Introduction

ProstaScint is a monoclonal antibody scanning technique that has implications in the staging of patients newly diagnosed with PC as well as use in evaluating patients believed to have recurrent disease. This monoclonal antibody, or MoAb, reacts with prostate cancer, benign prostatic hypertrophy and to a lesser extent, normal prostate tissue. The MoAb complex is an Indium111 labeled conjugate of the murine MoAb 7E11-C5.3. This antibody appears to recognize a prostate specific membrane glycoprotein that is chiefly expressed by prostatic epithelial cells, both benign and malignant, and whose DNA coding sequence has partial homology to that of the human transferrin receptor. ProstaScint scanning, therefore, involves an intact IgG1 immunoconjugate reactive with prostate specific membrane antigen (PSMA). Patients having a ProstaScint scan are given an iv injection of 0.5 mg of ProstaScint labeled with approximately 5mCi of 111 indium chloride. Initial computerized tomographic images are obtained on the day of the injection and additional tomographic images are acquired on approximately day 4 after injection with many patients undergoing additional scanning between days 5 and 7 to allow time for blood pool and bowel clearance.

Why is staging important?

Prostate cancer is the leading form of cancer for men in the U.S., and the second leading cause of cancer-related deaths in men. The American Cancer Society estimates that over 300,000 new cases of prostate cancer will be diagnosed this year. In the management of prostate cancer patients, prior to any local therapy as well as in monitoring for recurrence, defining the precise site(s) of disease is difficult since soft tissue metastases from prostate cancer are often undetected by existing diagnostic modalities such as MRI and CT. There is a significant need, presently unmet, for a more accurate diagnostic agent to detect both the location and extent of the prostate cancer. Information regarding the location of the cancer is critical to the success of initial therapy when deciding between local vs systemic treatment options in the newly diagnosed prostate cancer patient. In addition, the most beneficial treatment for patients with occult recurrent disease is dependent upon whether or not recurrence is local vs systemic. An accurate staging tool would result in therapy that is appropriate for the location of the malignant process.

Staging of early disease

The ProstaScint scan from Cytogen Corporation appears valuable in the staging of prostate cancer prior to the consideration for any local therapy. An abnormal ProstaScint scan may detect metastatic prostate cancer in lymph nodes or other sites. This would identify patients who are not candidates for local therapy such as radical prostatectomy(RP), external radiation therapy(RT), cryosurgery or brachytherapy. In a study of 152 patients undergoing RP, ProstaScint scanning was used to evaluate pelvic lymph node status. These results were correlated with the pelvic lymph node pathology obtained from the subsequent RP specimens. In Table I the specificity and sensitivity of the ProstaScint scan is shown along with positive and negative predictive values in Table 1. In this series there were a significant number of RP's where only one or two lymph nodes were sampled. This would lower the specificity of the ProstaScint scan if pathologic nodes were missed because of sampling errors at RP (Specificity = True negatives ¸ True negatives + False positives). In other words the number of false positive ProstaScints would increase due to scant node sampling at RP and missed metastatic lymph nodes. If this were the case then post-RP PSA readings should show rising values. This is confirmed by the greater specificity and positive predictive value seen using post-RP PSA values vs the pathology findings at RP. Along the same lines, the sensitivity of the ProstaScint would be falsely elevated since false negative instances of the ProstaScint would be missed by inadequate node sampling. In such cases a rising PSA post-RP would disprove the ProstaScint prediction and lower the true sensitivity (Sensitivity = True positives ¸ True positives + False negatives). This also is the case as shown in Table 1. PSA failure was defined as a rising PSA post- RP and/or a PSA value > 0.2 ng/ml.

Table 1. ProstaScint Evaluation of Pelvic Lymph Nodes Prior to RP.

If the ProstaScint results above are compared to the findings of MRI or CT of the pelvis utilizing the pathology at RP as the basis for comparison then the number of false negatives seen with ProstaScint are far less than that associated with either MRI or CT scanning (see Table 2).

The above findings for sensitivity are true apparently due to the fact that MRI and CT are associated with a high occurrence of false negative results in comparison with ProstaScint; false positives, in contrast, are not common with MRI and CT.

