Marina Hodolic˘ • Stanley J. Goldsmith
Prostate carcinoma is the most common life-threatening cancer affecting men in the Western world. In the United States, it is estimated that almost 250,000 new cases are diagnosed annually and that approximately 1 in 10 will ultimately die of the disease despite improved methods of early diagnosis, evaluation, and management. Prostate cancer is the second highest cause of cancer-related death per year, second only to bronchogenic carcinoma in the United States.1 Rates of detection vary widely, with the incidence in South and East Asia less frequent than in Europe and United States.2 Prostate carcinoma tends to develop in men over the age of 50; it is diagnosed in 80% of men by the age of 80. Recently, there has been recognition that the disease in older men may not merit the same vigorous intervention as in younger men. This insight evolves from greater understanding of the complex biology and clinical course of this tumor.
In the development of prostate cancer, many factors have been implicated: genetics and diet among them. The American Dietetic Association and Dieticians of Canada report a decreased incidence of prostate cancer in men who follow a vegetarian diet.3 However, there is no established relationship between any environmental factor and the incidence or aggressive nature of prostate carcinoma.
In the majority of cases, in the early stages, prostate cancer is harmless and symptom free. This leads to the assumption that appropriate and sensitive diagnostic procedures are crucial for a good survival rate. The serum marker prostate specific antigen (PSA) provides an early clue to the presence of prostate carcinoma but it is a nonspecific biomarker. It is increased in the serum of men as they age and the prostate enlarges, as well as in patients with prostatitis. Nevertheless, an elevated PSA value should lead to other diagnostic procedures such as digital rectal examination, endorectal ultrasound (US) and biopsy resulting in earlier detection of malignancy than had been the case prior to the availability of PSA determinations. The earlier and improved detection of prostate carcinoma has contributed to an apparent increase in the incidence of prostate malignancy. Nevertheless, clinical management remains complex including the choice of therapeutic intervention. This depends somewhat on the age of the patient at the time of detection as well as the nature (degree of aggressiveness) and extent of disease. In recent years, a variety of imaging modalities have become available: US, computed tomography (CT), and magnetic resonance imaging (MRI) improve detection of disease within the prostate gland but they do not identify nodal or distant metastases early in the course of the disease nor do they characterize the degree of aggressiveness of the tumor. Identification of lymph node involvement by either CT or MRI is based primarily on size criteria; nor do these modalities determine the degree of aggressiveness of the tumor, a feature that would be useful to guide therapy. In summary, the following represents needs that are not satisfied by conventional imaging methods (CT, MRI).
• Early detection and localization of tumor within the prostate gland (to avoid false-negative biopsies)
• Characterization of the degree of aggressiveness of the tumor foci (to avoid under- or overestimating therapeutic options)
• Early detection of lymph node metastases
• Early detection of distal metastases
CLINICAL FEATURES OF PROSTATE CARCINOMA
Early disease is detected by elevation of a serum PSA value leading to a workup that involves a digital rectal examination, referral to a urologist, endorectal US, and biopsy. In addition to providing a diagnosis of malignancy, biopsy material provides a means to assign a Gleason grade. The Gleason scoring system is based upon the microscopic architecture which provides a measure of the degree of aggressiveness of the malignant tissue and serves as a prognostic indicator, thus assisting in determining management strategy. The grades range from 1, with small closely packed, relatively orderly pattern, to 5, with larger poorly differentiated cells, lack of glandular architecture, and considerable disarray. The sum of the two most common patterns provides the overall Gleason score from 2 to 10. Higher Gleason scores (i.e., a Gleason score of 7 and above) are associated with poorer prognosis.
With the widespread availability of serum PSA, patients are now seen early in the course of disease where many patients will not have obvious findings of pelvic or distal involvement. Treatment in these cases is focused on the prostate gland. This involves either surgical prostatectomy or external beam radiation or brachytherapy (insertion of radioactive seeds directly into the prostate). In recent years, other techniques to remove tumor without sacrificing the entire prostate gland (such as cryosurgery) have become available but they are not widely used. Improved mapping of the intraprostatic distribution of tumor and characterization of the degree of aggressiveness of the tumor would enable better informed decision making and perhaps modify surgical and subsequent clinical management. These options may be accompanied by hormonal therapy; that is, elimination of androgen hormones that have a stimulating or supportive effect on prostate tissue and tumors. It is no longer necessary to surgically castrate these patients; the hormonal suppression of testosterone is sufficient to be considered pharmacologic castration. The serum PSA value falls to very low or undetectable levels and is measured periodically. In approximately one of three patients, after a quiescent period up to 5 years after initial treatment with no biochemical (PSA) evidence of disease, a rise in the serum PSA is detected. If the PSA level rises, the next challenge is to identify the location and extent of the source:
• prostate bed recurrence and/or
• pelvic lymphadenopathy and/or
• distal osseous and/or
• soft tissue involvement
Obviously, if the patient has not undergone surgical prostatectomy, the assessment of recurrent disease in residual prostate gland tissue is another challenge.
Each of these possibilities, from extent of disease at presentation to the reappearance of PSA in the treated patient, presents many decisions and choices for the patient and urologist or oncologist. Until recently, US, CT, MRI, and 99mTc methylene diphosphonate [99mTc-MDP] bone scintigraphy were the only imaging procedures available to assess the extent of disease in patients with prostate carcinoma. Radionuclide bone scintigraphy, of course, was only useful to determine if bone metastatic disease was present. Regardless of whether it was positive or negative, it did not exclude soft tissue involvement. In the United States, In-111 pendetide caproate [Prostascint], a radiolabeleled monoclonal antibody, has been approved for its use to determine the extent of disease in newly identified patients who were at high risk for early metastatic disease based on the Gleason score of biopsied tissue and to identify the source of rising PSA values in patients who had undergone surgical prostatectomy. The technique, however, has had limited utility.
The conventional imaging methods used to assess and localize disease burden in patients with known or suspected prostate carcinoma are limited to CT and traditional radionuclide bone scintigraphy with 99mTc-methylene diphosphonate. A number of new imaging techniques are at various stages of clinical investigation. Some are currently used regularly in specific medical centers that have access and are in locales that provide reimbursement. MRI has evolved and now has available many additional pulse sequences that provide further insight into the biology of the changes observed in the image provided. Nevertheless, there is no consensus about the optimal imaging technique or the criteria for the use of MRI in patients with suspected or proven prostate carcinoma. MRI quality improves with the use of an endorectal coil. It is likely, though not yet confirmed that 3T magnets will outperform 1.5T systems. Apparently the reliability of results (sensitivity) varies with the location of lesions within the prostate; more superficial lesions detected and characterized more consistently than lesions deeper in the prostate. There is high signal intensity on T2-weighted images in the peripheral zone of the gland whereas deeper foci of prostate carcinoma have decreased signal intensity. The sensitivity of the technique is less reliable in the transition zone or the anterior portion of the prostate gland (further from the endorectal coil). Nevertheless, there is no consensus about the optimal criteria for the use of MRI in patients with suspected or proven prostate carcinoma.
Nevertheless, there is no consensus about the optimal criteria for the use of MRI in patients with suspected or proven prostate carcinoma.
There has been persistent interest in the potential use of MR spectroscopy to assess regional metabolic differences in prostate tissue. Although the spatial resolution of MR spectroscopy is significantly less than MRI, some data has emerged, likely compromised, however, by volume averaging of the metabolic data. MR spectroscopy can identify relative levels of citrate and choline. The normal prostate tissue has relatively high levels of citrate whereas malignant tissue has higher levels of choline and relatively reduced citrate levels. This may reflect the increased choline utilization involved in membrane synthesis associated with tumor growth.4
Nuclear medicine imaging has evolved also in recent years and numerous single photon and positron emission radiopharmaceuticals have been developed (Table 15.1). There are two broad groups of radiopharmaceutical imaging agents: positron-emitting tracers and single photon emitters. Because of the coincident nature of the signal associated with positron emitter, imaging always provides transaxial tomographic images; hence the term positron emission tomography (PET). Single photon emitters have been used to obtain planar images for many years but for the past 25 years, instrumentation that can provide tomographic images from single photon emitters has been available. Single photon emission computed tomography (SPECT) and PET imaging are currently used to best advantage in combination with CT acquisition and image fusion.
