Rising PSA Level in an Anxious Postprostatectomy Patient

September 15, 2016

A 66-year-old Caucasian man with a history of hypertension, hyperlipidemia, and rheumatoid arthritis was diagnosed with prostate cancer.

The Case

A 66-year-old Caucasian man with a history of hypertension, hyperlipidemia, and rheumatoid arthritis was diagnosed with prostate cancer. Transrectal ultrasound-guided biopsy revealed Gleason 3+4=7 disease in 1 of 12 cores and Gleason 3+3=6 disease in 2 of 12 cores. His prostate-specific antigen (PSA) level at biopsy was 3.5 ng/mL. The patient’s prostate cancer was asymptomatic: he had minimal lower urinary tract symptoms, was continent, and had erections sufficient for penetration without medical or mechanical assistance. He underwent open radical retropubic prostatectomy 6 months after diagnosis. His postoperative course was unremarkable and he was discharged on post-op day 1. His prostate specimen weighed 44 g and consisted of 9% adenocarcinoma tumor. Final surgical pathology revealed Gleason 4+3=7 disease with tertiary Gleason pattern 5 disease. There were positive margins (3 mm at the right periphery and 1 mm at the apex) and perineural invasion but no extracapsular extension, seminal vesicle invasion, or lymph node invasion. Final pathologic stage was pT2c.

Postoperatively, the patient’s PSA level was undetectable (< 0.1 ng/mL) for the first 19 months (Figure). His PSA level had risen above 0.1 ng/mL by 19 months postoperatively; it remained between 0.1 and 0.2 ng/mL until 31 months postoperation, at which time it reached 0.2 ng/mL. His PSA level had climbed to 0.22 ng/mL by 37 months, and to 0.33 ng/mL by 43 months; it then fell back to 0.25 ng/mL at 49 months postprostatectomy. After his PSA level became detectable, PSA doubling time was 24.3 months, with a velocity of 0.1 ng/mL/yr. The patient’s functional status was excellent. He did not require any pads by 7 months post-surgery; and he had an American Urological Association (AUA) symptom score of 6 and a bother score of 0. He eventually developed excellent urinary control. By 13 months postoperation, he reported that with a phosphodiesterase inhibitor he was able to sustain satisfactory erections for sexual activity (International Index of Erectile Function score = 18), and his erections slowly continued to improve. The ability to resume sexual activity was deeply gratifying to him.

The patient understands that his PSA level meets criteria for biochemical recurrence, which is justification for proceeding with further treatment of his prostate cancer. However, he feels very fortunate to have had excellent return of urinary and erectile functioning, and at age 70 years, he is still relatively healthy. Thus, he is loath to undergo treatment that might have a negative impact on his quality of life. He is very wary of the potential side effects and complications of radiation therapy and androgen deprivation therapy and he resists their implementation. He has already discussed such concerns with the care team, but remains paralyzed by the prospect of potential adverse effects and is having difficulty reaching a decision regarding his treatment. Very nervous, he returns to the clinic for a routine follow-up visit.

What would be the best next step in this patient’s management?

A. Proceed with radiation therapy, since his rising PSA level places him at risk for clinical recurrence.

B. Continue with periodic PSA surveillance.

C. Order a genetic biomarker test to determine cancer aggression.

D. Provide reassurance that this is likely a PSA elevation due to benign prostate tissue in situ.

Discussion

The management of this patient, who has a rising PSA level after radical prostatectomy, should ideally balance the desire for cancer control with the patient’s goal of preserving potency and continence. The patient’s life expectancy remains unknown, adding to the uncertainty regarding the implications of the various management options. Thus, it is important that any management decision assuage the patient’s anxiety and help him resolve his indecision. It is the negotiation of these many undefined factors, both medical and personal, that makes determination of the next step in management an especially delicate one.

A rising PSA level after surgery could reflect biochemical recurrence (defined as PSA level ≥ 0.2 ng/mL, with confirmation on repeat PSA testing) or it could represent a benign elevation from residual nonmalignant prostate tissue. Patients with tertiary Gleason pattern 5 disease are both more likely to have a biochemical recurrence[1] and to experience biochemical recurrence sooner than patients without tertiary Gleason pattern 5 disease.[2] Positive margins are also an adverse pathology feature, and biochemical recurrence within 3 years of prostatectomy increases the likelihood of prostate cancer–specific mortality.[3] Both the AUA and the National Comprehensive Cancer Network (NCCN) practice guidelines recommend salvage radiation with or without androgen deprivation therapy when biochemical recurrence is detected.[4,5] In light of these recommendations, it would be rash to directly reassure the patient that his PSA elevation is benign at this point (Answer D), despite that possibility and his slower PSA doubling time.