Detection of recurrent disease

111 In-CYT-356 scanning may also prove valuable in assessing patients who have a PSA elevation after "definitive" local therapy. In the management of patients with occult recurrent disease, local external beam radiation therapy is often used to destroy the cancer missed by the initial treatment. If the cancer is limited to the area treated by radiation, a curative effect is possible. However, if cancer has spread to areas beyond the field of the radiation, e.g., extraprostatic sites, radiation treatment is of little or no therapeutic value and can cause significant adverse effects such as incontinence, cystitis and proctitis. Additionally, it is estimated that the majority of patients who receive radiation therapy are not cured suggesting that the therapy was inappropriate.

Dr. Peter Levesque, Department of Urology, Lahey Clinic, presented clinical trial results involving 48 men with a rising PSA after radical prostatectomy. All of these patients were imaged with ProstaScint. Dr. Levesque stated, "There is presently no effective criteria to determine therapy for patients with recurrence after radical prostatectomy. The ProstaScint scan may be helpful in selecting which patients should receive local radiation or hormone therapy." Thirty-eight patients had positive ProstaScint scans suggesting the presence of cancer. Of these, 3 patients had activity in the prostatic fossa alone, 19 patients showed evidence of disease in the prostatic fossa and extraprostatic soft tissue sites, and 16 patients showed uptake only in extraprostatic sites. The most common sites of extraprostatic localization were areas beyond the potential therapeutic benefits of radiation therapy. If an abnormal ProstaScint scan is found confined to the prostatic bed it may support the rationale for local radiation therapy. If distant disease is found it would eliminate the need for local therapy and direct treatment towards a systemic approach.

In one early pilot study of patients with rising PSA's post-RP, the ProstaScint was positive in the prostatic fossa in 14 patients. 13 of these patients had biopsies with 8 (62%) confirming the ProstaScint scan; 7 biopsies showed prostate cancer and 1 showed residual prostate tissue. (Kahn D, Williams RD, Seldin DW et al. Radioimmunoscintigraphy with 111 indium labeled cyt- 356 for the detection of occult prostate cancer recurrence. J Urol 152:1490- 1495, 1994).

Richard Williams M.D. of the University of Iowa summarized that "The findings are encouraging and demonstrate a possible role using ProstaScint to better select patients for salvage pelvic radiotherapy." Clinical results involving 17 men with recurrent prostate cancer suggest that the men who responded poorly when treated with local salvage radiotherapy was presumably due to undetected occult metastatic disease outside the local radiation field. The 17 men were divided into three groups: group 1 (n=9) had ProstaScint scans which showed recurrent tumor localized to the prostatic fossa, group 2 (n=5) had ProstaScint scans which demonstrated recurrent tumor in sites outside of the prostatic fossa, and group 3 (n=3) had ProstaScint scans which failed to localize any specific site of recurrence. In group 1, six of the nine patients (67%) had a complete response to radiotherapy. In group 2, 0 of 5 patients (0%) had a complete response to pelvic radiotherapy. In group 3, 2 of the 3 patients (67%) had a complete response (Table 3)

Table 3. Positive predictive value (PPV) of ProstaScint in patients with positive scan in the fossa only (Williams et al)

A larger trial using ProstaScint scanning involved 181 men of whom 158 men underwent fossa biopsies. with rising PSA's post-RP. Transrectal 4- quadrant needle biopsies of the prostatic fossa were performed. The ProstaScint was abnormal in the fossa in 59 patients. In 29 of these the transrectal biopsies confirmed true positive ProstaScint scanning. In the remaining 29, biopsies were negative and the scans in these men were considered to be false positives. This gave a positive predictive value of 50% and a sensitivity of 49% (see Table 4). In the remaining 99 men the ProstaScint was negative in the fossa. Biopsies were confirmed to be negative in 70 of these patients (true negative ProstaScints) and were positive in 30 (false negative ProstaScints). These findings are shown below.

Of the 158 men in the study above, 43 received fossa RT. The PSA response to RT was then used as the basis for determining sensitivity and specificity versus the ProstaScint results and also comparing RT response versus the biopsy results. A PSA decrease of > 25% was used as an indicator of positive response to RT. The average PSA decrease in such patients was 76%. These findings are shown in Table 5.