RADIOTRACERS USED TO IMAGE PROSTATE CARCINOMA
Although not tumor specific, 18F-FDG PET/CT is currently the most widely available and widely used nuclear medicine procedure to identify primary and metastatic cancers. The utility of 18F-FDG is based upon the increased anaerobic glucose metabolism present in most tumors. In early stages, prostate cancer is not characterized by a significant increase in the metabolic activity on 18F-FDG PET/CT imaging. Based on the low overall sensitivity for the detection of prostate carcinoma in early clinical studies, the general impression evolved that 18F-FDG is not useful to image prostate cancer or that its use is limited to the most aggressive cancers.5–9 The conclusion that 18F-FDG is not useful is certainly not the complete picture. 18F-FDG has poor overall sensitivity for the detection of prostate carcinoma early in the course but it is sensitive to detect aggressive tumors and hence, it is useful to characterize the degree of aggressiveness of the tumor. Furthermore, both primary and metastatic prostate carcinomas have been detected as an incidental finding in men undergoing 18F-FDG PET/CT for nonprostate disease or on follow-up of other abdominopelvic tumors (Fig. 15.1).10 Low-grade prostate carcinoma has a low metabolic rate and low levels of the glucose transport protein, Glut-1 and consequently, relatively low levels of anaerobic glucose metabolism and 18F-FDG uptake. Certainly, when the tumor is more aggressive (higher Gleason scores), glucose utilization is increased and 18F-FDG images are revealed. Since 18F-FDG uptake correlates with the degree of tumor aggressiveness, identification of metastatic prostate cancer with 18F-FDG indicates a poor prognosis. In comparison with radiotracers like 11C-Choline or 18F-FCH, 18F-FDG sensitivity is better associated with the Gleason score; that is, tumors identified on 18F-FDG PET imaging are more apt to have higher Gleason scores whereas 18F-FCH is, in general, equally positive in both high and low Gleason score foci. Since 18F-FDG is insensitive to prostate carcinoma in general, a negative 18F-FDG does not reliably exclude tumor. Accordingly, 18F-FDG is generally viewed neither as a screening tool nor as the imaging agent of choice. Nevertheless, nuclear medicine physicians should be alert to the finding of focal increased 18F-FDG in the prostate as it may identify prostate carcinoma in men undergoing 18F-FDG PET/CT for other reasons. Moreover, in aggressive disease, 18F-FDG imaging can be used to assess tumor response to chemotherapy.
FIGURE 15.1. A 69-year-old man who is presented with anemia unresponsive to therapy; referred with diagnosis of aplastic anemia. The whole-body maximal intensity projection (MIP) image reveals 18F-FDG focal uptake in the prostate gland right posterior quadrant (black arrow ). 18F-FDG activity also identifies a right inguinal lymph node (white arrow).
Glucose (and hence 18F-FDG) enters the cell via glucose transport proteins. In tumor cells, this is most commonly the Glut-1 transporter which is underexpressed in prostate cancer in its early stages (low Gleason scores) but increases in primary prostate adenocarcinomas with higher Gleason scores and in metastatic disease when it becomes androgen (or castrate) independent. Aside from the variable biology of prostate carcinoma, imaging of the prostate itself is compromised somewhat by its proximity to the bladder. Finally, in assessing tracer sensitivity, characterization of any tracer is complicated by the question being asked:
• detection of disease within the intact prostate
• detection of residual or recurrent disease in the prostate bed
• detection of tumor in pelvic or distal lymph nodes
• detection of disease in bone marrow and/or bone
Each of these specific indications involves site-specific issue including the sufficiency of blood flow and tissue perfusion, the tumor-to-background tissue perfusion and metabolic activity.
Nevertheless, despite early random observations that prostate carcinoma, in general, was not 18F-FDG avid, reports of successful identification of prostate cancer with 18F-FDG began to appear in the 1990s.5–9 Initial reports with mixed patient populations, meaning patients at various clinical stages with various disease burdens, had a wide range of sensitivities, some as low as 4% and others as high as 81%. This suggests that the populations studied were very heterogeneous with some patients with early stage disease and others with clinically more aggressive disease. Shreve et al., for example, reported a sensitivity of 65% for bone metastases whereas Yeh et al. reported only an overall 20% sensitivity in a small group of patients.7 Oyama reported that 18F-FDG SUVs appeared to be somewhat proportional to the Gleason score of the primary tumor and that the SUVmax was higher in lymph node and bone metastases compatible with the suspicion that more aggressive metastatic lesions had a higher rate of glucose utilization and hence higher SUVmax values.9 In a later study, Oyama evaluated the SUVmax, PSA, and prostate size in 10 patients with moderately aggressive disease prior to therapy and 1 to 5 months later after a 28-day course of antiandrogen therapy with an LH–RH agonist (goserelin). The 18F-FDG SUVmax decreased in all cases with decreases in serum PSA and prostate gland size. In addition, although there was an occasional unexplained exception, there was a decrease in SUVmax in metastatic lymph nodes and bone lesions.11 By contrast, Liu et al. found no correlation between Gleason scores and 18F-FDG uptake in patients with prostate carcinoma confined to the prostate.12 In 2002, Morris reported that 18F-FDG PET was useful to discriminate osseous metastases with active tumor from quiescent boney lesions, Of 134 lesions in 17 patients identified as positive on 18F-FDG and/or bone scintigraphy, only 95/134 (71%) were subsequently determined to be active lesions. All lesions seen on 18F-FDG PET were subsequently determined to be active tumor sites demonstrating that 18F-FDG was more specific than bone scintigraphy for the detection of active tumor foci in the skeleton.13
In patients with the so-called biochemical failure or PSA relapse, that is rising PSA after surgical or radiation prostatectomy, 18F-FDG PET (PET/CT) has frequently identified the site or sites of recurrence with a reasonable degree of accuracy, that is, most positive findings are true positive (Fig. 15.2).14–16 Depending on the PSA values and PSA doubling time, there are various levels of sensitivity since the utility of 18F-FDG PET depends upon the degree of aggressiveness of the tumor. Obviously, since alternate imaging methods (bone scans, CT, MRI) failed to identify sites for biopsy, the overall sensitivity and validity of negative 18F-FDG PET scans cannot be assessed because there are no findings for comparison or identification of a site to biopsy. Schoeder et al. found that 18F-FDG PET was most useful in patients with a PSA >2.4 ng/mL or a PSA doubling time >1.3 ng/mL/yr.16
By 1999, reports began to appear comparing 18F-FDG to other tissue substrates such as 11C-Methionine,17,18 11C-Acetate [11C-Ac],19–24 11C-Choline [11C-Ch], 18F-Fluorocholine [18F-FCH] and more recently to prostate tissue-specific PET and SPECT tracers. By far, the most widely investigated substrate has been 11C-Choline and 18F-Fluorocholine [18F-FCH].24–66
The increased amino acid transport and metabolism associated with tumor growth can be assessed with the positron-emitter–labeled amino acid 11C-Methionine. As might be expected, 11C-Methionine identifies more tumor sites in patients with metastatic prostate tumor than 18F-FDG but 18F-FDG identifies the more aggressive metastatic sites.17 In a study of patients with multiple likely metastatic sites identified on conventional imaging, 11C-Methionine PET imaging identified 72% of the sites whereas 18F-FDG PET imaging identified only 48%. In fact, it was suspected that the negative 11C-Methionine sites may have been due to tumor necrosis and that rather than being false-negative sites on 11C-Methionine imaging, the data actually demonstrated false-positive findings on bone scintigraphy.18
FIGURE 15.2. The same patient as in Figure 15.1.18F-FDG uptake in metastatic prostate cancer lesions: PET/CT (A, D), CT (B, E), PET (C, F). A–C: transaxial slices at level of the prostate gland revealing 18F-FDG avid focus in right posterior quadrant of intact prostate gland (black arrow). D–F: transaxial slices, slightly cephalad to prostate gland revealing 18F-FDG avid metastatic focus in right iliac bone (open arrow).
Low levels of GLUT-1 transporters are characteristic of normal and malignant prostate cells. Hence, 18F-FDG has limited utility as a diagnostic imaging tracer for detection and extent of disease in patients with prostate cancer. Whereas citrate is usually produced by the tricarboxylic cycle (TCA) in prostatic epithelium and is present in excess in normal cells perhaps because of the relatively quiescent metabolism of these cells, malignant prostate cells oxidize citrate as an energy source. Since glucose transport in prostate carcinoma cells is limited, acetate can serve as an alternate substrate for the TCA cycle.
