Applied Radiology

Prostate cancer has an annual incidence of about 334,500 and a mortality rate of about 41,800.1 Management of the disease and prognosis depends on the stage of the disease, which, in turn, depends on whether tumor has extended beyond the capsule, whether regional or distant lymph nodes are involved, and whether bony metastases are present. Existing methods of staging include digital rectal examination, measurement of prostate specific antigen (PSA) levels, transrectal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). All are of some use in examining the prostate, but none are very helpful in determining whether regional or distant lymph nodes are involved.2

The radionuclide bone scan is the procedure of choice when looking for skeletal metastases.3 In late 1996, capromab pendetide (ProstaScint®) was approved by the U.S. Food and Drug Administration (FDA) for routine clinical use in detection of nodal metastases in prostate cancer patients. It was developed by Cytogen Corporation (Princeton, NJ) as a murine whole antibody toa 100 kilodalton glycoprotein foundon the surface of both normal and abnormal prostate epithelium-the prostate specific membrane antigen (PSMA), which is very different from PSA. 0.5 mg ofthe antibody, is labeled to 5 millicuries of Indium-111 chloride for imaging studies.4

Evaluation of capromab pendetide (clinical trials)

Cytogen Corp. conducted several multi-institutional trials from 1991 to 1996, in a total of 224 preoperative and 259 postoperative patients. In the preoperative group there were 190 (85%) positive studies, out of which 76 (40%) had only prostate or periprostatic abnormality, 83 (44%) had extraprostatic involvement within the pelvis, and 31 (16%) had scintigraphic evidence of extrapelvic disease.

In the postoperative group there were 187 (72%) positive studies. Fifty-seven patients (31%) had only prostate or periprostatic abnormality. Fifty-five (29%) had extraprostatic involvement within the pelvis, and 75 (40%) had scintigraphic evidence of extrapelvic disease.

Indication

Capromab pendetide use is generally indicated in two groups of patients:

1) Those with a new diagnosis of prostate cancer with high risk of pelvic metastases.4 These are patients with PSAs of greater than 10 ng/mg and/or high Gleason histopathologic classifications (>7). As compared with histopathology, the sensitivity of capromab pendetide imaging ranged from 52 to 62% and the specificity was 72 to 96% in detecting pelvic lymph node metastases.5,6 This compares favorably with the 10% and 15% sensitivity of CT and MRI, respectively. Another study reported that CT, MRI, and ultrasound had a combined sensitivity of 20% and specificity of 68% compared with 75% sensitivity and 86% specificity of capromab pendetide.7

2) Those with suspected occult recurrent or residual disease.4 These are patients with occult rises of PSA post-operatively. In the prostatic fossa, two different studies found a specificity of 77% and 35%, and sensitivity of 49% and 71% using histopathological diagnosis as the gold standard.5,5 Another study found capromab pendetide scans to be superior to positron emission tomography. The positive predictive values for capromab pendetide and positron emission tomography were found to be 60% and 33%, negative predictive values were 75% and 29%, and sensitivity 86% and 17%, respectively.9

Capromab pendetide scans do not reliably detect skeletal lesions. This may be because only about 44% of bony lesions express PSMA.10 A radionuclide bone scan should therefore be performed prior to a capromab pendetide scan to exclude skeletal metastases.

In clinical trials, pelvic and abdominal lymph nodes often were visualized scintigraphically. These nodes generally were not confirmed histopathologically, but the incidence of these findings closely matches autopsy data.11 The most common nodes were found in the periaortic, external, and internal iliac chains.

Imaging techniques

Two acquisition protocols for prostate immunoscintigraphy using capromab pendetide are currently in use. The first uses single photon emission computed tomographic (SPECT) imaging of the pelvis performed about 30 minutes post-injection. SPECT data is gathered over 360 degrees in six degree intervals, with 20-second sampling at each stop. A large field of view gamma camera, with a parallel hole, medium energy collimator is used. These blood pool images are essential in order to distinguish normal vascular activity from possible nodal metastases. The patient returns to the department three to five days later, when whole body planar and SPECT imaging of the abdomen and pelvis is performed.

