Undetectable Prostate-Specific Antigen Level Following Prostate Brachytherapy: An Apples-to-Apples Comparison with Radical Prostatectomy

ABSTRACT

INTRODUCTION: Following radical prostatectomy for adenocarcinoma of the prostate, a long-term undetectable PSA level is associated with cure. Cure may also be defined by persistently low PSA levels after radiation, with the assumption that residual benign prostate tissue may produce low levels of PSA. There is no established PSA nadir following radiation therapy that has been universally associated with cure. The purpose of this study was to determine the frequency of undetectable PSA following prostate brachytherapy.

METHODS: A total of 163 patients were treated with radioactive iodine-125 seed implantation as definitive treatment, between 1996 and 2003. No patients received external radiation or hormone therapy. Posttreatment PSA levels were reviewed to ascertain the number of patients with PSA levels that were undetectable, ≤ 0.2, ≤ 0.3, and ≤ 0.5 ng/mL. PSA failure was based on the ASTRO consensus definition.

RESULTS: At a median follow-up of 85.2 months, 120 patients (73.6%) achieved and maintained an undetectable PSA level. Twenty-three patients (14%) experienced biochemical failure by the ASTRO definition; 80%, 83%, and 85% achieved and maintained PSA nadirs of ≤ 0.2, ≤ 0.3, and ≤ 0.5 ng/mL, respectively.

Comparing outcomes of patients treated with radical prostatectomy and radiation therapy for prostate cancer is difficult, due to different PSA patterns following treatment and varying definitions of success. The present study showed that an undetectable PSA level after brachytherapy is consistently associated with disease-free state, which reflects the durability of that biochemical status. It matches the most stringent definition of disease freedom following prostatectomy.

CONCLUSIONS: Comparing outcomes of patients treated with radical prostatectomy and radiation therapy for prostate cancer is difficult, due to different PSA patterns following treatment and varying definitions of success. The present study showed that an undetectable PSA level after brachytherapy is consistently associated with disease-free state, which reflects the durability of that biochemical status. It matches the most stringent definition of disease freedom following prostatectomy.

KEYWORDS: Prostate cancer; Brachytherapy; Prostatectomy

CORRESPONDENCE: William L. Barrett, MD, Department of Radiation Oncology, University of Cincinnati College of Medicine, 234 Goodman Street ML 0757, Cincinnati, Ohio 45267-0757 USA ().

CITATION: Urotoday Int J. 2010 Apr;3(2). doi:10.3834/uij.1944-5784.2010.04.16

ABBREVIATIONS AND ACRONYMS: ASTRO, American Society for Therapeutic Radiology and Oncology; I-125, iodine-125; PSA, prostate-specific antigen.

INTRODUCTION

Prostate cancer is one of the most common cancers diagnosed in America, second only to skin cancer. There were 219 000 cases of prostate cancer in 2007 and 27 000 deaths [1]. Seventy-five percent of men have presumed localized disease at the time of diagnosis, although occult extraprostatic extension of disease is common [2]. Patients with presumed localized disease have multiple management options from which to choose, either alone or in combination. The options include observation or watchful waiting, prostatectomy, external radiation therapy, or brachytherapy.

Prostate-specific antigen (PSA) level following treatment has become the most reliable and earliest indicator of treatment success or failure [3,4,5]. Following prostatectomy, a long-term undetectable PSA level is associated with cure [6,7]. Multiple definitions of treatment failure have been used for patients treated with prostatectomy, as well as for those treated with radiation therapy. Following prostatectomy, some authors have defined treatment failure as any detectable PSA, while others have considered PSA levels > 0.2 ng/mL, > 0.3 ng/mL, > 0.5 ng/mL, or > 0.6 ng/mL as the threshold for defining disease persistence or recurrence [4,6,7,8,9].

The most stringent definition of treatment success following prostatectomy is a durable, undetectable PSA level. PSA levels can become detectable long after prostatectomy, signaling disease recurrence. However, that phenomenon becomes progressively less likely the longer the PSA is undetectable. Biochemical disease freedom following radiation therapy is even more confounding due to the characteristic gradual decline in PSA following radiation therapy, the frequent presence of persistent benign prostatic tissue capable of producing PSA, and the frequent phenomenon of transient elevations in PSA levels following external or interstitial radiation with subsequent decline [3,10]. Multiple definitions have been used to characterize biochemical disease freedom or recurrence following external radiation and/or brachytherapy. The definitions have included: (1) the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus statement, which considers biochemical recurrence following radiation therapy as 3 consecutive rises in PSA at least 3 months apart from each other; (2) nadirs of â‰¤ 0.2, 0.5, 1.0, or 4.0 ng/mL as signifying disease freedom; and (3) nadir plus 2 ng/mL as signifying disease recurrence [3,4,11,12,13,14,15].