Based on these observations, Oyama et al. reported on the utility of 11C-Acetate as an imaging agent to identify prostate carcinoma.19 Using a 740 MBq (20 mCi) dose of 11C-Acetate, PET showed primary lesions within the prostate prior to treatment in 22 of 22 patients (100% sensitivity) with histopathologically confirmed prostate carcinoma. 18F-FDG PET detected tumor in 15 of 18 evaluable patients (83% sensitivity) in the same patient group. In general, 11C-Acetate uptake was greater than18F-FDG uptake and tumor foci were more readily detectable. Five patients had lymph node metastases, all readily detected with 11C-Acetate whereas only 2 of 5 were detectable with 18F-FDG. Similarly, in bone metastases, 11C-Acetate was positive in all but one lesion detected on bone scintigraphy whereas 18F-FDG PET only identified a subset of patients. In addition, 11C-Acetate activity was not observed in the urine. There was no correlation between Gleason score and uptake of either 18F-FDG or 11C-Acetate although patients with advanced clinical stage disease showed higher 18F-FDG uptake than patients with earlier stage disease.19
Kotzerke et al. investigated the utility of 11C-Acetate to detect recurrent disease in patients with increasing PSA following a “complete” prostatectomy. Patients were imaged 5 minutes after an IV injection of 800 MBq 11C-Acetate. The results were compared to transurethral ultrasound (TRUS) followed by biopsy. 11C-Acetate PET demonstrated local recurrence in 15 of 18 patients identified by TRUS and biopsy. No focal prostate bed activity was identified in 13 patients with subsequent negative biopsies. Lymph node involvement and bone metastases were identified in five patients each.20
Fricke et al. reported similar results in 25 patients suspected of relapse or metastatic disease following primary treatment. 11C-Acetate detected prostate tumor in 20/24 patients (83%) whereas 18F-FDG detected only 10/15 malignant lesions in local recurrences or lymph node metastases. Observing that 18F-FDG was more accurate in the detection of distal, presumably more aggressive, metastases, Fricke et al. proposed combined 11C-Acetate/18F-FDG PET imaging in the follow-up of prostate carcinoma patients.21
Albrecht et al. performed 11C-Acetate PET in 32 patients with evidence of early relapse; that is, rising PSA after initial treatment. Seventeen of the patients had been treated with radiotherapy and 15 were treated surgically. The PET scans were coregistered with separately acquired CT scans. A subset of 12 patients underwent endorectal MRI and 9 patients had MR spectroscopy. The results were similar to those reported by others. The authors conclude that 11C-Acetate PET “may have significant potential for the detection of recurrent prostate cancer.” One of the advantages being that PET offers a single technique to assess local prostate gland/bed recurrence, regional and distal lymph nodes, and possible skeletal metastases.22 In the most extensive study reported to date, Haseebuddin et al. performed 11C-Acetate PET/CT imaging on 107 men with intermediate- or high-risk disease based on Gleason scores comparing treatment failure and failure-free survival in patients who were PET-positive and PET-negative. The median treatment-failure free survival of PET-positive patients was 1.3 months whereas PET-negative patients had a median value of 31.5 months. Interestingly, patients who were false positive on PET/CT (compared to subsequent biopsy evaluation) had a worse treatment–failure-free interval than patients who were true negative suggesting that 11C-Acetate PET/CT correctly identified disease that was missed on subsequent hostopathologic evaluation.23
In 2007, Morris and Scher reviewed most of the published 11C-Acetate PET imaging studies published to that time, commenting on the results in a total of 154 patients. They stressed that there is a need for a consistent imaging protocol to include comparison with traditional bone scintigraphy and CT scans. Foremost in their recommendation, in addition to a call for studying a larger number of patients, was defining a specific prostate carcinoma patient population: untreated patients; postinitial treatment with rising PSA but no evidence of tumor recurrence on traditional imaging; extent of disease in patients with known metastases; response to therapy (presumably antiandrogen).24
Choline and Choline Analogs
By far, 11C-Choline and 18F-Fluorocholine aside from 18F-Fluorodeoxyglucose have been the most extensively reported radiotracers used for the detection of prostate carcinoma. Choline was discovered in 1864 by the German chemist, Adolph Strecker. It was chemically synthesized in 1866 and over 100 years later in 1998, it was classified as an essential nutrient by the Food and Nutrition Board of the Institute of Medicine in the United States in 1998.25As a component of cell membrane phospholipids, choline when labeled with a PET tracer such as 11C is an excellent biomarker to assess increased proliferation and malignant transformation.26
Many cancers show alterations in choline metabolism: The increased choline uptake in tumor tissue is associated with modulation of enzymes that control anabolic and catabolic pathways. The increased level of choline-containing compounds is associated with increased synthesis of phospholipids in cellular membranes.
Initially, choline was labeled with 11C (11C-CH). Radiolabeled choline is indistinguishable from natural choline. In vitro experiments demonstrated that radiolabeled choline is incorporated into tumor cells by active transport and subsequently phosphorylated in the cells and integrated into phospholipids.
11C-CH is primarily eliminated by the liver which is advantageous since there is little radioactivity in the urinary tract. The 20-minute half-life of 11C limits its utility at sites without a cyclotron and PET radiochemistry facilities.
Since choline itself is a natural component of human diets and has been demonstrated to be safe when ingested, the 11C-Choline tracer has been approved by the FDA in the United States as an imaging agent “that helps detect prostate cancer.” The Mayo Clinic in Rochester, MN is the first facility to receive specific approval. Because of its short half-life, it is not likely to become commercially available.
FIGURE 15.3. PET maximum intensity images (MIP) of 18F-FCH biodistribution at 1 minute (LOWER) and 45 minutes (UPPER) after administration in a patient with metastatic prostate cancer (Gleason score 9, PSA 500 ng/mL).
The advantages of the longer-lived radionuclide, 18F (half-life: 110 minutes), led Hara et al.27 to synthesize the fluorocholine analog, 2-[18F]-fluoroethyldimethyl-2-hydroxyethylammonium (FEC). The rates of FEC phosphorylation were low and the phosphorylation step is crucial for PET imaging. In 2000, DeGrado synthesized no-carrier-added choline analog [18F]-fluoromethyl-dimethyl-2-hydroxyethylammonium (FCH) and evaluated it in a murine PC-3 human prostate cancer xenograft model. Both compounds showed similar properties with minor differences (later peak uptake for FEC).28
The longer half-life of 18F provides 18F-Choline analogs allow to be distributed to centers lacking an on-site cyclotron and makes it possible to perform repeated (dynamic) imaging. The shorter positron range of 18F, also provides better spatial resolution and better imaging quality.29 18F-Choline analogs, however, are eliminated via the kidneys which is a disadvantage since urinary activity can be mistaken for malignant tissue in the pelvis. This effect is minimized with early dynamic imaging, prior to tracer appearance in the bladder, and delayed imaging, after voiding.
Biokinetics and Dosimetry of 18F-FCH
The distribution of radioactivity varies in various organs. Based on the biokinetic compartmental model in prostate cancer patients, dosimetry of 18F-FCH has been calculated. The highest radioactivity has been found in the kidneys (reference patient, 0.079 mGy/MBq; individual values, 0.033 to 0.105 mGy/MBq) and liver (reference patient, 0.062 mGy/MBq; individual values, 0.036 to 0.082 mGy/MBq).30 A large amount of radioactivity appears in urine after a time lag of 5 minutes. The reference patient received between 0.017 and 0.030 mGy/MBq dose to the wall of the urinary bladder, depending on frequency of voiding. Blood clearance is rapid and in 1 minute, blood level is minimal. The uptake in prostate cancer tissue is rapid with significant uptake after 1.5 minute (Fig. 15.3). The effective whole-body dose equivalent from administration of 4.07 MBq/kg (0.110 mCi/kg) is approximately 0.01 Sv.31
Physiologic Distribution of 18F-FCH
Physiologic 18F-FCH uptake is noted in salivary glands, liver, pancreas as well as renal parenchyma and urinary bladder. Faint uptake is seen in spleen, bone marrow, and muscles. Bowel activity is variable (Fig. 15.4).
FIGURE 15.4. Physiologic distribution of 18F-FCH.
Patient Preparation and 18F-FCH PET/CT Acquisition Protocols
Patients should fast 6 to 10 hours prior to the scan and should be well hydrated. The influence of androgen deprivation therapy on choline uptake in patients with prostate cancer disease has not yet been clarified. Nevertheless, most patients continue their antiandrogen therapy prior to choline-PET/CT acquisition. 18F-FCH PET/CT in patients with prostate cancer is most frequently performed using a dose of 2.5 to 4 MBq/kg of 18F-FCH intravenously.
At present, there is no standardized 18F-FCH PET/CT acquisition protocol. Many nuclear medicine departments incorporate late imaging with early (dynamic) imaging, to avoid interference from bladder accumulation. Dynamic acquisition over the pelvis immediately after injection of the tracer (0 to 15 minutes) allows visualization of the pelvic disease without interference from physiologic filling of urinary activity in the bladder.31–36 Whole-body acquisition is usually performed 45 to 60 minutes later. Late acquisition allows better sensitivity for distal disease.37–44 Fused PET/CT images of early and late acquisitions, and coregistered CT data are used for interpretation.
CLINICAL APPLICATION OF 18F-FCH PET/CT
18F-FCH PET/CT imaging has been investigated for a variety of indications in prostate cancer patients:
• Initial staging of prostate cancer disease (high-risk prostate cancer patients)
• Restaging of prostate cancer disease (biochemical evidence of recurrence)
• Localization of prostate cancer (elevated PSA level and negative biopsy)
• Treatment monitoring of prostate cancer disease
• Therapy planning of prostate cancer disease
Initial Staging of Prostate Cancer Disease (High-Risk Prostate Cancer Patients)
18F-FCH PET/CT is a useful imaging modality that characterizes extent of disease in the entire body, both soft tissue and the skeleton especially in high-risk prostate cancer patients.
Choline uptake in inflamed tissue as well as in cancer cells is resulting in suboptimal specificity. Suboptimal sensitivity is mainly due to limited spatial resolution of PET/CT systems (detection of lymph node micrometastases, extracapsular extension, seminal vesicle involvement). The role of 18F-FCH PET/CT to detect regional lymph node metastases varies among reports. In a large study involving 912 lymph node samples (in 130 patients with intermediate- or high-risk prostate cancer), greater sensitivity to detect lymph node involvement was found in the lymph nodes equal or greater than 0.5 cm in size. Sensitivity and specificity were 66% and 96%, respectively.44 By contrast, in a study of patients with intermediate-risk prostate cancer disease (Gleason score >6 and PSA >10 ng/mL), a sensitivity of only 10% and a specificity of 80% were observed in patients where sentinel lymph nodes were identified and pathologic choline uptake was compared with histology.45 FCH PET/CT showed very good results for the early detection of bone metastases in men at initial staging of prostate cancer disease.46,47 Some bone metastases have no detectable morphologic changes on CT—probably due to bone marrow involvement, but they are positive on 18F-Fluorocholine scans.