The second protocol saves camera time and obtains a better comparison of the blood pool and antibody images. In this method the patient is not imaged on the day of injection. Instead, on the third or fourth day after injection, the patient's red blood cells are labeled by a standard in vivtro technique with technetium-99m (Tc-99m). Whole-body planar imaging, followed by SPECT imaging of the abdomen and pelvis, is performed with simultaneous image acquisition by the camera using both Tc-99m and In-111 windows. Normal uptake in the liver, spleen, and bone marrow is observed on the antibody scan. If there is a lot of activity in the colon, the patient may have to be recalled for another set of images following administration of a cathartic. Alternatively, the patient may be routinely prepared with a cathartic prior to the study. If desired, subtraction and/or co-registration techniques may

be employed.

Adverse effects

Adverse effects were reported in 4% of 529 patients in the trials who received a single dose of capromab pendetide.8 The most common adverse effects were elevated bilirubin, hypertension, and hypotension, each of which had an incidence of 1%. Elevated liver enzymes and local reactions at the injection site were experienced in less than 1% of the patients. Almost all patients who experienced adverse effects had mild and reversible symptoms.

Human antimouse antibodies

Because capromab pendetide is a murine antibody, there is a possibility of the development of human antimouse antibody (HAMA) after a single injection, which can reduce the sensitivity of the study if a second injection of a murine based antibody is made. Twenty of 239 study patients (8%) developed HAMA after a single dose of capromab pendetide, but after repeat infusions, the incidence was 5 of 27 (19%).8 HAMA levels often fall to negligible levels in a few months. Before a patient undergoes a repeat capromab pendetide scan, his HAMA level should be determined.

Dosimetry

The estimated total body absorbed dose from the 111-In-capromab pendetide scan is around 0.14 mGy/MBq, and the effective dose is 0.25 mSv/MBq when scanned with 185 MBq (5 mCi) of 111-In labeled to 0.5 mg of capromab pendetide.12 If activity passing through the gastrointestinal tract is also taken as a source, the effective dose is 18% higher. The liver is the critical organ here, receiving an absorbed dose estimate of 1 mGy/MBq. These doses are similar in magnitude to those from other whole antibody studies such as OncoScint®, which has a total body dose of 0.15mGy/MBq and an effective dose of 0.23mSv/MBq.12

Image interpretation

Examples of pelvic and extrapelvic metastases and recurrences are illustrated in figures 1-3.

Common causes of false positive studies include colostomy, degenerative joint disease, abdominal aneurysms, post-operative bowel adhesions, and local inflammatory changes associated with inflammatory bowel disease, surgery or radiation.13

Discussion

Treatment of prostate cancer depends on the stage of the disease. In general, curative treatment is only offered to those with organ-confined disease. However, clinical staging often is inaccurate, and a combination of several methods is optimal for staging. PSA levels are only a rough indicator of the extent of disease and cannot be used for staging purposes. The PSMA detected by capromab pendetide is separate from PSA, and the expression of PSMA rises with dedifferentiation of the tumor.14 Unlike PSA, PSMA is not down regulated by hormonal therapy,15 and so it is possible that low PSA levels do not necessarily signify tumor reduction.16 Transrectal ultrasound is about 70% accurate,17 but is applicable only for imaging of disease localized to the prostate bed. CT and MRI are not useful for staging, as they provide only gross anatomic information. Extensive lymph node dissection could give the necessary information, but the associated morbidity limits its utility.

It is important to identify the presence of extrapelvic disease in both pre-operative and post-operative patients, as this disease would be outside the usual surgical field or the usual radiotherapy treatment portals. It has been shown recently that in post-operative patients with occult disease demonstrated by only rising PSA levels, those who had no scintigraphically demonstrable disease outside the planned radiation field had a better response to radiation (significant drop in PSA) than those with scintigraphic evidence of disease outside the planned radiation field.18

Researchers also have tried monoclonal antibodies against prostate acid phosphatase19 and PSA19,20 to image metastatic involvement from prostate cancer, but these lacked sensitivity and had high incidences of HAMA formation (up to 50%),21 compared to a much lower incidence with capromab pendetide.

