Management of Prostate Cancer

doi:10.1056/NEJMclde0805491

A 63-year-old man who has been under your care for the past3 years undergoes an annual check-up. He believes he is in excellenthealth, and he has no medical problems to report. In 2006, hisphysical examination and routine laboratory tests were normal,and the prostate-specific antigen (PSA) level was 1.5 ng permilliliter. There had been no new findings in 2007, except thatthe PSA level had risen to 3.1 ng per milliliter. This year'sannual check-up reveals a PSA level of 3.8 ng per milliliter,and a digital rectal examination is normal.

Concerned about the rising PSA level, you refer the patientto a urologist, who performs ultrasonography and biopsy of theprostate. The prostate volume is 22 cm³, and of 12 biopsy cores,2 (10% of one and 20% of another) show involvement with adenocarcinoma,with a Gleason score of 6.

The patient, a widower with normal sexual function, plans tocontinue to run his advertising business. He does not smoke,drinks only occasionally, and jogs 2 miles three times a week.He has inquired specifically about expectant management.

What kind of treatment would you find most appropriate for thispatient? Three options are outlined and each is defended ina short essay by an expert in the management of prostate cancer;read the essays and then cast your vote.

Treatment Option 1

Expectant Management

Fritz H. Schröder, M.D.

The case vignette recounts a common situation in which expectantmanagement, radiotherapy, and radical prostatectomy are likelyto come up for discussion. Expectant management is applicableonly to men who are eligible for potentially curative management.The purpose of follow-up is to recommend potentially curativemanagement to men whose cancer progresses and to avoid the sideeffects and cost of treatment, at least temporarily, in menwhose cancer does not progress.¹

This patient is clearly eligible for radical surgery or radiotherapy.Expectant management, also known as active surveillance, wasbrought up for discussion by the patient himself. A key questionin this case is whether the cancer is potentially indolent,in which case treatment can be deferred or possibly avoidedcompletely. A nomogram based on two large series of patientswho underwent radical prostatectomy helps to identify potentiallyindolent prostate cancer.² It has been validated and updatedby Steyerberg et al.³ for prostate cancer that is detected onscreening. Considering the fact that PSA tests were repeatedover a period of 3 years in our patient and that a PSA levelof 3.8 ng per milliliter is considered to be an indication forbiopsy, this patient's prostate cancer can be considered tohave been detected on screening, and thus the nomogram of Steyerberget al. (available at www.uroweb.org) can be used.

Use of the nomogram requires knowledge of the PSA level, theprostate volume, the Gleason score, and the millimeters of prostate-cancertissue and normal tissue in the core biopsy specimens. All thisinformation is available for our patient. Assuming a lengthof each biopsy core of about 16 mm, the tumor has a length ofabout 5 mm. Since the indicator of the risk of prostate canceris based on sextant-pattern biopsy, the length of 5 mm can bedivided by 2, assuming that the sextant biopsies would havedetected less prostate cancer than a standard 10- or 12-corebiopsy, in which the length of the prostate-tissue specimencould exceed 100 mm. According to the nomogram, our patient'srisk of having potentially indolent prostate cancer is 72%.With a probability threshold of 70% for identifying an indolentcancer, the chance that a potentially aggressive tumor is misclassifiedis only 6%. Thus, we can legitimately consider expectant managementfor our patient.

If the patient chooses this option, a strict follow-up regimenis required, including the measurement of PSA level and digitalrectal examination every 3 months for 2 years. Biopsy shouldbe repeated after 3 months or 1 year, or both. If the diseaseremains stable, frequency of the follow-up procedures can berelaxed to every 6 months or every 12 months. During the follow-upperiod, active treatment would be recommended if there werea PSA doubling time of less than 3 years, an abnormal rectalexamination, or progression to a higher Gleason score on biopsy.With the recommended follow-up procedures, encouraging resultshave been obtained within observation periods of up to 10 years.⁴

There is, however, a serious limitation to this option. A PSAdoubling time of 1.8 years translates into a PSA velocity of0.77 ng per milliliter per year. If this rate of increase inthe PSA level is confirmed in our patient, I would have to recommendactive treatment. To evaluate more accurately the PSA velocity,follow-up visits (at least two) at 3-month intervals would beneeded to relieve concerns that the rise in PSA level was dueto normal biologic fluctuation. The relation between progressionof nonpalpable biopsy-detected, untreated prostate cancer (T1cdisease) and PSA kinetics is unknown; however, data on PSA levelsbefore and after potentially curative management suggest strongassociations between PSA doubling times and mortality from prostatecancer. A PSA doubling time of more than 15 months is associatedwith death from any cause within a median of 15 years, whereasthe median time to death from prostate cancer was not yet reachedat 16 years.⁵

With proper information on risks and potential benefits, thepatient could be supported in his choice of active surveillance.The benefit would be the avoidance of the adverse effects oftreatment. But if PSA levels increase at the same rate withintwo or three more observation periods of 3 months each, my advicewould change. Although the prostate is relatively small andhas already been biopsied 12 times, repeat biopsy in advanceof the 1-year follow-up visit might be advisable to excludehistologic progression or misclassification during the firstbiopsy.

