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Results of a Surgically DerivedNomogram to Predict Gleason ScoreUpgrading Applied to a Cohort of PatientsWith “Favorable-risk” Prostate CancerTreated With Permanent Seed BrachytherapyDavid Bowes, Juanita M. Crook, Kris Wallace, Andrew Evans, Ants Toi, Antonio Finelli,Michael A. S. Jewett, Neil Fleshner, and Charles Catton

OBJECTIVE To examine a 2-year cohort of patients treated with brachytherapy to determine the likelihood ofunfavorable pathologic features using a nomogram recently developed at our center to estimate thelikelihood of Gleason score upgrading for patients with favorable prostate cancer undergoing radicalprostatectomy. The brachytherapy outcomes for patients with a high likelihood of upgrading werecompared with those with a lower likelihood to affirm the effectiveness of brachytherapy in thissetting. Information on the likelihood of upgrading could help in the selection between activetreatment and surveillance for patients with favorable-risk prostate cancer.

METHODS The records were examined for 259 men undergoing prostate brachytherapy in 2006 to 2007, ofwhom 217 had favorable risk cancer. The likelihood of Gleason score upgrading (GSU) waspredicted using the radical prostatectomy-derived nomogram.

RESULTS The median age was 62 years (range 44-77), and the median prostate-specific antigen level was4.71 ng/mL (range 0.56-9.87). Central pathology review was available for 88%, and 83% hadundergone extended biopsies. Two men had received androgen deprivation therapy for prostatedownsizing. The median predicted likelihood of GSU was 51.2%. The median prostate-specificantigen level for 199 patients without treatment failure after a median follow-up of 4.2 years inthis cohort was 0.07 ng/mL (interquartile range undetectable to 0.23).

CONCLUSION In the present cohort of patients with favorable-risk prostate cancer treated with brachytherapy,the estimated likelihood of GSU using the surgically derived nomogram was substantial.Follow-up with prostate-specific antigen measurement has indicated that brachytherapy is ahighly effective treatment option despite less favorable clinical and pathologic factors. Patientsshould not be discouraged from brachytherapy on the basis of a high likelihood of

GSU. UROLOGY 80: 649–655, 2012. © 2012 Elsevier Inc.

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The pathologic grading of prostate cancer using theGleason system is an important predictor of out-come after radical prostatectomy (RP),1 external

eam radiotherapy (EBRT),2 and brachytherapy (BT).3,4

Approximately 30%-40% of men undergoing RP willexperience Gleason score upgrading (GSU), with ahigher Gleason grade in the surgical specimen than at the

Financial Disclosure: The authors declare that they have no relevant financialinterests.

From the Department of Radiation Oncology, British Columbia Cancer Agency,Kelowna, British Columbia, Canada; and Departments of Radiation Medicine, Pathol-ogy, Radiology, and Urology and Surgical Oncology, and Department of RadiationOncology, University Health Network, Toronto, Ontario, Canada

Reprint requests: Juanita Crook, M.D., Department of Radiation Oncology, BritishColumbia Cancer Agency, Cancer Center for the Southern Interior, 399 Royal

iAvenue, Kelowna, BC V1Y 5L3 Canada. E-mail: jcrook@bccancer.bc.ca

Submitted: February 7, 2012, accepted (with revisions): March 21, 2012

© 2012 Elsevier Inc.All Rights Reserved

initial diagnostic biopsy.5 Men whose final surgical patho-ogic findings demonstrated a greater Gleason score com-ared with biopsy have tended to have outcomes similar tohose with high-grade disease diagnosed at the outset, sug-esting the importance of accurate pretreatment pathologicvaluation for the selection of treatment.6

Although permanent seed BT is an effective treatmentoption for men with clinically localized prostate cancer,BT monotherapy7,8 is often thought to be more appro-riate for favorable risk disease. In some jurisdictions, itsse has been restricted to this patient category. Crook etl9 at Princess Margaret Hospital recently reported aisease-free survival rate of 95.2% at 7 years for a cohortf 1111 patients treated consecutively with BT. Al-hough the biopsy Gleason score is known to be an

mportant prognostic factor for outcome after both EBRT

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and BT, patients who are treated nonsurgically neverhave confirmatory whole prostate pathologic examina-tion, and the pretreatment biopsy findings might notaccurately represent the actual pathologic features owingto sampling error.

