In-111 Capromab Pendetide (ProstaScint7) in the Evaluation of Prostate-Specific Antigen-Only Progression of Prostate Cancer

Prostate Cancer Information

Advanced Prostate Cancer

Judd W. Moul, MD, FACS, COL., MC, USA

Urology Service, Department of Surgery
Walter Reed Army Medical Center
Washington, D.C. 20307-5001

Center for Prostate Disease Research
Department of Surgery
Uniformed Services University of the Health Sciences
Bethesda, MD 20814-4799

Welcome to the Prostate Cancer Education Council's Article Series: 2000 website.

Below is the fifth in a series of six articles by a select panel of distinguished urologist addressing a topic related to advancements in prostate cancer treatment, research, and prevention. Informative sidebars throughout the article, along with highlighted technical vocabulary hyperlinked to a prostate cancer glossary, create an easily digestible format for consumers.

Article Series: 2000 is presented on behalf of the Prostate Cancer Education Council (PCEC). Founded in 1988, the PCEC is a consortium of physicians, health educators, scientists, and patient advocates dedicated to increasing prostate cancer awareness and knowledge. Here is a list of currently available and upcoming articles.

The author of this article, his second of the series, is Col. Judd W. Moul. Dr. Moul is a Professor of Surgery at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, MD, and is an attending Urologic Oncologist at the Walter Reed Army Medical Center (WRAMC) in Washington, DC.

Dr. Moul is a Colonel in the US Army Medical Corps and has been at his current position since 1989 after having completed a Urologic-Oncology Fellowship at Duke University. Dr. Moul is a Summa Cum Laude graduate of the Pennsylvania State University and received his medical degree from Jefferson Medical College, having been elected to Phi Beta Kappa and Alpha Omega Alpha. Moul is Director of the Center for Prostate Disease Research (CPDR), a Congressionally-mandated research program of the Department of Defense based at USUHS and WRAMC and has a strong research interest in the molecular biology and clinical outcomes of prostate cancer.

Doctor Moul has had funded research projects related to testicular and prostate cancers from USUHS, WRAMC, the Department of Veterans Affairs and CaPCure and currently manages the 24 million dollar CPDR grant from the US Army Research and Materiel Command. Moul has authored or co-authored over 200 scientific manuscripts and book chapters including articles in the New England Journal of Medicine and the Journal of the American Medical Association.

Doctor Moul has received honors including the 1995 American Medical Association Young Physicians Section Community Service Award for his national involvement in prostate cancer patient support groups. He has also received the 1996 Sir Henry Wellcome Research Medal and Prize from the Association of Military Surgeons of the United States and was selected as a 1994 Fellow for the American Urological Association/European Association of Urology International Academic Exchange Program. Dr. Moul was selected as the 1997 recipient of the prestigious AGold Cystoscope Award by the American Urologic Association.

Doctor Moul is on the Editorial Board for the national journals Oncology, Techniques in Urology, and Prostate Cancer and Prostatic Diseases and the periodicals Oncology News International and Primary Care and Cancer. Moul is a medical advisor to the National Association for Continence (NAFC) and the US TOO International, Inc., prostate cancer support group network and is a member of numerous professional organizations. Moul has given numerous scientific presentations at national and international meetings, has been a visiting professor and invited lecturer at universities and national symposia, and has appeared on ABC, CNN, and other media as a prostate cancer authority.

INTRODUCTION

Although the rate of prostate cancer has fallen somewhat since the early 1990's peak, the American Cancer Society estimates that there were approximately 179,300 cases in 1999.

The SEER program finds that radical prostatectomy rates rose from 17.4 per 100,000 in 1988 to 54.6 per 100,000 in 1992. By 1992, 36.6% of localized and regional disease patients received radical prostatectomy and 32.3% received radiation therapy.

There was a three- to four-fold rise in the rate of radical prostatectomy in men aged 45-59 years, and a rise of two- to three-fold in men aged 60-69 years. Rates of radiation also rose one- to two-fold for men aged 45 - 79 years.

An estimate of more than 50,000 men per year develop a PSA-only early progression.