Comparisons of outcomes between prostatectomy and radiation therapy are particularly difficult because of the dissimilar posttreatment PSA patterns that follow different treatments and the various definitions of biochemical control. Durable undetectable PSA level following prostate brachytherapy would match the most stringent definition of biochemical disease control following prostatectomy. The purpose of the present retrospective study was to describe the PSA level outcomes of patients treated with brachytherapy alone for cancer of the prostate.

METHODS

The records of 163 consecutive patients with minimum 3-year follow-up data were reviewed. Each patient was treated only with brachytherapy, between January 1996 and January 2003. No patient received external radiation therapy or hormone therapy.

All patients were clinically without evidence of extraprostatic disease at the time of treatment. The diseases were stage T1A through stage T2C, with the majority being stage T1C or stage T2A. The median Gleason score was 6 (range, 5-8). The median PSA level was 6 ng/mL (range, 1.6-17.7 ng/mL).

Brachytherapy Treatment

Management options, including combined modality approaches, were discussed with each patient. The selection of brachytherapy alone was made by patient choice.

All patients were treated with transperineal radioactive iodine-125 (I-125) seed implantation under ultrasound guidance by 1 physician. The prescribed dose to the periphery of the prostate was 14 400 cGy in all patients (16 000 cGy prior to TG-43). Median preimplant prostatic volume was 37 cc (range, 13-113 cc). One patient had a preimplant prostate volume of 113 cc; all others had prostate volumes lower than 85 cc. Median total implanted activity per patient was 40 mCi (range, 10.6-73.6 mCi). The median activity per I-125 seed was 0.37 mCi (0.4 prior to TG-43).

Follow-up Evaluations and Data Analysis

PSA levels were drawn 1 month and 3 months following the implant, every 3 months for the rest of the first year, and every 4 to 6 months thereafter.

The ADVIA CentaurÂ® PSA assay (Siemens Healthcare Diagnostics Inc, Deerfield, IL, USA) was used to measure PSA levels, with a threshold for detection of 0.1 ng/mL. Postimplant PSA levels were reviewed to ascertain the number and percentage of patients achieving and maintaining undetectable PSA levels (PSA < 0.1 ng/mL), as well as PSA levels of ≤ 0.2, ≤ 0.3, and ≤ 0.5 ng/mL. The number and percentage of patients experiencing biochemical recurrence of disease, as defined by the ASTRO consensus statement, were also determined.

RESULTS

At a median follow-up of 85.2 months, 120 patients (73.6%) had achieved and maintained an undetectable PSA level (< 0.1 ng/mL). Median time to achieving an undetectable PSA level was 40 months following the brachytherapy implant. Both the mean and median number of PSAs obtained per patient was 19. Ninety-one (64%) of the patients who were biochemically free of disease experienced a PSA bounce (transient elevation). Twenty-three patients (14.1%) experienced biochemical recurrence by the ASTRO consensus statement definition. None of the patients who obtained an undetectable PSA following prostate brachytherapy had a subsequent rising PSA. Further, 80.4% of the patients achieved and maintained a PSA level ≤ 0.2 ng/mL; 83.4% of the patients achieved and maintained a PSA level ≤ 0.3 ng/mL; and 85.3% achieved and maintained a PSA level ≤ 0.5 ng/mL.

Out of the 23 patients who had a biochemical recurrence according to the ASTRO consensus statement, 6 patients then had salvage therapy. This consisted of hormonal therapy with luteinizing-hormone-releasing hormone (LHRH) agonist in all 6 patients, and chemotherapy with hormonal therapy in 1 patient. To date, 1 patient has passed away due to prostate cancer. The median PSA doubling time for all ASTRO failures was 9.1 months (range, 4-39.9 months), and the mean PSA doubling time was 12.6 months.

Twenty-six patients had prostate volumes > 50 cc. Neoadjuvant hormonal therapy was not used in attempt to decrease prostate volume prior to implant. For this group, 15 patients (57%) had undetectable PSAs and 17 patients (65%) had PSAs ≤ 0.2 ng/mL. Biochemical failure, according to the ASTRO consensus definition, occurred in 5 patients (19.2%).