Kulkarni et al,10 from the Princess Margaret Hospital/University Health Network, recently published a nomo-gram to estimate the likelihood of GSU in patients withfavorable-risk prostate cancer undergoing RP and recom-mended that the nomogram be applied to patients withfavorable-risk prostate cancer being considered for BT toidentify those who might harbor high-grade diseasemissed at the initial biopsy. They suggested that suchmen might not be candidates for BT. The purpose of thepresent report was to apply this nomogram to a popula-tion of men with favorable-risk prostate cancer success-fully treated with BT at the same institution to estimatethe likelihood of GSU.

MATERIAL AND METHODS

Study PopulationFrom January 1, 2006 to December 31, 2007, 259 patientsreceived permanent iodine-125 BT at Princess Margaret Hos-pital. The 217 patients with favorable risk disease according tothe Canadian Consensus Guidelines11 (clinical Stage T1 or T2,iopsy Gleason score �6, and pretreatment prostate-specificntigen [PSA] �10 ng/mL), were included in the present study.ll patients had undergone diagnostic transrectal prostate ul-

rasonography (TRUS) at Princess Margaret Hospital, and 88%ad received central uropathology review of their diagnosticiopsies. Neoadjuvant androgen deprivation therapy was giveno only 2 patients for prostate downsizing, and no patienteceived EBRT. The prescribed dose to the prostate was 145y. Details regarding implant technique, dosimetry, and post-

reatment follow-up have been previously reported.9 The de-mographic, clinical, pathologic, and treatment-related informa-tion were collected prospectively in a database and accessedwith university research ethics board approval. Additional in-formation that was required for use of the nomogram wasobtained from the prostate biopsy and TRUS reports. PSAmeasurement during follow-up (every 3 months for the first 2years and every 6 months thereafter) was collected to determinethe PSA trend and whether biochemical failure using thePhoenix definition12 had occurred.

The likelihood of GSU was estimated using the Kulkarniomogram10 (Fig. 1), which incorporates 9 factors predictive ofSU: patient age, PSA level, digital rectal examination results,

resence of a hypoechoic lesion on TRUS, sextant versus ex-ended biopsy pattern, TRUS-determined prostate volume, pa-hologist expertise, total cancer volume in the biopsy specimen,nd the presence of prostatic intraepithelial neoplasia.

Continuous variables are reported as the mean, median, andange and categorical variables as binary functions. Statisticalnalysis was performed using SPSS, version 17.0, softwareSPSS, Chicago, IL). Pearson and Spearman analyses were usedo compare the correlations between values, and the paired test was used to compare the mean values of the populations.ll P values reported are 2-sided, and P � .05 was considered

ignificant.

650

RESULTSIn 2006 and 2007, 217 patients with favorable-risk pros-tate cancer were treated with BT. The clinical andpathologic information was available for 204 patients toallow completion of the Kulkarni nomogram. The baselinecharacteristics of the patients are listed in Table 1. Themedian prostate volume was 33.4 cm3 (range 15.0-72.3).

ata from the central pathology review was available for8%, and 83% had undergone extended biopsies. The me-ian percentage of positive cores was 25% (range 5%-00%), with a median maximal percentage of involvementer core of 20% (range 1%-100%). The mean � SD post-mplant minimal dose delivered to 90% of the prostateland was 169.5 � 15.7 Gy. Only 7 patients had a doseelivered to 90% of the prostate gland �140 Gy.

Using the nomogram, the median predicted likelihoodf GSU was 51.2% (mean 50.3% � 21.5%, interquartileange 34.1%-66.0%). Only 17 (8%) of the 204 patientsere predicted to have a likelihood of GSU of �20%. In

he original cohort of surgical patients (n � 175) used toenerate the nomogram, 34% were upgraded by the finalurgical pathologic findings. Only 25% of our cohort ofatients treated with BT were predicted to have a like-ihood of GSU of �34%.