Despite different conclusions in various studies, 18F-FCH PET/CT appears to have a role in the initial staging in patients with biopsy-proven high-risk prostate cancer (Fig. 15.5).
Restaging of Prostate Cancer Disease (Biochemical Evidence of Recurrence)
The greatest contribution of 18F-FCH PET/CT in patients with prostate cancer disease is in the evaluation of patients with evidence or suspicion of recurrent disease. This modality provides information about locoregional as well as distant sites of recurrence (Figs. 15.6 and 15.7). Thus, 18F-FCH PET/CT helps to determine appropriate treatment (radiation therapy, antihormonal treatment, salvage surgery, chemotherapy, or combination of these) in patients with recurrent prostate cancer.
FIGURE 15.5. 18F-FCH PET/CT scan in initial staging in a patient with prostate cancer (Gleason score 9, PSA 10 ng/mL): positive left iliac lymph node.
FIGURE 15.6. 18F-FCH PET/CT scan in a patient with recurrent prostate cancer disease (Gleason score 7, PSA 4 ng/mL): local recurrence in prostatic bed.
FIGURE 15.7. 18F-FCH PET/CT in a patient with recurrent prostate cancer disease (Gleason score 9, PSA 1.3 ng/mL): recurrence in right pubic bone.
After radical prostatectomy, a confirmed PSA value >0.2 ng/mL represents recurrent prostate cancer disease—biochemical relapse.48 Following radiation therapy, a confirmed PSA value >2 ng/mL represents recurrent prostate cancer disease.49,50 Approximately 19% to 53% patients initially treated with radical prostatectomy or radiotherapy will have recurrent disease.51,52 Currently, there are no guidelines regarding imaging procedures in patients with biochemical relapse; CT and bone scintigraphy are sensitive at PSA levels >20 ng/mL.52 MRI showed good results in the evaluation of prostatic bed but it is not routinely recommended.52,53
Several studies showed that 18F-FCH PET/CT is sensitive to detect recurrent prostate cancer disease if PSA is greater than 2 ng/mL.54,55 In patients with PSA <2 ng/mL, the detection rate is 30% to 40%.56 PSA doubling time (PSA DT) is an independent predictor of choline PET/CT results.57 In another study, 81% of patients with PSA DT <3 months had positive 11C-CH PET/CT scan. Also, PSA DT, but not PSA alone, distinguished patients with pathologic tracer uptake in the skeleton versus patients with pathologic tracer uptake in prostatic bed.57,58 Gleason score is another important factor that can influence sensitivity of 18F-FCH PET/CT in evaluation of recurrent prostate cancer disease. In a study of 100 patients with biochemical relapse,59 Cimitan et al. concluded that 18F-FCH PET/CT is not likely to have a significant impact in the therapeutic care until PSA increases to >4 ng/mL in patients with Gleason score 7 or <7.60 In conclusion, in patients with recurrent prostate cancer disease, the overall sensitivity of 18F-FCH PET/CT seems to be higher among patients with higher PSA, higher initial Gleason score, and shorter PSA DT.
Localization of Prostate Cancer (Elevated PSA Level and Negative Biopsy)
The false-negative biopsy rate in patients with prostate cancer is 20%.61 Radiolabeled choline uptake seems to be similar in benign changes like prostatitis and prostatic hypertrophy as well as in prostate cancer. This is the main limitation for the use of radiolabeled choline to identify primary prostate tumor. In patients with repeatedly negative biopsies, 18F-FCH PET/CT is able to localize prostate cancer, but because the tracer is not specific, it cannot be generally recommended as the primary procedure for the localization of prostate cancer. A study of 20 patients with elevated PSA level and negative biopsy showed that 18F-FCH PET/CT correctly identified prostate malignancy in 25% of the patients.62
Treatment Monitoring of Prostate Cancer Disease
In patients receiving antiandrogen treatment, conventional imaging modalities very often do not show any significant morphologic changes in involved lymph nodes or other sites of tumor involvement. In these patients 18F-FCH PET/CT has a potential role to demonstrate metabolic response to hormonal therapy (Fig. 15.8). 18F-FCH PET/CT has a sensitivity of 96%, specificity of 96%, positive predictive value 99%, and a negative predictive value 81% for the detection of bone and soft tissue metastases in castrate-resistant patients.63 False-positive results can be due to inflammatory changes (e.g., after radiation therapy); false-negative results can be due to small size of the lymph nodes. Nevertheless, 18F-FCH PET/CT is useful for the detection of prostatic recurrence, lymph node, and skeletal lesions especially with high-risk prostate cancer patients with PSA value >4 ng/mL during antiandrogen therapy.64
Therapy Planning of Prostate Cancer Disease
Most patients with prostate cancer have one or two dominant intraprostatic lesions. Due to gastrointestinal and genitourinary toxicity of external irradiation, definition of volumes for focal radiotherapy, in primary or recurrent prostate cancer disease, is crucial. In a study of 66 patients, intraprostatic lesions were identified in all patients, mostly in the periphery of the prostate, within 5 to 10 mm of the bladder or rectal wall.65 In a study of 183 patients after radical prostatectomy, Gleason score >7 and PSA <1.5 ng/mL, who were considered for local salvage radiotherapy, Cimitan et al. found that 18F-FCH PET/CT showed distant metastases in one-third, making radiotherapy inappropriate.60
FIGURE 15.8. 18F-FCH PET/CT in a patient with prostate cancer before (DOWN) and after (UP) hormonal treatment (Gleason score 9, PSA before hormonal treatment 2,646 ng/mL).
In 16 European countries, 18F-Fluorocholine has been approved and is widely used to image patients with prostate cancer. With the approval of 11C-Choline in the United States for this purpose, a large-scale clinical trial of 18F-FCH PET/CT with standardized 18F-FCH PET/CT protocols should be considered.66
Since the androgen receptor is vigorously expressed in prostate tissue and is involved in the catalytic release of PSA from the larger tissue molecule from which circulating PSA is derived, it might be worthwhile to image the androgen receptor utilizing a radiolabeled testosterone analog, dihydrotestosterone which is known to be the primary ligand for the androgen receptor. Utilizing an 18F-radiolabeled testosterone derivative (16β-18F-fluoro-5-α-dihydrotestosterone), a group at MSKCC in New York performed a feasibility study in seven patients with metastatic prostate cancer. Although the labeled preparation underwent considerable metabolism and serum protein binding of metabolites, tumor uptake was observed in 46 of 59 lesions observed by conventional imaging; 18F-FDG was positive in 57 of 59. The average SUVmax was 5.22. On repeat imaging following testosterone treatment, the 18F-dihydrotestosterone uptake was decreased. Unfortunately, the synthesis takes at least 100 minutes and is a challenging one. Furthermore, the rapid conversion to metabolites renders quantitative studies even more challenging. No further studies using this tracer have been published.67
Over 30 years ago, Goldenberg et al. demonstrated that antibodies could be developed against tumor-associated antigens.68 These antibodies can then be radiolabeled and serve as relatively tumor-specific radiolabeled markers of tumor location. Since that time, the use of immunoglobulins as tumor-specific carriers of radionuclides (or other signaling agents or therapeutics) has been aided by the development of monoclonal antibody technology, thus allowing production of large quantities of a specific immunoglobulin with well-characterized sensitivity and specificity. Subsequently, investigators have identified many tumor-associated antigens that have been used to produce antibodies to serve as radiodiagnostic or radioimmunotherapeutic agents. Several PSAs have been identified and while present in normal prostate tissue, these antigens are expressed in increased amount in prostate carcinoma: PSA, prostate mucin antigen and prostate-specific membrane antigen (PSMA).
PSA is a glycoprotein enzyme that has peptidase properties. It is secreted by the prostate into the seminal fluid but also appears in small quantities in the serum. In fact, the circulating PSA is a fragment of a larger molecule within the prostate cell membrane. Although the expression of the tissue PSA and the cleavage of the circulating component are influenced by androgen stimulation of the androgen receptor, there is considerable variation among individuals and not all of the factors that influence the level of circulating PSA are understood.69 Antibodies to the circulating component of PSA make possible a widely used, sensitive and specific immunoassay for the detection of PSA in serum. Serum PSA has become the essential clinical biomarker to assess diseases of the prostate gland, both benign and malignant. PSA values rise gradually with age reflecting prostatic enlargement and bursts of PSA activity are observed in prostatitis. PSA is also a marker of prostate cancer. Despite the nonspecific reasons for PSA elevation, an accelerated rise in PSA, not associated with prostatitis, raises suspicion for prostate carcinoma leading to further evaluation including transrectal biopsy followed by decision making in terms of selection and extent of therapy. Following prostatectomy, the PSA falls to very low levels. Subsequent, post prostatectomy monitoring of serum PSA levels provides a practical means to detect recurrent disease. In fact, a significant number of patients will have elevated PSA levels without detectable tumor recurrence on currently available imaging techniques. Increasing PSA levels following prostatectomy without identification of a metastatic site on conventional imaging is known as biochemical failure and represents an opportunity and need for prostate-specific radiolabeled imaging agents to identify the location of recurrent disease. The patient with biochemical failure is also an appropriate candidate for targeted radionuclide therapy.