DISCUSSION

It has been difficult to compare the outcomes of patients treated with radical prostatectomy versus radiation therapy, due to different PSA patterns following treatment and varying definitions of success and failure. Controversy remains regarding the relative efficacy of the available modalities, in the absence of a completed prospective randomized trial comparing prostatectomy to external and/or interstitial radiation. Further, although PSA level following treatment for cancer of the prostate is capable of detecting persistent or recurrent disease long before clinical manifestations appear, controversy also remains regarding the PSA level and timing associated with cure following prostatectomy and radiation therapy. Definitions of biochemical disease freedom following prostatectomy have included PSA levels of < 0.05 ng/mL (undetectable), < 0.1 ng/mL (undetectable), < 0.2, < 0.5, and < 0.6 ng/mL, by different authors. If all malignant disease and benign prostate tissues have been removed surgically, the PSA level should be undetectable. Definitions of biochemical control, including PSA levels of < 0.2, < 0.5, and < 0.6 ng/mL, allow for small amounts of residual benign prostate tissue producing low and presumably stable amounts of PSA. Cure in the setting of a low-but-detectable postoperative PSA level is not common.

Interpretation of PSA level following radiation treatment is confounded by the typical slow regression of disease following radiation treatment, the persistence of some viable benign prostate tissue capable of producing some level of PSA, and the not-infrequent occurrence of a transient rise in PSA following radiation treatment with subsequent sustained decline [10,16]. Multiple definitions have been recommended for disease freedom following radiation treatment by different authors, including PSA levels ≤ 0.2 ng/mL, ≤ 0.5 ng/mL, and ≤ 1.0 ng/mL. The ASTRO consensus statement defines biochemical recurrence as 3 consecutive PSA rises at least 3 months apart following external radiation, and this definition frequently has been extrapolated for brachytherapy as well. Nadir plus 2 has been proposed as an alternative definition of biochemical failure following radiation treatment, in attempt to differentiate small â€œbenignâ€ rises in PSA from true treatment failure. Because of the differences in PSA pattern following prostatectomy versus radiation therapy, an â€œapples-to-applesâ€ comparison using PSA is difficult but not necessarily impossible.

Pound et al [7] defined disease freedom as an undetectable PSA level 10 years following nerve-sparing prostatectomy in a select group of 1623 patients, with 68% of the patients considered cured using that definition. Catalona and Smith [9] used a PSA level of < 0.3 ng/mL following prostatectomy as the threshold for their definition of disease freedom, with 85% of their patients meeting this criterion. Nielsen et al [17] reported PSA recurrence-free survival after radical prostatectomy in 78.1% of 2570 men, defined as PSA ≤ 0.2 ng/mL at 15 years. Gretzer et al [18] also defined biochemical control as ≤ 0.2 ng/mL, and found biochemical freedom from failure at 15 years in 68% of in 2691 men treated with radical prostatectomies.

Following brachytherapy combined with external beam radiation therapy, Critz and Levinson [12] advocated a PSA level of ≤ 0.2 ng/mL as representing disease freedom; this level was achieved in 83% of their patients. In a subsequent review of 539 patients reaching a PSA nadir of 0.2 ng/mL, Critz [19] found the median time to nadir to be 27 months. He showed that 99% of patients reached a nadir by 5 years, and failure to do so tended to indicate persistent disease. Wallner et al [11] considered a PSA level < 1.0 ng/mL as being associated with disease freedom, and that level was maintained in 63% of their patients.

Sharkey et al [20] compared 1177 patients treated with Pd-103 brachytherapy to 281 patients treated with prostatectomy at a single institution. They failed to show superiority of prostatectomy over brachytherapy. The authors defined biochemical control as PSA < 0.4 ng/mL for patients treated with prostatectomy, and absence of 3 successive rises in PSA for patients treated with brachytherapy. Using these defined criteria, 94% of patients treated with prostatectomy and 89% of patients treated with brachytherapy experienced disease control at a median of 3 years.

In the reported series, 73.6% of the patients treated with brachytherapy achieved and maintained undetectable PSA levels, while 80%, 83%, and 85% of patients were disease-free using PSA levels ≤ 0.2, ≤ 0.3, ≤ 0.5 ng/mL, respectively. In the present authors' experience, 98% of patients achieving a PSA level of ≤ 0.2 appear to be cured on the basis of a subsequent nonrising PSA, while 90% of patients reaching a PSA level â‰¤ 0.5 ng/mL have not experienced a subsequent PSA elevation. Although the current series is relatively small and of intermediate follow-up duration, the disease characteristics of the patients treated with brachytherapy alone in the current series are similar to those of the patients selected for prostatectomy in many series [7,9,17,18,20], and the biochemical outcomes are similar (see Table 1 and Table 2).

CONCLUSION

Using identical biochemical endpoints, brachytherapy appears to confer similar disease-free status to prostatectomy.

Conflict of Interest: none declared

REFERENCES

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer Statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66.

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