The median current PSA value in the study cohort forhe 199 patients without treatment failure was 0.07g/mL (mean 0.19 � 0.29) at a median follow-up of 4.2ears (mean 4.0 � 1.12) after BT. PSA follow-up data for3 years were available for 84%. The median PSA of this

roup was 0.07 ng/mL (mean 0.13 � 0.19). For patientsith �3 years of PSA follow-up data, no correlation was

ound between the last recorded PSA value and theredicted likelihood of GSU using the nomogram.Five patients (2.5%) developed biochemical failure.

his included 1 patient with an increasing PSA level of.25 ng/mL at 4.2 years after BT, who had not yet methe nadir � 2 definition of biochemical failure and hadot yet undergone further investigation. His PSA trendas been very suggestive of failure. The other 4 patientsith biochemical failure underwent repeat prostate biop-

ies. All had negative findings from systemic staging,ncluding computed tomography of the abdomen/pelvisnd bone scan. One patient with a PSA level of 1.91g/mL at 4.3 years after BT had a positive biopsy of theight seminal vesicle (Gleason score 7/10). The estimatedikelihood of GSU from the original biopsies for thisatient was 79.1% using the nomogram. The remaining 3atients have had negative 12-core TRUS-guided pros-ate biopsies. Their estimated likelihood of GSU was0%, 74%, and 64%. Despite the high prediction ofpgrading, none of these patients experienced local treat-ent failure within the prostate.

COMMENTIn a population of men with favorable-risk prostate can-cer treated with BT, the estimated likelihood of GSU

using this surgically derived nomogram from the same

UROLOGY 80 (3), 2012

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center was substantial. Long-term data on the biochem-ical recurrence rates and survival for patients included inthe current study are not yet available, although ourcohort was taken from a larger population of patientstreated during a 10-year period. For that larger popula-tion, the 7-year disease-free survival rate was 95.2%.9

Because the clinical and pathologic details and the im-plant quality in this cohort were similar to those in thelarger series, the outcomes should be comparable.

For the entire group of 204 patients, the median PSAvalue at a median follow-up of 4.2 years was 0.08 ng/mLand, for those patients with �3 years of follow-up, 0.07ng/mL. In the larger parent cohort, the mean interval toPSA nadir was 37.3 � 18.4 months, suggesting that manyin our cohort have not yet reached their PSA nadir andwill continue to have a declining PSA trend.9 Evenwithout this assumption, their latest PSA levels havebeen solidly in the “safe zone,” in which subsequent laterecurrence is rare. Hayden et al13 found only 1 late

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Figure 1. Nomogram predicting likelihood of GSU for patienor clinical use).

iochemical relapse among 762 patients with a PSA level

UROLOGY 80 (3), 2012

f �0.2 ng/mL at 48-60 months after implant. Stock etl14 have demonstrated that the PSA level at 5 years after

BT is highly predictive of the outcomes, reporting a 98%biochemical control rate (Phoenix definition) for a cohortof 661 men with a PSA level of �0.2 ng/mL at 5 years after

T. Of the 172 patients in our cohort with �3 years of PSAollow-up data, 132 have already crossed this threshold. Allthers (aside from the 5 patients with biochemical failure)ave had a stable or declining PSA level. We acknowledgehat the follow-up period is still relatively short, particularlyor favorable-risk prostate cancer; however, the PSA out-omes have been highly encouraging and indicative of ul-imate biochemical control, in line with that reported byayden et al13 and Stock et al.14

When considering patients with �3 years of PSAfollow-up, no relationship was found between the pre-dicted likelihood of GSU and the most recent PSAlevel. This suggests that occult high-grade disease wasequally responsive to BT. Critz15 has reported a shorter

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Gleason scores treated with a combination of EBRTand BT, supporting our inability to detect a differencein PSA response in those patients found to likely behave higher grade cancer. Of the 5 patients in thiscohort with biochemical failure, 4 underwent repeat12-core TRUS-guided prostate biopsies. None of thesebiopsies demonstrated local treatment failure. One pa-tient had disease in the seminal vesicle, which isoutside the typical prostate implant volume. Not sur-prisingly, the nomogram predicted a high likelihood ofGSU for this patient.

