptable vehicle to carry F18 into prostate is required. NaF is widely used in laboratories to determine serum AP concentration. F may be replaced by F18. However, it may be better to procure and use F18 tagged to an antiandrogen (such as flutamide) or DES, if approved. Similar methodology may be employed for PSA using an appropriate radio-nuclide homing on to the PSA molecule intracellularly. If the FAP-PET can be demonstrated to be accurate, it would probably be easier and cheaper method as compared to the methods using monoclonal antibodies. Also, the FAP-PET is more likely to have greater specificity than FDG-PET. REFERENCES
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