There is no doubt that serum PSA assays detect many men with prostate cancer who would have not been identified until the disease had become more advanced and widespread. However, currently the US Preventive Services Task Force does not recommend PSA screening as it may result in “overdiagnosis” and overtreatment” which involves risks of complications.70 Since PSA assays identifies malignant tissue in the prostate of so many men, it has become more important to better characterize the degree of tumor aggressiveness and intraprostatic tumor mapping to guide decision making and choice of therapy.
PSA itself has not been a suitable target for radionuclide imaging and/or therapy. PSMA offers another potential target that distinct from both PSA and prostate mucin antigen (PMA). PSMA is a transmembrane, 750 amino acid glycoprotein which has an enzymatic role in cell physiology as folate hydrolase I or glutamate carcoxypeptidase II. It is abundant in prostate epithelium (with some expression in other secretory tissues) and has increased expression in prostate carcinoma. The degree of expression is somewhat proportional to tumor aggressiveness; that is, greater expression of PSMA on more aggressive tumors. It has been recognized as an antigen with an extra- and intracellular component. These epitopes are distinguishable by specific monoclonal antibodies and can serve as a target for prostate cancer imaging and therapy.
PSMA Antibody Imaging (Radioimmuoscintigraphy)
Multiple antibodies to PSMA have been developed and characterized, two of which, 7E11 and J591, have been extensively evaluated as either a vehicle for diagnostic imaging or targeted radionuclide therapy.71
7E11 (Antibody to Intracellular Epitope of PSMA)
7E11 recognizes the intracellular component of PSMA raising the issue of whether an intact immunoglobulin can gain access to the intracellular component of a transmembrane protein. In cell suspensions, 7E11 bound to 95% of prostate cancer tissue samples tested. The success in identifying PSMA in tissue samples generated impetus for the development of a radiolabeled preparation that could be imaged in intact patients. Because of the slow clearance of immunoglobulins from plasma, 111In was chosen as the tracer to allow sufficient time for plasma and extracellular fluid to clear as the detection of tumor foci depends upon both the tumor uptake and the contrast with background activity.
111In is linked to the murine immunoglobulin via GYK DTPA, a chemically stable linker that is covalently attached to the immunoglobulin prior to combination with 111In. GYK DTPA serves as a chelator to bind the radiometal. Following clinical trials, 111In-capromab pendetide was approved by the Food and Drug Administration (FDA) and marketed in the United States as Prostascint.
As a murine immunoglobulin, 7E11 has the potential to lead to the development of human antimurine antibodies (HAMAs) which have been observed after a single infusion in about 8% of the patients and up to 19% after repeat infusions. (Package Insert) Although serious adverse reactions have not been reported, the presence of HAMA precludes normal biodistribution and limits tumor access to radiolabeled antibody as it is rapidly cleared from the blood stream following conjugation with HAMA.
The initial FDA approval of 111In-capromab pendetide Prostascint was for two indications:
• Preoperatively, to assess extent of disease for high-risk patients based on a high Gleason score identified on biopsy material.
• Identify location and extent of disease recurrence following surgical prostatectomy who after a period of low PSA values have experienced a rise in serum PSA.
Prostascint was introduced prior to the routine use of digital displays and certainly before the use of fused SPECT and either separately acquired or sequential CT or MR imaging. The initial protocol involved planar whole-body images and SPECT acquisition of the pelvis and other areas if suspicious. The transaxial radionuclide distribution was challenging to interpret as the radiolabeled antibody remained in the vascular spaces, specifically the femoral and iliac vessels and the bone marrow sinuses. Some activity was often seen in the bladder urine and there was some secretion of activity into bowel contents. The strategy was to image on day 0, approximately an hour or 2 after infusion of the 111In-capromab pendetide and to reimage 3 to 5 days later. Interpretation was based upon identification of a focus or foci on the delayed images that was not present on the earlier acquisition. Since patients had usually undergone radionuclide skeletal imaging prior to referral for Prostascint, the foci of interest were usually in the region of the prostate bed indicating local recurrence or the lymphatic drainage which was particularly challenging because the lymph nodes ran along the great vessels and had to be distinguished from the nearby vascular activity.
Subsequently, the technique was modified to include 99mTc labeling of red blood cells on days 3 to 5 when the patient appeared for imaging. Simultaneous acquisition of the upper 111In peak and the 99mTc peak was performed. This provided direct comparison of transaxial activity distribution and eliminated the need to image on the day of infusion. The application of SPECT/CT, however, was the greatest advance to image acquisition and interpretation. Patients were imaged on days 3 to 5. The Prostascint images were read alongside as well as fused with the CT images. At about the same time, software was developed that fused separately acquired transaxial images (CT or MR) with the radiopharmaceutical distribution using intrinsic anatomical markers as the basis for anatomic correlation. These techniques significantly reduced patient-scanner time, technologist processing time, and physician interpretation time. Moreover, the interpretations based on fusion imaging had greater credibility with referring physicians who could “see” the foci considered significant for themselves.72 This led to the addition of new applications beyond those approved by the FDA:
• external beam radiation therapy and
• assess local or metastatic disease involvement in patients who had not undergone surgical prostatectomy (such as those treated with brachytherapy or other prostate in situ interventions)
In a comprehensive review of the early Prostascint imaging experience, Blend and Sodee reported sensitivities for the detection of pelvic and abdominal lymph node metastases from 62% to 92% in various studies compared to CT and MRI with sensitivities from 4% to 52%.73 In these early studies, compared to surgical sampling of pelvic lymph nodes, SPECT imaging with Prostascint had a sensitivity of 62% and a specificity of 72% for the detection of tumor involvement. In general, the technique was insensitive to detect involvement in lymph nodes <1.5 cm. Although the overall accuracy in the pelvis, therefore, is not great, it provided additional information to guide the extent of surgical intervention. The technique performed better at extrapelvic sites with positive and negative predictive values of approximately 80%. There is no doubt that the addition of hybrid imaging that provided fused SPECT/CT images markedly improves the sensitivity and specificity of this technique. With SPECT/CT, Schettino et al. excluded 74 of 161 suspicious foci identified on nonfused images. Nodal metastases were excluded in 25 of 58 patients.74At the New York-Presbyterian/Weill Cornell Medical Center, SPECT/CT of Prostascint significantly reduced imaging time; that is, patient time on the imaging table as well as technologist time involved in image acquisition and processing and finally, nuclear medicine physician involvement in interpretation. SPECT/CT fusion images had greater credibility with referring physicians who could more readily comprehend the anatomical location of identified foci when the SPECT data were fused with even nondiagnostic CT images. Even recurrent intraprostatic foci were confidently and accurately identified in several instances in which the prostate had not been removed as the patient was treated with brachytherapy or cryotherapy (Fig. 15.9). Finally, the correlation of disease mapping with anatomic detail provided a basis for utilization in field planning in radiotherapy. Jani et al. reported significant changes in the clinical target volume based on the immunoscintigraphic defined extent of disease.75,76 The technique facilitated improves mapping of treatment fields, boosting radiation doses to tumor, and reducing or eliminating exposure of nearby normal tissue.77,78
J591 (Antibody to Extracellular Epitope of PSMA)
Since the 1990s, a group led by Dr. Neil Bander, a urologist at Weill Cornell Medical College with additional training and experience in laboratory and clinical immunology, have performed extensive laboratory and clinical assessments of the monoclonal antibody, J591. J591 binds with high affinity and specificity to the extracellular component of the membrane enzyme, PSMA. The antibody–antigen complex is subsequently internalized. As an extracellular epitope, it is more readily exposed to the extracellular fluid (and its contents) than 7E11 and has therefore been of interest to several groups of investigators.71 In a “nonimmunogenic” (humanized) form, it has been evaluated for over a decade as a radioimmunotherapy agent. More recently, humanized J591 has been evaluated as a SPECT and/or PET imaging agent to identify tumor expression of PSMA in an effort to explain the variations in therapeutic response and to assess the degree of expression of PSMA to identify patients who are more apt to benefit from J591 radioimmunotherapy. Because of the relatively long plasma half-life of the labeled J591, it is necessary to image after an interval of 3 to 5 days following administration of the labeled antibody. The physical half-lives of 99mTc, 123I, 18F, and 11C are too short to be utilized as tracers. Accordingly, imaging has been performed with either 111In-labeled J591 or by imaging the γ-component of the therapeutic preparation Lutetium-177 [177Lu]-DOTA-J591. Planar and SPECT/CT imaging has been performed with these tracers. More recently, J591 has been labeled with Zirconium-89, a positron emitter with a 78-hour half-life.
FIGURE 15.9. 111In-capromab pendetide (Prostascint) SPECT/CT; transaxial slices, LEFT to RIGHT: CT, SPECT/CT, SPECT demonstrating intraprostatic focus in a patient who declined surgery and EBRT.
Whereas it would be useful if scintigraphic or conventional imaging accurately determined the extent and location of prostate malignant tumor, in many instances there is biochemical evidence of relapse without positive image findings. Detection of tumor with scintigraphy and/or effective targeted radionuclide therapy depends upon the tracer receptor (or epitope) affinity, the physical characteristics of the radionuclide, the lesion size, the absolute amount of the radiolabeled tracer within the primary tumor or metastatic focus, and the tumor-to-background contrast. Hence, the initial radioimmunoscintigraphy studies utilizing 111In-DOTA-J591 were performed to obtain pharmacokinetic data for dosimetric calculations and, if possible, to confirm targeting of lesions, particularly during an early trial of 90Y-labeled J591 since 90Y did not have a γ-emission that would make external imaging and quantitation possible. In studies using 177Lu, it was possible to perform radioimmunoscintigraphy which has been used to assess the degree of J591 binding to determine if the variation in radioimmunotherapy responses were due to the degree of expression of PSMA. In both cases (111In-J591 and 177Lu-J591), whole-body and, when deemed appropriate, SPECT/CT imaging were performed from 2 to 5 days following injection of appropriate doses of 111In-J591 or 177Lu-J591.