The actual likelihood of GSU in this BT populationwas clearly dependent on the accuracy of the nomo-gram. Although the Kulkarni nomogram has not beenexternally validated, 1 strength of our study was that itwas generated at our institution. Thus, the pathologicand TRUS information critical to the nomogram wasobtained from the same specialists for our BT cohort asfor the Kulkarni nomogram. This might have mini-mized some of the differences one might expect to seein the interpretation of prostate biopsies and TRUSexaminations.

Compared with other surgically derived nomograms,

Table 1. Baseline characteristics of 204 patients evalu-ated in analysis of Kulkarni nomogram

Characteristic Value

Patients (n) 204Age (y)

Median 62Range 44-77

PSA level (ng/mL)Mean 4.83 � 2.03Median 4.71Range 0.56-9.87

TRUS volume (cm3)Median 33.4Range 15.0-72.3

Cancer volume in biopsy specimen (%)Median 20Range 1-100

Mean postimplant D90 (Gy) 169.5 � 15.6Uropathology review (n)

Yes 183 (88)No 21 (12)

Sextant biopsies (n) 32 (17)Extended biopsies (n) 172 (83)Presence of hypoechoic lesion (n)

Yes 95 (46)No 109 (54)

Digital rectal examinationPositive (T2a) 70 (34)Negative (T1c) 134 (66)

Prostatic intra-epithelial neoplasiaYes 81 (40)No 123 (60)

Inflammation in biopsy specimenYes 20 (10)No 184 (90)

PSA, prostate-specific antigen; TRUS, transrectal ultrasonogra-phy; D90, minimal dose delivered to 90% of prostate gland.

some inherent differences are worthy of note. Chun et l

652

al16,17 developed a nomogram to estimate the rate ofGSU in patients undergoing RP that has been externallyvalidated, although their nomogram does not apply ex-clusively to patients with favorable-risk cancer. Iremash-vili et al18 applied the nomograms created by Chun etal,19 Capitanio et al,20 Moussa et al,21 and Kulkarnit al10 to a surgical population and found only a limitedbility to predict GSU, although the Kulkarni nomogramppeared to be more predictive than the other nomo-rams evaluated.

The Budäus nomogram,22 similar to the Kulkarni no-mogram, applies to patients with favorable-risk cancerbeing considered for BT; however, the maximal potentiallikelihood of GSU that can be estimated is only 80%,fewer pathologic features are incorporated, and patientswith a TRUS-measured volume �50 cm3 are excluded(11 patients in our BT cohort). The effect of prostatevolume also differs among these nomograms. A largerprostate volume was associated with a greater likelihoodof GSU in the study by Kulkarni et al.23 Sampling errors less likely in a smaller TRUS volume, making detec-ion of small foci of Gleason pattern 4 or 5 more likelyhan in a larger prostate in which small foci of high-gradeisease might not be revealed until the entire prostate haseen sectioned. Turley et al24 and Freedland et al25 found

the opposite effect. Despite these differences, the Budäusnomogram predicted a risk of upgrading of 44%, withreasonable agreement with the Kulkarni nomogram(Pearson coefficient 0.578).

In recent years, active surveillance for men with favor-able-risk prostate cancer has become increasingly popu-lar. Although initially intended for men with a limitedlife expectancy or very low-volume, favorable-risk dis-ease, it is now offered more widely and was legitimized inthe recently closed National Cancer Institute of CanadaPR11 trial (Active Surveillance Therapy Against RadicalTreatment in patients diagnosed with favorable-risk pros-tate cancer, Cancer and Leukemia Group B trial 140602,Southwestern Oncology Group trial PR11, and RadiationTherapy Oncology Group trial 0873). As mature data ac-cumulate reporting the excellent long-term biochemicaldisease-free survival for BT, its efficacy could be trivializedby the supposition that many of the men treated might havedone just as well with surveillance. The application ofsurgically derived nomograms to this BT population hasindicated that this is not the case, because the medianpredicted likelihood of finding higher grade disease was�50%. Klotz et al26 reported on a cohort of men treatednitially with active surveillance and who ultimately under-ent definitive therapy. The 5-year recurrence-free survival

ate after treatment was only 47%, regardless of the treat-ent modality. Those in our BT cohort with occult high-

rade disease were treated effectively with BT and spareduch an unfavorable outcome; thus, the treatment was jus-ified and warranted in these men.