The "PSA-era" (1988 to present) has dramatically altered the face of prostate cancer in the United States and in many other industrialized countries. Although the rate of prostate cancer has fallen somewhat since the early 1990's peak, the American Cancer Society estimates that there were approximately 179,300 cases in 1999.¹ Along with this large shift in incidence has come an unprecedented stage migration. The Surveillance, Epidemiology and Endemiology and End Results (SEER) program of the National Cancer Institute (NCI) has shown a 52% drop in the rate of distant (stage D) stage prostate cancer between 1990 and 1994.² At the same time, the rate of diagnosis of localized disease skyrocketed. With this change in stage distribution, the treatments also changed. The SEER program finds that radical prostatectomy rates rose from 17.4 per 100,000 in 1988 to 54.6 per 100,000 in 1992.² By 1992, 36.6% of localized and regional disease patients received radical prostatectomy and 32.3% received radiation therapy. Furthermore, there has been a shift in the age-adjusted rate of these treatments. Most notably, there was a three- to four-fold rise in the rate ofradical prostatectomy in men aged 45-59 years, and a rise of two- to three-fold in men aged 60-69 years.² Rates of radiation also rose one- to two-fold for men aged 45 - 79 years.

In the late 1990's, we are now seeing the effects of the diagnosis and localized treatment boom of the early 1990's.³ A large number of generally younger men who were treated for clinically localized prostate cancer have already or are now experiencing disease recurrence. With an estimate of more than 50,000 men per year developing a PSA-only early progression, it is obvious that this is a key issue for clinicians, and perhaps, most importantly, for the man and his family.

What is PSA Progression in Surgery and Radiation Patients

The use of an ultra sensitive PSA assay may result in the identification of relapsing patients 1-2 years earlier than with the conventional assay.

In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) held a consensus panel to determine guidelines for PSA recurrence after radiation therapy. The panel agreed on four guidelines:

Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure.
Three consecutive increases in PSA is a reasonable definition of biochemical failure after radiation therapy.
No definition of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival.
Nadir PSA is a strong prognostic factor, but no absolute level is a valid cut point for separating successful and unsuccessful treatments.

The level of PSA at which to define a failure after radical prostatectomy varies in the literature.⁴ Some series have used any detectable level, some a single value greater than 0.4 or 0.5 ng/mL, and others two consecutive values greater than or equal to 0.2 ng/mL. The use of an ultra sensitive PSA assay may result in the identification of relapsing patients 1-2 years earlier than with the conventional assay.⁵ Until recently, defining a PSA-recurrence after radiation therapy was widely debated.^6,7 In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) held a consensus panel to determine guidelines for PSA recurrence after radiation therapy.⁸ The panel agreed on four guidelines:

1. Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure. It is, however, an appropriate early end point for clinical trials.

2. Three consecutive increases in PSA is a reasonable definition of biochemical failure after radiation therapy. For clinical trials, the date of failure should be the mid-point between the post-irradiation nadir PSA and the first of three consecutive rises. The use of three, rather than two, consecutive values reduces the risks of falsely declaring biochemical failure due to "bouncing" PSA. This phenomenon results when sequential PSA determinations show one or two rises followed by a fall and a subsequent failure to rise again.

3. No definition of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival.

4. Nadir PSA is a strong prognostic factor, but no absolute level is a valid cut point for separating successful and unsuccessful treatments. Nadir PSA is similar in prognostic value to pretreatment prognostic variables.

Evaluation of PSA Progression: Role of Traditional Staging Tests

Most patients evaluated for an elevated post-treatment PSA undergo radiographic studies, including CT and/or bone scanning. However, for patients with a PSA- only progression, the yield of these studies is extremely low.

The clinical utility of bone scan and CT is limited in the setting of PSA-only recurrence after surgery or radiation unless the PSA value is quite high. More importantly, these tests would appear to be of no added value unless the rate of PSA rise is more than 20 ng/mL/year.