No potential conflict of interest relevant to this article wasreported.

From the Department of Urology, Erasmus University Medical Center,Rotterdam, the Netherlands.

Treatment Option 2

Radiotherapy

Mack Roach, III, M.D.

A permanent prostate seed implant involves the placement ofradioactive seeds directly into the prostate under guidanceof transrectal ultrasonography and is an ideal option for thislow-risk patient. This type of treatment is a form of brachytherapy.Only in the past 20 years has computer technology evolved toa point at which we can take optimal advantage of brachytherapy.

The major goals of this treatment are to control cancer, preservesexual function, and maintain urinary continence while minimizingthe risk of serious rectal or bladder complications. Permanentprostate seed implantation appears to have a more pronouncedeffect on prostate tissues than external-beam radiotherapy.⁶When assessed by means of endorectal magnetic resonance imagingand spectroscopy, the median time to the resolution of spectroscopicabnormalities was 32.2 months with external-beam radiotherapyand 24.8 months with permanent prostate seed implantation. Moreover,the degree of atrophy and the magnitude of the decline in PSAlevels were more pronounced after a permanent seed implantationthan after external-beam radiotherapy.

Permanent prostate seed implantation and radical prostatectomyappear to confer similar rates of control of prostate cancer.⁷Low-risk men 62 years of age or younger had a 7-year rate ofcancer control of 93% when assessed on the basis of a PSA thresholdfor treatment failure of 0.4 ng per milliliter or higher.⁷ Permanentprostate seed implantation also results in better rates of continenceand sexual potency than is expected with radical prostatectomy.⁸

In a recent, large, multi-institutional series involving a validatedquality-of-life instrument to assess urinary incontinence 1year after treatment, 85% of men reported having "no problemor [a] very small problem" with urinary incontinence after permanentprostate seed implantation as compared with 76% after surgery.⁸With regard to sexual function 1 year after treatment, 53% ofmen reported having "no problem or [a] very small problem" afterpermanent prostate seed implantation as compared with 29% aftersurgery. If erectile dysfunction does occur, it is typicallyresponsive to phosphodiesterase type 5 inhibitors such as sildenafil.

Five years after undergoing a well-performed implantation, mostmen have a PSA level of less than 0.1 ng per milliliter, andless than 1% have serious rectal or bladder complications.⁷The risk of a late complication such as a radiation-inducedsecond cancer appears to be low, as long as 20 years after treatment.⁹In a recent study, one of the largest studies of permanent prostateseed implantation, men who underwent the irradiation did notappear to have a significantly increased risk of developinga secondary cancer at any of the 20 most common sites, as comparedwith men who were not irradiated.¹⁰ This risk should be weighedagainst a very low (but not negligible) 30-day operative mortalityrate associated with radical prostatectomy.⁹^,¹¹ Permanent prostateseed implantation is a more convenient approach than radicalprostatectomy or external-beam radiotherapy, since it does notrequire hospitalization, is associated with easier recovery,and has shorter overall treatment time — many men returnto work the next day.

The key to a successful outcome after permanent prostate seedimplantation is to deliver a high dose of radiation to the entireprostate while sparing adjacent normal tissues. These goalsare generally best accomplished by ensuring that the procedureis performed by an expert team including a radiation oncologist,a urologist, and a medical physicist.

Dr. Roach reports receiving consulting fees from AstraZeneca;TAP Pharmaceuticals; Bennett, Bigelow, and Leedom; Siemens;Davis, Polk, and Wardell; CareCore National; Molecular Insight;General Electric; Novartis; and Compact Particle AccelerationCorporation. No other potential conflict of interest relevantto this article was reported.

From the Department of Radiation Oncology, University of California,San Francisco, Helen Diller Family Comprehensive Cancer Center,San Francisco.

Treatment Option 3

Radical Prostatectomy

Peter Scardino, M.D.