BT is a highly effective treatment option for clinically

ocalized prostate cancer, and the intermediate- to long-

UROLOGY 80 (3), 2012

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term data have demonstrated high rates of biochemicalcontrol for low-risk and intermediate-risk disease.9,14,27-30

Local failure is a rare event after prostate BT when a highquality implant is achieved.30 Crook et al9 demonstrated

93.5% actuarial rate of freedom from local recurrence atyears in patients with intermediate-risk disease treatedith BT monotherapy. In our cohort, a high likelihood ofSU was not associated with the PSA level at the last

ollow-up. The patients with a predicted GSU likelihoodreater than the median had a median PSA level of 0.085g/mL at the last follow-up visit (vs �0.05 ng/mL forhose with an estimated GSU less than the median). Noatients in our cohort have experienced tumor recur-ence within the prostate; thus, additional (or different)ocal therapy would not have been of value. BT mono-herapy has been accepted for intermediate-risk prostateancer, although not universally. The Radiation Therapyncology Group have conducted a randomized trial com-

aring BT either alone or combined with EBRT (Radi-tion Therapy Oncology Group trial 0232), the results ofhich will help define the need for supplemental EBRT

n this population. If a change in Gleason score from 6 towould alter management, those at high risk of upgrad-

ng should undergo repeat biopsy. Otherwise, if BT alones the treatment of choice, repeat biopsy is probably notecessary.The use of a validated nomogram could help in coun-

eling patients with favorable-risk prostate cancer con-erning their options. A high likelihood of upgradingight prompt one to avoid active surveillance. Further-ore, the BT technique can be tailored to ensure a more

enerous margin in the sites of disease. Our evaluation ofhis 2-year cohort of BT patients has indicated that aigh risk of upgrading is not an indication to avoid BT.

CONCLUSIONSA high likelihood of GSU was predicted using a surgi-cally derived nomogram from the same institution for acohort of patients with favorable-risk prostate cancertreated with permanent seed BT. The PSA outcomeshave indicated that BT is equally effective in thosepatients predicted to have a high likelihood of occulthigh-grade disease. Permanent seed BT is a highly effec-tive treatment option for patients with favorable-riskdisease even in the presence of less favorable clinical andpathologic factors. The use of a nomogram to indicatethe likelihood of GSU might be a helpful adjunct todetermine which patients can be appropriately managedwith active surveillance. However, BT should not bediscouraged on the basis of a high likelihood of GSU.

References1. Stephenson AJ, Kattan MW, Eastham JA, et al. Prostate cancer-

specific mortality after radical prostatectomy for patients treated inthe prostate-specific antigen era. J Clin Oncol. 2009;27:

274300-274305.

UROLOGY 80 (3), 2012

2. Zhou P, Chen MH, McLeod D, et al. Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy.J Clin Oncol. 2005;23:6992-6998.

3. Potters L, Roach M, Davis BJ, et al. Postoperative nomogrampredicting the 9-year probability of prostate cancer recurrence afterpermanent prostate brachytherapy using radiation dose as a prog-nostic variable. Int J Radiat Oncol Biol Phys. 2010;76:1061-1065.

4. Potters L, Purrazzella R, Brustein S, et al. The prognostic signifi-cance of Gleason grade in patients treated with permanent prostatebrachytherapy. Int J Radiat Oncol Biol Phys. 2003;56:749-754.

5. D’Amico AV, Renshaw AA, Arsenault L, et al. Clinical predictorsof upgrading to Gleason grade 4 or 5 disease at radical prostatec-tomy: potential implications for patient selection for radiation andandrogen suppression therapy. Int J Radiat Oncol Biol Phys. 1999;45:841-846.