There is not a great deal of 111In-J591 imaging data. 111In-J591 was initially used in a 90Y-J591 radioimmunotherapy trial to demonstrate that the antibody did indeed bind to metastatic lesions. It had previously been demonstrated in nude mice that the pharmacokinetics (plasma clearance) and biodistribution of 111In-DOTA-J591and 90Y-DOTA-J591 were similar, thus justifying the use of the 111In-DOTA-J591 as a proxy molecule for 90Y-DOTA-J591. Of 29 patients in the trial who initially received 185 MBq (5 mCi) of 111In-DOTA-J591 (total protein: 20 mg), 19 patients had focal lesions on skeletal scintigraphy and 13 had soft tissue lesions on conventional imaging. Seventeen of the 19 patients (89%) with skeletal foci and 9 of 13 patients (69%) with soft tissue lesions localized 111In-DOTA-J591. Of course, it is now recognized that tumor-specific tracers may be more accurate than bone scintigraphy because of their specificity since focal uptake on skeletal imaging is nonspecific and may represent the osseous response from nonviable tumor, trauma, or degenerative changes.79,80
Although 177Lu-J591 is an investigational agent for targeted radionuclide therapy, it emits a 210-KeV γ-ray with an 11% abundance, making planar and SPECT imaging possible in patients receiving doses of approximately 1.4 GBq (40 mCi) or more. Since the clinical trials usually began at 0.7 GBq/m2, the photon flux is sufficient to image but diagnostic imaging with 177Lu-J591 was not a realistic possibility. In radioimmunotherapy trials, imaging was performed to compare targeting with lesions identified on skeletal scintigraphy to determine the degree of variability in the percent targeting. 177Lu-J591 planar images were scored on a 4-point scoring system; “0” if the known site had no detectable activity, “1” if faint tumor activity was seen, “2” if the activity was prominent but not equal to the liver intensity, and “3” if the tumor activity was approximately equal to the liver activity (Fig. 15.10). In addition, a more quantitative scoring system, the so-called tumor targeting index (TTI) was also determined in which the ratio of background corrected tumor counts/area was compared to the whole-body counts/area. With both indices, a greater fraction of patients with higher scores had either stabilization or reduction of the PSA levels than the patients with lower scores. In conclusion, 177Lu-J591imaging is useful to assess fractional uptake of the dose administered as a therapeutic but has no role as a diagnostic agent.81
FIGURE 15.10. 177Lu-DOTA-J591 and 99mTc-MDP whole-body images revealing large right sacroiliac lesion with vigorous uptake of both tracers. In clinical trials, vigorous uptake of 177Lu-DOTA-J591 at sites of osseous metastases correlated with a good (albeit temporary) therapeutic response. 177Lu images are possible because of the γ-emission component of 177Lu which has been studied as a radioimmunotherapy agent at Weill Cornell Medical Center in New York for over a decade. 111In-DOTA-J591has served as a proxy molecule for 177Lu-DOTA-J591 in dosimetry studies and others evaluating PSMA expression prior to infusion of 177Lu-DOTA-J591 for therapy.
As stated previously, image resolution and lesion detection are improved with PET technology; a consequence of the abundant photon flux and coincidence circuitry localization of events. In general, PET imaging has been performed with short-lived positron tracers. Imaging of a large molecule like immunoglobulins requires sufficient delay after administration to allow for background clearance. Hence, 11C and 18F are not appropriate tracers for intact or large fragments of immunoglobulins. 89Zr is a positron-emitting radiometal with a relatively long half-life (t1/2 78 hours). Accordingly, 89Zr is of increasing interest as a tracer for immuno-PET; PET imaging using a radiotracer linked to specific immunoglobulins. Since the binding chemistry of 89Zr is sufficiently different from 111In and 177Lu, the usual DOTA moiety is unsatisfactory to chelate 89Zr. A group at Memorial Sloan-Kettering Cancer Center in New York conjugated desferrioxamine B (DFO) to the humanized J591 immunoglobulin that had been extensively studied initially as a radioimmunotherapy agent labeled with 177Lu (or less frequently 90Y) and more recently to image PSMA positive tumors when labeled with 111In or 177Lu. The DFO-J591 conjugate was subsequently labeled with 89Zr and injected into mice previously prepared with either PSMA+ or PSMA– tumors. The immunoreactive fraction was determined to be 0.95+/–0.03 and the radiolabeled preparation remained active for 7 days. High tumor-to-background tissue contrast was observed with tumor-to-muscle ratios greater than 20 in the mice with LNCaP xenografts. Based on these encouraging findings in laboratory animals, the group is currently assessing the use of this tracer for clinical assessment of patients with prostate carcinoma. To date, there is no published data but localization of 89Zr-J591 at metastatic sites has been identified in a patient with soft tissue and osseous metastases. The degree of 89Zr-J591 uptake correlated with the qualitative assessment of subsequent 177Lu-J591 uptake on planar and SPECT imaging.82
89Zr has also been used to perform immuo-PET using an alternate prostate cancer target, the precursor of the circulating marker PSA. Circulating PSA itself is not a satisfactory target for radioimmunoscintigraphy or radioimmunotherapy. Serum PSA is actually a component of a larger molecule within the cell membrane that functions as a serine protease. A portion is catalytically released from the larger molecule (“free” PSA or fPSA) into the circulation in a noncatalytic form (the so-called “complexed” PSA). Since androgen receptor signaling more directly augments expression of the intact PSA molecule, it was postulated that direct assessment of the intact tissue PSA may be a more meaningful determination to assess the degree of androgen receptor expression as a determinant of tumor aggressiveness. An antibody, 5A10, has been developed that selectively binds fPSA at an epitope adjacent to the catalytic cleft of fPSA from which “complexed” PSA is released into the circulation.69 Using desferroximine B as a chelator, 89Zr was conjugated to 5A10 and in vivo studies were obtained in a male mouse model bearing subcutaneous xenografts of a PSA-positive prostate cancer cell line that overexpresses the androgen receptor (LNCaP-AR). A high degree of specific binding to the tumor tissue was observed, confirmed by lack of binding to tumor implants that did not express PSA or the androgen receptor. Furthermore, there was minimal localization of a nonspecific immunoglobulin. Testosterone stimulation of the androgen receptor resulted in significant increases in intratumoral PSA and in the binding of 89Zr-5A10. Finally, administration of an antiandrogen inhibited tumor growth, fPSA expression, and radiotracer localization. Although no direct comparison has been made to date between 89Zr-5A10 and 89Zr-J591, the authors point out that PSMA expression is neither specific for cancer nor is the effect of antiandrogen therapy on PSMA expression known.69
Small Molecule Imaging
Although PSMA was initially utilized as an antigen and antibodies that had high affinity for various epitopes of PSMA have been exploited for both scintigraphy and targeted therapy, more recently attention has focused on PSMA as a transmembrane protein with enzymatic activity. PSMA is specific peptidase found in high concentration in prostate tissue and to a lesser extent in other secretory epithelium. As an enzyme, PSMA binds specific molecules with high affinity. Various analogs have been developed including molecules that bind to the enzyme to such a high degree that they effectively serve as inhibitors of the enzymatic activity. These molecules are described as heterodimers; the essential core being two amino acids linked by a urea moiety. The glutamate–urea–lysine complex has a high degree of affinity and specificity for the external component of the complex PSMA molecule.83 Based on this specific and high affinity, it was recognized that these heterodimers could serve as carriers of radionuclides. After preliminary studies involving animal models bearing human prostate carcinoma successfully imaged implanted tumors, initial imaging studies were performed in patients with metastatic prostate carcinoma comparing two 123I-radioiodinated compounds with glutamate–urea–variable amino acid cores. The side chains of these compounds were modified to provide differences in their biodistribution and mode of excretion. In a “First-in-Man” publication, both 123I-iodinated compounds had similar biodistribution although one had greater renal clearance and therefore cleared the plasma more rapidly. Tracer uptake was seen in the liver, bowel, kidneys, lacrimal, salivary, and parotid glands. In the case of slower plasma clearance, more activity was seen in organs and metastatic lesions. Nevertheless, uptake and background clearance was sufficient to detect most metastatic lesions within 2 hours after dose administration. Some uptake was seen in the prostate gland of normal volunteers but in patients with prostate cancer, foci of increased uptake could be identified (Figs. 15.11 and 15.12).
FIGURE 15.11. 123I-labeled heterodimer [Glu-Urea-Lys] with demonstrated high affinity for PSMA. Minimal uptake is seen in the normal prostate (LEFT); well-defined uptake in prostate gland with a confirmed as yet untreated prostatic adenocarcinoma.