This patient has a multifocal prostate cancer (present in 2of 12 needle-biopsy cores) of intermediate grade (Gleason scoreof 6). His PSA level, although relatively low (3.8 ng per milliliter),has risen rapidly (1.15 ng per milliliter per year on average)over the past 2 years. He has a small prostate for his age (volume,22 cm³), and his PSA density (the serum PSA level divided bythe prostate volume) is high (0.173 ng per milliliter per cubiccentimeter). The PSA velocity and density suggest a larger volumeand more aggressive cancer than is indicated by the biopsy,which often underestimates the extent of cancer.

Expectant management of prostate cancer is attractive becauseit avoids the immediate side effects of treatment. Successfulimplementation requires the accurate identification of cancersposing little immediate risk to the patient's life or healthand intervention early enough to cure the cancer once it progresses.However, the feasibility of long-term expectant management remainsunproved.¹² There is no validated test to signal the impendingspread of the cancer soon enough for successful delayed intervention,which is likely to be less effective and carry greater risksthan immediate therapy.

In population-based studies, as compared with expectant management,active treatment with surgery or radiotherapy within 6 monthsafter diagnosis reduced the risks of death from any cause andfrom prostate cancer.¹³ In the only prospective randomized trialof active therapy as compared with watchful waiting, radicalprostatectomy reduced the risks of metastasis and death fromcancer or any cause over 10 years, regardless of the featuresof the cancer at the time of diagnosis.¹⁴

Radiotherapy is associated with 5-year rates of cancer controlsimilar to those with radical prostatectomy and could be usedto treat this patient's cancer. However, effective radiation,whether external beam or brachytherapy, requires very high dosesand is associated with troublesome sexual and urinary side effects(from brachytherapy) or bowel side effects (from both external-beamradiotherapy and brachytherapy).⁸ In a recent comparative studyof the quality of life after treatment of localized cancer,both forms of radiotherapy were associated with one or morebothersome complication — rectal urgency, frequency ofelimination, pain, fecal incontinence, or hematochezia —in 9% of patients within the first year after treatment.⁸ Withradiation, it is difficult to be sure that the cancer is eradicated,since PSA levels rarely become undetectable. Local recurrencetends to be detected late, if at all, when additional localtherapy is hazardous and seldom effective. No randomized trialscomparing survival rates after radiation and surgery have beenpublished, but population-based studies show lower overall andcancer-specific survival rates after radiation for all riskgroups.¹⁵

Given this patient's low PSA level and small-volume cancer onbiopsy, it is highly likely (probability, 88%) that his canceris confined to the prostate gland, making him an excellent candidatefor nerve-sparing surgery. The operative mortality rate in ahealthy 63-year-old is less than 0.1%. In a multi-institutionallongitudinal study of the quality of life after radical prostatectomy,2 years after the procedure, 20% of patients reported incontinencerequiring the use of one or more incontinence pads daily, buturinary obstruction and irritation improved significantly, andoverall distress from urinary symptoms was less than at baseline.Sexual function, especially the quality of erection, deterioratedsubstantially in the first 3 months but had improved at 2 years,especially in young men with low PSA levels who had undergonenerve-sparing surgery.⁸ Although these side effects are troublesome,they can be mitigated through treatments that, albeit cumbersome,are widely available. If experienced surgeons perform the surgery,the risks are much lower. Radical prostatectomy provides betterlong-term cancer-specific and overall survival¹³^,¹⁴^,¹⁵ thanexpectant management or radiotherapy.

The probability that this patient's PSA level would become undetectableafter radical prostatectomy and remain so for over 10 yearsis 98% (according to the nomogram at www.mskcc.org/mskcc/html/10088.cfm),¹⁶minimizing the need for further therapy that would adverselyaffect his quality of life. After radical prostatectomy, unlikeradiotherapy or expectant management, any rise in the PSA levelsignals recurrent cancer, which can be treated safely and effectivelywith the use of low-dose radiotherapy.¹⁷

Radical prostatectomy is a delicate, technically challengingprocedure. Optimal results, attainable with the open retropubic,laparoscopic, or robotic-assisted approaches, depend more onthe experience of the surgeon than on the technique itself.I would counsel this patient to find an experienced surgeonwith a history of excellent results and to have his cancer treatedthrough radical prostatectomy.

No potential conflict of interest relevant to this article wasreported.

From the Department of Urology, Memorial Sloan-Kettering CancerCenter, New York.

Given your knowledge of the condition and the points made bythe experts, which treatment option would you choose? Base youropinion on the published literature, your past experience, recentguidelines, and other sources of information, as appropriate.Cast your vote below. You may also submit comments after youvote (maximum of 175 words).