Table 5. ProstaScint & Fossa Biopsy Results versus RT Results

The positive predictive value of a positive ProstaScint scan would be clinically important. It would be more important to know the PPV in patients who had positive scanning in the prostatic fossa and also outside of the fossa. In such patients, RT theoretically should be associated with a decrease in PSA and then increase as the disease outside of the RT port increases in volume. If ProstaScint scanning were shown to be accurate in this setting then its PPV would have a major advantage over prostatic fossa biopsies which also had a high PPV. 12 patients were found to have ProstaScint scans that were abnormal outside the fossa area. RT did not result in durable decreases in PSA's in 10 of the 12 patients. In the 2 patients with durable PSA decreases to RT, both showed persistent ProstaScint abnormalities in the retroperitoneum on follow-up scans. One of the patients showed new uptake in the neck as well. Of importance is that the repeat ProstaScints showed that the positive uptake in the fossa disappeared in both patients after RT. (Haseman et al) These studies appear to point out that multiple parameters for response evaluation need to be used. We would suggest that PAP and CGA (chromogranin A) be used along with PSA.

The overall sense of utility for ProstaScint in the setting of a rising PSA post- local therapy, based on the above studies, would suggest that ProstaScint scans that are abnormal exclusively in the prostatic fossa should reflect local disease amenable to RT and that patients with extra-prostatic scan abnormalities would be poor candidates for RT to the fossa. In the absence of extra-fossa localization, ProstaScint negative findings in the fossa however are too often associated with false negative results to be used with certainty as a criterion for or against RT.

Potential role as a marker for androgen-insensitive disease

Studies have been done that involve immunohistochemical staining of human PC tissue and showed that CYT-356 staining was highest in androgen- deficient lesions. If CYT-356 is a marker of hormone insensitive disease then a therapeutic isotope of CYT-356 might have value in the treatment of refractory patients. This appeared to be the explanation in two patients who were positive with ProstaScint scanning in the same location both before and after hormone blockade despite a drop in PSA to less than 0.1. If the ProstaScint was being picked up in hormone-sensitive PC then the scan activity should have decreased or disappeared with the decrease in PSA. Further studies are needed. Growth of such specimens in cell culture with the addition of testosterone would clarify the issue of hormone sensitivity or independence.

Considerations for Future ProstaScint Trials

Newly diagnosed PC patients would be stratified according to the Partin Tables for nodal risk for disease, i.e. up to 10%, 11-24%, 25-49%, 50-74%, 75-100%. Each patient would have baseline RT PCR PSA and PSM determinations. PAP determinations at baseline would also be done. PSA doubling times would be calculated when at least 3 PSA's were available. This data would not be related to the physician reading the ProstaScints until after an final dictated report had been rendered. ProstaScint scanning would next be done. Patients positive for abdominal or pelvic nodal disease would have a mini-Lap with node sampling and silver clip placed at biopsy sites. Those refusing to have a mini-lap would be asked to have a lymphangiogram instead. What should we predict that this would tell us?

First, as the Partin prediction for nodal disease increases, the PSA and/or PSM RT PCR increases as do the PAP abnormal results as well as the frequency of positive ProstaScint scans. The accuracy of the Prostascint with sensitivity (true positive/true positive + false negative) and specificity (true negative/true negative + false positive) would be determined by the mini-lap and/or the lymphangiogram results. All lymphangiograms would be sent out to 3 different experts e.g. Ron Castellino, Manny Viamonte, Sydney Wallace.

For patients who have had a RP or RT or Cryo or Seed Implant with a rising PSA, I would use the Partin 2 table and/or the PSA doubling time to predict who would be at high risk for systemic disease. RT PCR would again be done. I would follow this up with ProstaScint scanning and continue on as above. Those patients with a high likelihood of local recurrence, with a PSADT of greater than 12 months, and a ProstaScint positive only in the prostatic fossa would be eligible for fossa RT. After RT they would be followed with serial PSA readings and other clinical parameters such as a chemistry panel, CBC, physical exam, and where indicated CGA, bone scan and MRI.

If negative ProstaScint and other findings indicative of low risk for extra-prostatic disease: patient followed through therapy to ascertain sensitivity, specificity, etc. If ProstaScint negative but high risk findings per Partin or PAP or RT PCR or PSADT then proceed with workup utilizing MRI, lymphangiograms, mini-laparotomy.

If ProstaScint positive in pelvic or abdominal nodes: see text in section under "Considerations for Future ProstaScint Trials".

Patients with less than 50% chance of local recurrence based on Partin II table, those with PSADT of 3 or less months, those having a ProstaScint positive outside the fossa, and those with positive RT PCR findings are considered at high risk for non-local recurrence. Those patients would be told therapeutic options of systemic therapy with either hormonal blockade or chemohormonal therapy. Any radiologic or clinical tool can be used to evaluate and confirm extra-prostatic disease with these patients, e.g. MRI, lymphangiogram

Stephen B. Strum M.D.
Mark C. Scholz M.D.