Traditionally, most patients evaluated for an elevated post-treatment PSA undergo radiographic studies, including CT and/or bone scanning.^9,10 However, for patients with a PSA- only progression, the yield of these studies is extremely low. Recently, Cher, et al. studied 144 bone scans in 93 patients being evaluated for a PSA recurrence after radical prostatectomy.¹¹ The lowest PSA value associated with a positive bone scan in the absence of adjuvant hormonal therapy was 46 ng/mL. In a univariate and multivariate analysis, the stage, grade, preoperative PSA value and time to recurrence did not predict whether a bone scan would be positive; only the value of the recurrence PSA and a very rapid slope of PSA rise (i.e. 5.0 ng/mL/month) were predictive. These authors recommended that bone scans not be used unless the recurrence PSA value was greater than 40 ng/mL. Considering that the vast majority of patients are evaluated long before the PSA even gets close to 40 ng/mL, bone scans are probably not necessary in the vast majority of patients. Conversely, Johnstone, et at. in a smaller study of 24 post-radical prostatectomy and 20 post-radiation PSA-only recurrences, found one of 20 (5%) of surgery patients and 6 of 20 (30%) radiation patients had a positive bone scan.¹² The median PSA value for the 7 patients with positive bone scans was 6.79 ng/mL., however, the rate of PSA rise was exceedingly high (21.5 ng/mL/year).

Regarding the clinical utility of computed tomography of the abdomen and pelvis for PSA-only recurrence, results are similar to bone scan. Johnstone, et at. Also studied CT and found out 2 of 18 (11%) surgery recurrence patients and 3 of 10 (30%) radiation recurrence patients positive.¹² The mean PSA value for those 5 patients was 12.4 ng/mL and the mean velocity was very high at 30.6 ng/mL/year. Only one of the 5 scan documented unique distant recurrence information (3 showed local recurrence only and one confirmed a bone lesion also seen on bone scan).

In summary, the clinical utility of bone scan and CT is limited in the setting of PSA-only recurrence after surgery or radiation unless the PSA value is quite high. More importantly, these tests would appear to be of no added value unless the rate of PSA rise is more than 20 ng/mL/year.

Evaluation of PSA Progression: Role of ProstaScint®

Considering that many patients with early prostate cancer metastases have distant micro-metastases without pelvic or obturator metastases, it is not surprising that ProstaScint® is improving the prediction of response to salvage radiation.

A FDA-approved scintigraphic radiolabeled monoclonal antibody imaging study of the prostate specific membrane antigen (PSMA) called In-111 capromab pendetide (ProstaScint®) may have clinical utility in the setting of PSA recurrence after radical prostatectomy. Initial studies demonstrated residual disease in 60% of those with an elevated PSA.^13,14 A number of studies shed more light on ProstaScint®.^{15,16,17,18,19,20} At the time of FDA-approval for ProstaScint®, the sensitivity, specificity and overall accuracy of the test was listed at 62, 72 and 68%, respectively.^13,14 More recently, Hinkle, et. at. reported a multicenter study of the test and found sensitivity of 75%, specificity of 86% and accuracy of 81%, which compared favorably to an accuracy of only 48% for CT/MRI in soft tissue assessment.¹⁹ Similarly, Elgamal, et al. report sensitivity of 89%, specificity of 67% and accuracy of 89% in a series of 100 patients.²⁰

Regarding ProstaScint® in PSA-recurrence, Levesque, et al studied 48 patients with an elevated PSA after prostatectomy (mean PSA 28.7% ng/mL, median 13.8 ng/mL) and found that 73% had antibody activity beyond the prostatic fossa.¹⁵ Only 3 patients (6%) had activity only in the prostatic bed (Table 1). Furthermore, 65% had activity in the pelvic nodes despite prior negative lymphadenectomy at the time of surgery and 23% had more distant nodal activity. Of the 48 men, 13 underwent radiation to the prostatic fossa.