Conclusion

Capromab pendetide scanning can demonstrate evidence of metastases of lymph nodes, both in the pelvis and outside, in a pattern and incidence similar to available autopsy data. Knowledge of the presence or absence of lymph nodal metastases helps in management decisions in the high risk pre-surgical patient, as well as the post-surgical patient being considered for radiotherapy. Further investigation should be able to substantiate the important contribution that capromab pendetide imaging is making to management decisions in patients with prostate cancer. AR

References

1. Cancer facts and figures 1997. American Cancer Society, Atlanta, GA, 1997.

2. Amis ES, Newhouse JH: Essentials of Uroradiology, pp 326-328. Boston, Little-Brown Co., 1991.

3. Jacobson AF: Bone scanning in metastatic disease. In: Collier BD, Fogelman I, Rosenthall L (eds): Skeletal Nuclear Medicine, pp 108-109. St. Louis, Mosby-Year Book Publications, 1996.

4. Lamb HM, Faulds D: Capromab pendetide: A review of its use as an imaging agent in prostate cancer. Drugs Aging 12:293, 1998.

5. Cytogen Corporation, Princeton, NJ: Background dossier for ProstaScint® (capromab pendetide). July 10, 1997.

6. Gulfo JV: Clinical utility of monoclonal antibodies in prostate cancer. Prostate Cancer 77-94, 1994.

7. Burgers JK, Hinkle JH, Haseman MK: Monoclonal antibody imaging of recurrent and metastatic prostate cancer. Semin Urol XIII(2):103-112, 1995.

8. Cytogen Corporation, Princeton, NJ: ProstaScint® (capromab pendetide) package insert. Aug. 7, 1997.

9. Haseman MK, Reed NL, Rosenthal SA: Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen- positron emission tomography and biopsy correlation. Clin Nucl Med 21:704, 1996.

10. Silver DA, Pellicer I, Fair W, et al: Prostate specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81, 1997.

11. Saitoh H, Yoshida KL, Uchijima Y, et al: Two different lymph node metastatic patterns of a prostate cancer. Cancer 65:1843, 1990.

12. Mardirossian G, Brill AB, Dwyer KM, Nelp W: Radiation absorbed dose from Indium-111-CYT-356. J Nucl Med 37:1583, 1996.

13. Krynyckyi B, Li Y, Ganeles A, et al: Patterns of metastatic prostate cancer as determined by In-111 Cyt 356 (ProstaScint®). J Nucl Med 37:10P, 1996.

14. Wright GL, Haley C, Beckett ML, et al: Expression of prostate-specific membrane antigen in normal, benign and malignant prostate tissue. Urol Oncol 1:18, 1995.

15. Wright GL, Grob B, Haley C, et al: Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 48:326, 1996.

16. Olefelein MG, Smith N, Carter M, et al: The incidence of prostate cancer progression with undetectable serum prostate specific antigen in a series of 394 radical prostectomies. J Urol 158:2128, 1995.

17. Frydenberg M, Stricker PD, Kaye KW: Prostate cancer diagnosis and management. Lancet 349:1681, 1997.

18. Kahn D, Williams RD, Haseman MK, et al: Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy. J Clin Oncol 16:284, 1998.

19. Babaian RJ, Lamki LM: Radioimmunoscintigraphy of prostate cancer. Semin Nucl Med XIX(4):309, 1989.

20. Meyers FJ, Denardo SJ, Macey D, et al: Development of monoclonal antibody imaging of metastatic prostatic carcinoma. Prostate 14:209, 1989.

21. Babaian RJ, Murray JL, Lamki LM, et al: Radioimmunological imaging of metastatic prostate cancer with 111-indium-labeled monoclonal antibody PAY 276. J Urol 137:439, 1987.

Dr. Sinha and Dr. Freeman are with the Department of Nuclear Medicine at Montefiore Medical Center of the Albert Einstein College of Medicine in Bronx, NY.