FIGURE 15.12. LEFT to RIGHT: Anterior and posterior whole-body scans (99mTc-MDP, 123I-PSMA antagonist [MIP-1072], and 111In-capromab pendetide). Bone scan demonstrates lumbar spine metastases that are not seen on 111In-capromab pendetide scans. 123I-labeled heterodimer (PSMA antagonist) demonstrated lumbar spine lesions as well as multiple soft tissue metastases. There is a suggestion of tracer accumulation in the left medial groin on the 111In-capromab pendetide images. p.i., postinfusion.
Although these 123I-labeled small molecules were apparently successful to image metastatic prostate carcinoma, it was recognized that a 99mTc-labeled tracer would be more useful since it could be made available in a kit form so the tracer could be prepared in clinical nuclear medicine units and the γ-emission would be even more abundant. In fact, 99mTc-labeled versions have been developed and evaluated in normal subjects and prostate cancer patients (Figs. 15.13 and 15.14).84 The 99mTc-heterodimers produce images of good contrast and biodistribution in normal subjects similar to the 123I heterodimers. As with the 123I compounds, slight variations in the chemical side groups affected the route by which the tracer is eliminated (kidneys versus liver). Two 99mTc-radiolabeled versions with different degrees of renal excretion were evaluated.
The agent with the preferential renal clearance excreted 37% of the injected dose within 4 hours whereas the other agent eliminated a greater fraction of the administered dose via the liver. With either agent, it was possible to image the intact prostate and identify the intraprostatic distribution of multiple tumor foci. In preliminary studies, the mapping correlated with subsequent immunopathologic staining following removal of the intact prostate gland. Patients with a Gleason score ≥7 on 3 or more biopsy cores were imaged with SPECT/CT within 3 hours after receiving 10 mCi of the 99mTc-PSMA ligand heterodimer. A previously scheduled radical prostatectomy was performed within 2 weeks. The prostates were removed, stained for PSMA and analyzed on a 6-sector grid (right and left, 40 of the 48 sectors were positive for PSMA-expressing prostate carcinoma albeit not all with Gleason scores ≥7. Imaging overall had a sensitivity and specificity of 62.5%). The intensity of tracer localization appears to correlate with Gleason scores of 7 or above (Fig. 15.15).85
As with the 123I-labeled agents, the 99mTc-labeled heterodimers identified metastatic disease including lymph node involvement prior to initial surgery although findings could not be confirmed as the protocol did not include sampling of lymph nodes based on image identification. In a 71-year old patient with a rising PSA following prostatectomy, both 99mTc agents identified multiple foci of metastatic disease that had not been seen on a bone scan performed 2 months earlier. Three months later, repeat bone scintigraphy confirmed the presence of multiple osseous metastases.84
The quality of the 99mTc-heterodimer images is so impressive that it would be expected that this agent might be useful to identify the extent of regional disease prior to initiation of therapy and modify initial surgery to include harvesting of lymph nodes that might not otherwise be retrieved. Initial studies, in patients prior to surgery, have demonstrated excellent resolution capable of identifying intraprostatic tumor foci and distinguishing the degree of PSMA expression among several foci. The degree of uptake has correlated with the Gleason score of the individual foci. This is indeed exciting if confirmed with further clinical studies, it suggests that would be possible to noninvasively identify and map the location of the foci of highest Gleason score and greatest concern in terms of aggressiveness and prognosis; features that certainly would have an impact on choice of therapy. Currently, there is a great deal of discussion as to whether, given the potential consequences of a total prostatectomy, it is necessary to resect the entire prostate regardless of Gleason score or other evidence of the lack of tumor aggressiveness. This concept has not yet been subjected to a controlled clinical trial but data of this sort might provide a basis selection of appropriate patients for partial resection rather than total prostatectomy.85,86
FIGURE 15.13. 99mTc-anti-PSMA heterodimer (MIP-1404) whole-body scans demonstrating focal accumulation just below the bladder activity on the left.
68Ga-PSMA Ligand Heterodimers
Gallium-68 [68Ga] is a positron-emitting radiometal with a 68-minute half-life. Since the small molecule heterodimers with high affinity for PSMA provide good contrast between targeted tumor and background within a relatively short timeframe, physicians and biomedical scientists at the University of Heidelberg labeled the glutamine–urea–lysine heterodimer with 68Ga using the heterobifunctional agent N,N’-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid [HBED-CC]. This agent was used because it complexed 68Ga3+ much faster than DOTA at ambient temperatures. PET images were obtained at 1 and 3 hours after injection of 52 to 212 MBq of the 68Ga-PSMA ligand. The ligand localized in normal tissues in a pattern similar to the 123I- and 99mTc-labeled heterodimers. Activity appears promptly in the urine; it is advisable to have the patient empty the bladder before imaging. Thirty-one of 37 prostate carcinoma biochemical failure patients had at least one suspicious lesion. The detection rate was 60% at PSA values below 2.2 ng/mL and 100% in patients with PSA exceeding 2.2 ng/mL.87
PROSTATE SENTINEL LYMPH NODE IDENTIFICATION
Sentinel lymph node identification is a technique that involves injection of a radiocolloid into an organ of interest or in or near a known tumor followed by imaging to determine the lymphatic drainage pattern. The sentinel lymph node or nodes is the node receiving the initial drainage from the area of interest. It is not necessarily the closest lymph node. In patients with melanoma and breast carcinoma, sentinel lymph node dissection has been demonstrated to be of great value, reducing the morbidity as a sentinel lymph node resection is considerably less traumatic than a regional lymh node dissection in which relatively large areas are resected. Furthermore, in a patient without obvious lymph node metastases, it is more accurate as the pathologic examination is more rigorous with less tissue to examine. Finally, of course, an unexpected drainage pattern is readily identified.
Identification of pelvic lymph node involvement in prostate carcinoma patients is challenging. Although such involvement would have a significant impact on the choice of therapeutic options, resection of the multiple lymph node basins draining the prostate is not a standard of practice component because of the complication rate. In recent years, a limited number of medical centers have evaluated the potential of intraprostatic radiocolloid injection to identify the sentinel lymph node or nodes. In a relatively recent study, 35 patients with intermediate or poor prognosis who underwent extensive pelvic lymph node dissection had intraprostatic injections and were imaged shortly thereafter. The surgical procedure followed from 5 to 24 hours after injection. A radiation detection probe was available in the operating suite. In a review published by the European Association of Urology, Willem Meinhardt concludes that the sentinel lymph node identification technique is as reliable a diagnostic tool as extended pelvic lymph node dissection and occasionally more sensitive since it may identify relevant lymph nodes outside of the usual area resected.88,89
The standard radiopharmaceutical used in Europe is albumin nanocolloid. Veermeeren reported using a standard dose of 225 MBq in 0.4 mL. Planar images are obtained at 15 minutes and 2 hours. In addition, SPECT/CT was performed; an intraoperative probe was used at surgery and a portable γ-camera was available. In a study comparing the detection rate with 0.1 mg to 0.2 mg of nanocolloid, more lymph nodes were identified with the greater amount of nanocolloid (2 to 2.6 lymph nodes, respectively). In patients receiving the lesser amount of nanocolloid (but the same total activity), 84% of the lymph nodes were detected as were detected with the greater amount of nanocolloid.90 In a study of over 1,200 patients, Winter et al. found that sentinel lymph node pathology examination identified involvement in 3.2% of the low-risk patients (as categorized by the European Guideline nomogram), 14.8 % in the intermediate-risk group, and 37.4 % in high-risk patients. In total metastatic lymph node involvement would have been missed in 16% of the patients based on the current nomogram. They proposed a revision to include sentinel lymph node as a component of the assessment of risk in patients with the diagnosis of prostate carcinoma.91 In another study, Weckermann et al. reported that positive lymph nodes were found in 207 men (∼20 % of the total assessed). In this study, in 63.3% of the men, at least one lymph node was outside of the region of standard lymphadenectomy. The frequency of nodal involvement was greater than predicted from existing nomograms but was more likely in patients with higher PSA values and T stage. They conclude that if lymph node dissection is considered based on risk factors, sentinel lymph node identification should be performed since positive lymph nodes are identified beyond the usual extent of the dissection although in some cases, the sentinel lymph node was not the only involved metastatic site.92
FIGURE 15.14. The same patient as in Figure 15.13. A and B: Coronal and transaxial slices through prostate gland demonstrating tumor avidity with localization to the left side of the enlarged prostate gland. C and D: Coronal and transaxial slices of a small presacral lymph node with PSMA+ tumor.
FIGURE 15.15. Whole-body and transaxial SPECT/CT slices if a patient with a large, Gleason 9 tumor in the right hemiprostate gland. There is a second less FDG avid focus in the left anterior region of the prostate that correlates with histopathologic mapping of a Gleason 7 tumor focus.
Targeted Radionuclide Therapy
Metastatic prostate carcinoma appears to be an appropriate target for radionuclide therapy as the disease is often multifocal. Recurrent disease may present prior to the time when lesions are large enough to be seen by traditional or even novel imaging methods. Until recently, there has been no well-defined chemotherapy option particularly when hormonal manipulation is no longer effective. Targeted radionuclide therapy of prostate carcinoma has been largely pursued with radiolabeled monoclonal “humanized” immunoglobulins to the external epitope of the membrane protein PSMA. Recently, however, there has been activity utilizing molecules that inhibit the PSMA enzyme activity by high affinity binding.