Seven patients did not show ProstaScint® activity beyond the radiation field and only two have recurred to date. However, for the 6 radiated patients in whom the ProstaScint® showed more distant disease, radiation failed in 4. Kahn, et al. reported a multicenter study of 181 radical prostatectomy patients (mean PSA of 7.9 ng/mL/median 2.6 ng/mL) who underwent ProstaScint® for recurrence evaluation.¹⁶ The scan revealed disease in 108 of 181 (60%). Unlike the above study of Levesque, et al.,¹⁵ 32 of the 108 positive scan patients (29.6%) had recurrence detected only in the fossa (Table 1). However, even though it is 30% versus 6% fossa-only recurrence comparing these studies, the majority of men in both studies had distant ProstaScint® activity. A concern of both studies^15,16 is that the PSA levels at the time of the scans were quite high and the value of ProstaScint® with very low PSA recurrence values was unknown. Petronis, et al., studied 51 patients with ProstaScint®, 48 of whom were radical prostatectomy recurrences.¹⁷ Overall, 35 of 51 (70.6%) patients had a positive scan and only 8 of the 36 (22.2%) were positive in the prostatic fossa only (Table 1). By recurrence level of PSA, even for PSA values between and 1.0 ng/mL, ProstaScint® was positive in 60%. Between 1.1 and 10.0 ng/mL, the scan positivity ranged from 60.0 to 83.3%, but for PSA values at recurrence above 10.1 ng/mL, all patients had a positive scan (Table 2).

As noted above, Levesque, et al.,¹⁵ and others²¹ have postulated that ProstaScint® may be able to accurately differentiate local from distant recurrence after radical prostatectomy and improve the selection of men for salvage radiotherapy to the prostatic bed. In this setting, Kahn, et al., have recently reported on 32 men who were radiated for a PSA-only recurrence after radical prostatectomy and had 13 month median follow-up.¹⁸ Sixteen of 23 (70%) patients with a normal ProstaScint® outside the prostatic fossa achieved a durable complete response (PSA decline to < 0.3 ng/mL for at least 6 months prior to latest follow-up). Only 2 of 9 (22%) men who had a positive scan beyond the fossa achieved a durable complete response. Considering that many patients with early prostate cancer metastases have distant micro-metastases without pelvic or obturator metastases,²² it is not surprising to me that ProstaScint® is improving the prediction of response to salvage radiation. Longer follow-up is needed to determine if ProstaScint® positivity only in the fossa predicts long-term outcome, however, we are using ProstaScint® as a staging study prior to consideration of salvage radiation.

Summary

The majority of patients experiencing a PSA recurrence have a positive ProstaScint® test with disease beyond the prostate fossa.

By limiting salvage radiation therapy to the prostatic bed for post surgical recurrence patients to those with a negative ProstaScint® or those showing only fossa recurrence, the patient selection and long term outcome may be improved.

With the large increase in the diagnosis and treatment of clinically localized prostate cancer in the early and mid 1990's has come a significant increase in PSA-only recurrence in the late 1990's. For surgical patients a persistent PSA of greater than 0.2 ng/mL and for radiation patients three consecutive rises in PSA after the post-treatment nadir indicates recurrence. Staging work-up at the time of PSA recurrence has generally included bone scans and CT of the abdomen and pelvis, however, the value of these tests is low unless the PSA value is significantly elevated (10-40 ng/mL). In-111 capromab pendetide (ProstaScint®) is an FDA-approved radioisotopic nuclear medicine scan that is based on soft-tissue reactivity with the prostate specific membrane antigen (PSMA). Sensitivity and specificity are in the 60-80% range compared to less than 40% for bone scan and CT in this setting. The majority of patients experiencing a PSA recurrence have a positive ProstaScint® test with disease beyond the prostate fossa. By limiting salvage radiation therapy to the prostatic bed for post surgical recurrence patients to those with a negative ProstaScint® or those showing only fossa recurrence, the patient selection and long term outcome may be improved.

REFERENCES

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2. Stephenson, RA: Population-based prostate cancer trends in the PSA-era: Data from the Surveillance, Epidemiology, and End Results (SEER) Program. 1998 Monographs in Urology, 19(1): 1-19, 1998.

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15. Levesque PE, Nieh PT, Zinman LN, et. al.: Radiolabeled monoclonal antibody indium 111-labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy. Urology, 51: 978-984, 1998.

16. Kahn D, Williams RD, Manyak MJ, et. al.: 111Indium-capromab pendetide in the evaluation of patients with sesidual or recurrent prostate cancer after radical prostatectomy. Urology, 159:2041-47, 1998.

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In-111 Capromab Pendetide (ProstaScint7) in the Evaluation of Prostate-Specific Antigen-Only Progression of Prostate Cancer

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