However, this patient’s PSA doubling time of ≥ 15 months suggests that he would be at a lower risk for prostate cancer–specific mortality. With a biochemical recurrence within 3 years of prostatectomy, a PSA doubling time of ≥ 15 months, and a pathology finding of Gleason score ≤ 8, the nomogram of Freedland et al indicates that he has an estimated cancer-specific survival of 99% at 5 years, 93% at 10 years, and 81% at 15 years.[3] Given that the majority of men with pathology findings similar to this patient’s are predicted to survive even with untreated biochemical recurrence, and that life expectancy for an average American 70-year-old man is approximately 15 additional years,[6] proceeding with salvage therapy may be overtreatment and may put the patient’s quality of life at undue risk, which would be especially unfortunate given his elevated anxiety regarding the preservation of his functional recovery. Indeed, postoperative urinary incontinence and erectile dysfunction have been associated with decisional regret after prostatectomy,[7] and such psychological distress could be amplified if a patient were to happily regain these functions to a high degree only to lose them again after potentially unneeded salvage treatment.

Moreover, it is possible that the patient’s PSA rise is caused by benign residual prostatic tissue, rendering salvage treatment unnecessary. Benign glands are associated with high Gleason score and large prostate volume.[8] They most commonly occur at the prostatic apex, and literature suggests that precise apical dissection to improve continence recovery may leave patients at increased risk for such residual benign apical tissue.[9] Benign residual tissue has not been shown to impact disease progression or outcomes, despite increasing PSA levels.[10] The possibility of benign residual tissue in the context of the patient’s functional recovery, even if not confirmed, would restrain decision to immediately proceed with salvage treatment (Answer A).

Ultimately, this patient’s pathology, risks, and lifestyle preferences indicate that he does not neatly conform to routine management recommendations or nomogram-based care. A more individualized approach is necessary to further educate him and to propose a course of action that addresses the cancer while assuaging his emotional apprehension and indecision.

Commercial molecular genetics may provide information tailored to the patient’s disease that could direct his course of action. Tests such as Decipher, Prolaris, Oncotype Dx, and others examine mutations in or expression levels of certain genes in order to distinguish cancer from benign tissue and to investigate the aggressiveness of cancer.[11]While not a replacement for PSA testing, Gleason scoring, and more traditional measurements, such tests may be useful as supplementary tools when conventional measurements have conflicting implications. They may also provide valuable information when there is indecision or when patient preferences and physician recommendations are not completely aligned.

The field of commercial molecular biomarkers for prostate cancer has greatly expanded in the last 5 years, with different markers measured using samples from blood, urine, biopsy cores, and the prostatectomy specimen. Because of their novelty, such biomarkers have not been formally included in any management algorithms, and there have been no randomized controlled trials or direct comparisons among the novel biomarkers. Neither NCCN nor AUA guidelines for prostate cancer incorporate them into standard patient care pathways.[5,12] However, the authors of the 2016 NCCN prostate cancer guidelines utilize molecular biomarkers on a case-by-case basis and express excitement over their potential.[5]

Given this patient’s circumstances, his management might benefit from having a test such as the Decipher genetics test performed on his prostatectomy specimen (Answer C). Expert opinion stipulates that the Decipher test (GenomeDX Biosciences, San Diego, CA, and Vancouver, BC, Canada) may be used on prostatectomy specimens to determine whether patients should receive postoperative radiation,[11] although recent validation studies show that the test can also be used with biopsy cores. The Decipher test utilizes an RNA microarray assay to investigate the expression levels of 1.4 million genetic regions[13] and then creates a “genomic classifier score” that predicts 5-year metastatic disease probability; more recent versions also include risk of 10-year prostate cancer–specific mortality.