Radioimmunotherapy of prostate carcinoma, the use of appropriately labeled immunoglobulins to deliver targeted radiation to dispersed prostate tumor foci has been actively pursued in clinical trials for over a decade by a multidisciplinary team at the New York-Presbyterian Hospital and Weill College of Medicine of Cornell University in New York City. Although studies continue, a rather complete summary of results to date was recently published.93
As described in the imaging section, the antibody utilized for radioimmunotherapy investigations is J591, a monoclonal antibody that recognizes the extracellular epitope of the membrane protein PSMA. The antibody has been “humanized,” that is rendered nonimmunogenic by enzymatically cleaving a large nonspecific portion of the murine IgG and fusing the immunorecognition portion with the appropriate component of human IgG. To date, with more than 100 patients studied, there has been no evidence of HAHA or altered pharmacokinetics on repeated dosing. The chelating agent decatetraacetic acid (DOTA) is covalently linked to the antibody. On the day of infusion, the DOTA J591 is incubated with the chosen radiometal. The DOTA preparation has been used to bind 111In for biodistribution studies and to either Yttrium-90 or Lutetium-177 for radioimmunotherapy.94–96 Because of the likelihood that many patients might have small metastatic lesions in the bone marrow, the 177Lu-labeled preparation was selected for most studies based on the improved absorption fraction of lower-energy β-particles. In studies using the classic FDA clinical trial design, patients received escalating doses of 177Lulabeled antibody; three patients at each doses and observed for toxicity before moving the dose to be administered to the next level. Patients were observed for toxicity. The principal toxicity, as expected, was hematologic with a nadir of platelets and white blood cells at approximately 4 weeks. From these studies, it was determined that a single administration of 2.88 GBq (70 mCi)/m2was a maximal tolerated dose (MTD). Furthermore, using stabilization or decline of the PSA values as evidence of antitumor activity, it was observed that there was a striking difference between 2.68 GBq (65 mCi)/m2 and the MTD suggesting that even greater doses might be advantageous. The usual course among responding patients was stabilization of the PSA for several months and then a gradual PSA rise. An obvious next step would be to re-treat but this required a new protocol. Rather than wait for patients to relapse, a trial was designed giving less than the single MTD but repeating the dose 2 weeks after the initial dose. With this protocol, the MTD for divided doses was determined to be 1.48 GBq (40 mCi)/m2) × 2 for a total dose of 2.96 GBq (80mCi)/m2. Clinical responses at this level based on stabilization of the serum PSA level as a biomarker revealed more responders than the single dose 177Lu-J591 trial where patients received 370 MBq less.96
Currently, based on the promising results in patients with castrate-resistant metastatic disease, multiple protocols have been designed to evaluate the therapeutic potential of 177Lu-DOTA-J591 as well as 90Y-DOTA-J591:
• As adjuvant therapy
• Combination with chemotherapy
• Substitution with an α-emitter
7E11, the murine monoclonal antibody that recognizes the intracellular epitope of PSMA (and when labeled with 111In is marketed as Prostascint as an imaging agent). 7E11 has been also labeled with Yttrium-90 [90Y] and evaluated as a radioimmunotherapeutic agent. In a trial to evaluate the potential as a radioimmunotherapy agent, 90Y-7E11 was insufficiently effective to be considered further.97,98 Although exposure of the intracellular portion of PSMA in necrotic cells might provide a basis to image tumor foci, it would not be expected to serve as an effective basis for a radioimmunotherapy agent.
Small Molecule Targeted Radionuclide Therapy
Following the demonstration that urea-linked peptides (such as glutamate-urea-lysine) have a high affinity for the enzymatic function of PSMA and the successful demonstration that the molecule could be radiolabeled with 123I as well as other halogens and 99mTc as well as other radiometals as imaging agents, investigators in several laboratories replaced the diagnostic γ-emitting radionuclides with β-emitters like 177Lu and 131I.
When the external epitope of the PSMA moiety binds an antibody, the epitope–antibody complex is internalized, the iodinated amino acid within the immunoglobulin is labile and elutes from the cell. By contrast, either the radioiodinated high affinity enzyme antagonist molecules are not internalized but remain bound to the PSMA-expressing cells or the radioiodine labeling of the amino acid–urea heterodimers produces an iodinated molecule that is more stable than the usual iodotyrosine-labeled immunoglobulin as the iodine has remained at the targeted lesion rendering these molecules potentially useful for radioimmunotherapy.
Using a 177Lu-labeled heterodimer, Jiang et al. demonstrated tumorocidal effects in mice engrafted with human prostate cancer.99 The nuclear medicine group in Heidelberg, Germany have administered 5.55 GBq of 131I-labeled heterodimer in patients with metastatic prostate cancer with dramatic results. In one patient with a markedly elevated PSA, the PSA value declined over 2 months to barely detectable levels and the whole-body scan that had demonstrated multiple metastases virtually normalizing. Although no classic clinical trial has been reported to date, the results in terms of normalization of serum PSA and lesions identified on scintigraphy are dramatic and have been repeated in other patients although the duration of the response has not yet been reported.100
CONCLUSION AND FUTURE CONSIDERATIONS
After many years in which nuclear medicine’s role in the evaluation and treatment of patients with prostate carcinoma was limited in terms of diagnostic imaging to nonspecific bone scintigraphy to identify and monitor bone metastatic, there have been great strides toward development and clinical applications of advances using SPECT and PET imaging agents with excellent sensitivity and specificity. The first of these advances, an 111In-labeled anti-PSMA antibody, had limited access and application. Although prostate carcinoma was sometimes identified with FDG PET, it was found not to be sufficiently sensitive to detect all foci. Currently, the most sensitive agent for the detection of intraprostatic tumor, lymph node, and distal involvement appears to be 18F-Fluorocholine [18F-FCH] although it is not specific for PSMA nor does it differentiate between aggressive, higher Gleason score foci and less aggressive disease. Since it 18F has a 2-hour half-life, it can be prepared in regional centers and distributed similar to FDG. In fact, 18F-FCH is commercially available in Europe. In the United States, 11C-Choline has been approved by the FDA on a site-by-site basis. Approval of 18F-FDG is a more complex issue but it is certainly probably that the FDA requirements can be met. When it is approved and can be reimbursed, it is likely that 18F-FCH will become widely available for clinical applications. Although this would be a major contribution to the management of patients with prostate carcinoma, there are several drawbacks. First, 18F-Fluorocholine uptake is neither prostate tumor-specific nor does the degree of uptake reflect the degree of tumor aggressiveness. Since PSMA expression is somewhat proportional to the degree of tumor aggressiveness, tracers that bind PSMA with high affinity are likely to provide quantitative or semiquantitative information about the aggressivenes of primary and metastatic prostatic carcinoma foci. Although radiolabeled fragments of the anti-PSMA antibody, J591, that recognize the extracellular epitope of PSMA are being evaluated, the agent most likely to fill this niche is one of the small molecules that have high affinity binding to the enzymatic component of PSMA. The already developed 99mTc-versions of this class of compounds provide excellent resolution images capable of distinguishing discrete foci within the prostate as well as characterizing the degree of aggressiveness and locating local and distal metastases. At this point, it is not possible to predict whether the 99mTc-labeled radiopharmaceuticals will be supplanted in time by a positron-emitting version.
Targeted radionuclide therapy also has made great strides, predominantly with the antibody J591, radiolabeled with 177Lu. Although the clinical trials have been performed in only a limited number of Medical Centers, a Phase II trial of a divided dose regimen using 177Lu-DOTA-J591 is nearing completion after which it could become more widely available as a Phase III trial and potentially an approved form of therapy. In addition, there are several ongoing Phase I trials to assess the role of 177Lu-DOTA-J591 to treat earlier phases of recurrent disease as well as an adjuvant trial which would require participation of larger numbers of centers.
In summary, radiolabeled small molecules are likely to emerge as imaging agents to identify prostate carcinoma. It is unclear at this point if the comparatively long circulating time of radiolabeled antibodies which results in a larger fraction of the administered dose being delivered to tumor sites, thus increasing the radiation absorbed dose will be more effective than the total radiation delivered by very high affinity radiolabeled small molecules that are retained by tumor sites.
Although this chapter includes data from many sources, the authors are particularly grateful to several physicians and scientists who made various tracers, radioimmnunotherapeutics, and pre-clinical and clinical studies available to them in their respective departments. The 18F-Fluorocholine imaging and experience acquired by one of us (MH) would not have been possible without the support and encouragement of Mag. Christoph Artner of IASON, Graz, Austria, and the University Medical Center, Ljubljana, Slovenia. The experience and pleasure of participating in the evaluation of 123I- and 99mTc-labeled anti-PSMA heterodimers was only possible because of the access to these agents and the involvement of John Babich, PhD and the dedication of Anatasia Nikolopoulou, PhD and Shankar Vallabhajosula, PhD. Dr. Vallabhajosula is also responsible for the development of the DOTA labeling of the anti-PSMA antibody, J591 and the subsequent labeling, pharmacokinetic and dosimetry studies of this immunoglobulin with 177Lu and other radionuclides. Neil Bander, MD and Scott Tagowa, MD have guided many studies and have mentored one of us (SJG) in the biology and clinical aspects of prostate cancer for many years. To all of these individuals, we express our appreciation and gratitude.
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