The 5-year postprostatectomy metastatic probability ranges from 0% to 100%. A risk of metastasis lower than 4% is considered low risk, a 4% to 9% risk of metastasis is considered average risk, and a risk of metastasis greater than 9% is considered high risk. Because the Decipher results are based on an individual pathology specimen as opposed to population analysis and are easily accessible to patients, the test provides better information and greater anxiety relief than continued PSA follow-up (Answer B). A result indicating a low risk of metastasis or prostate cancer–specific mortality could allow patients to feel more comfortable with forgoing adjuvant or salvage treatment, or with delaying treatment (low-risk results may include a higher PSA threshold for treatment to be recommended). Even if treatment is only delayed, this creates additional time for urinary continence and erectile function to improve and for patients to enjoy functional recovery. On the other hand, hearing that he has a high risk of metastasis or prostate cancer–specific mortality provides a patient with knowledge that additional treatment is indeed necessary; this can potentially make acceptance easier, since any functional losses will be seen as necessities of survival.

In 2014, the Decipher test was approved for Medicare coverage for postprostatectomy patients with intermediate- and high-risk disease, adverse surgical pathology, or rising PSA levels after the initial nadir.[14] Given that this patient has Gleason 4+3=7 disease, tertiary Gleason pattern 5 disease, positive margins, and a postprostatectomy PSA level ≥ 0.2 ng/mL (and is over 65 years of age), he meets eligibility criteria for his Decipher test to be covered by Medicare with no out-of-pocket costs.

Outcome of This Case

The patient was counseled about biochemical and potential clinical recurrence, he was counseled about both radiation therapy and androgen deprivation therapy and their potential side effects, and he was counseled extensively about the Decipher test-its mechanism, its results, and how those results would inform management planning. Via joint decision-making, it was agreed that he would proceed with radiation therapy if his 5-year risk of metastatic disease was found to be average or high; he would continue with routine PSA follow-up if his 5-year risk of metastatic disease was found to be low. In this way, the Decipher test was a linchpin that allowed the patient to decide on a prudent management plan that was also compatible with his desire for continued continence and potency.

The patient’s Decipher score classified him as “low risk,” with a 5-year metastatic risk of 0.9% and a “Decipher risk” of 0.2 times that of the average patient with similar pathology. While he was very relieved and pleased with these results, he was counseled that Decipher results were not definitive and that he could still need salvage radiation if his PSA level continued to increase. This he understood, and he agreed to continue with conservative monitoring of his PSA level every 6 months.

Financial Disclosure:Dr. Moul received a modest honorarium from GenomeDx, Inc for speaking about molecular markers and Decipher. Mr. Qi has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.

If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.

References:

1. Sim HG, Telesca D, Culp SH, et al. Tertiary Gleason pattern 5 in Gleason 7 prostate cancer predicts pathological stage and biochemical recurrence. J Urol. 2008;179:1775-9.

2. Patel AA, Chen MH, Renshaw AA, et al. PSA failure following definitive treatment of prostate cancer having biopsy Gleason score 7 with tertiary grade 5. JAMA. 2007;298:1533-8.

3. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:433-9.

4. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO guideline. J Urol. 2013;190:441-9.

5. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer. Version 1.2016. J Natl Compr Canc Netw. 2016;14:19-30.

6. Social Security Administration. Life expectancy calculator. https://www.ssa.gov/cgi-bin/longevity.cgi. Accessed July 23, 2016.

7. Lavery HJ, Levinson AW, Hobbs AR, et al. Baseline functional status may predict decisional regret following robotic prostatectomy. J Urol. 2012;188:2213-8.

8. Shah R, Bassily N, Wei J, et al. Benign prostatic glands at surgical margins of radical prostatectomy specimens: frequency and associated risk factors. Urology. 2000;56:721-5.

9. Paul R, Hoppmann M, van Randenborgh H, et al. Residual benign prostatic glands at the urethrovesical anastomosis after radical retropubic prostatectomy: prediction and impact on disease outcome. Eur Urol. 2004;46:321-6.

10. Valotto C, Falconieri G, Pizzolitto S, et al. Residual prostatic tumour in the surgical bed following radical prostatectomy in organ-confined prostate cancer: possible prognostic significance. Arch Ital Urol Androl. 2011;83:78-82.

11. Ross AE, D’Amico AV, Freedland SJ. Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer. Prostate Cancer Prostatic Dis. 2016;19:1-6.

12. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106-31.

13. Erho N, Crisan A, Vergara IA, et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013;8:e66855.

14. GenomeDx. Centers for Medicare and Medicaid Services publishes draft coverage decision to reimburse the Decipher® test for intermediate & high risk prostate cancer. 2014 Oct 16. https://genomedx.com/press-releases/centers-medicare-medicaid-services-publishes-draft-coverage-decision-reimburse-decipher-test-intermediate-high-risk-prostate-cancer. Accessed January 18, 2016.