6. Pinthus JH, Witkos M, Fleshner NE, et al. Prostate cancers scoredas Gleason 6 on prostate biopsy are frequently Gleason 7 tumors atradical prostatectomy: implication on outcome. J Urol. 2006;176:979-984.

7. Ash D, Flynn A, Battermann J, et al. ESTRO/EAU/EORTC rec-ommendations on permanent seed implantation for localized pros-tate cancer. Radiother Oncol. 2000;57:315-321.

8. Davis BJ, Horwitz EM, Lee WR, et al. American BrachytherapySociety consensus guidelines for transrectal ultrasound-guided per-manent prostate brachytherapy. Brachytherapy. 2012;11:6-19.

9. Crook J, Borg J, Evans A, et al. 10-Year experience with I-125prostate brachytherapy at the Princess Margaret Hospital: resultsfor 1,100 patients. Int J Radiat Oncol Biol Phys. 2011;80:1323-1329.

10. Kulkarni GS, Lockwood G, Evans A, et al. Clinical predictors ofGleason score upgrading: implications for patients consideringwatchful waiting, active surveillance, or brachytherapy. Cancer.2007;109:2432-2438.

1. Lukka H, Warde P, Pickles T, et al. Controversies in prostatecancer radiotherapy: consensus development. Can J Urol. 2001;8:1314-1322.

2. Roach M, Hanks G, Thames H, et al. Defining biochemical failurefollowing radiotherapy with or without hormonal therapy in menwith clinically localized prostate cancer: recommendations of theRTOG-ASTRO Phoenix Consensus Conference. Int J Radiat OncolBiol Phys. 2006;65:965-974.

3. Hayden A, Morris W, Keyes M, et al. The PSA value at 4-5 yearsafter permanent prostate brachytherapy predicts for biochemicalfailure free survival. Radiother Oncol. 2010;96;(Suppl 2):S2.

4. Stock RG, Klein TJ, Cesaretti JA, et al. Prognostic significance of5-year PSA value for predicting prostate cancer recurrence afterbrachytherapy alone and combined with hormonal therapy and/orexternal beam radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74:753-758.

5. Critz FA. Time to achieve a prostate specific antigen nadir of 0.2ng/ml after simultaneous irradiation for prostate cancer. J Urol.2002;168:2434-2438.

6. Chun FK, Steuber T, Erbersdobler A, et al. Development andinternal validation of a nomogram predicting the probability ofprostate cancer Gleason sum upgrading between biopsy and radicalprostatectomy pathology. Eur Urol. 2006;49:820-826.

7. Capitanio U, Karakiewicz PI, Jeldres C, et al. The probability ofGleason score upgrading between biopsy and radical prostatectomycan be accurately predicted. Int J Urol. 2009;16:526-529.

8. Iremashvili V, Manoharan M, Pelaez L, et al. Clinically significantGleason sum upgrade: external validation and head-to-head com-parison of the existing nomograms. Cancer. 2012;118:378-385.

19. Chun FK, Briganti A, Shariat SF, et al. Significant upgradingaffects a third of men diagnosed with prostate cancer: predictivenomogram and internal validation. BJU Int. 2006;98:329-334.

20. Capitanio U, Karakiewicz PI, Valiquette L, et al. Biopsy corenumber represents one of foremost predictors of clinically signifi-cant Gleason sum upgrading in patients with low-risk prostate

cancer. Urology. 2009;73:1087-1091.

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21. Moussa AS, Kattan MW, Berglund R, et al. A nomogram forpredicting upgrading in patients with low- and intermediate-gradeprostate cancer in the era of extended prostate sampling. BJU Int.2010;105:352-358.

2. Budäus L, Graefen M, Salomon G, et al. The novel nomogram ofGleason sum upgrade: possible application for the eligible criteria oflow dose rate brachytherapy. Int J Urol. 2010;17:862-868.

3. Kulkarni GS, Al-Azab R, Lockwood G, et al. Evidence for a biopsyderived grade artifact among larger prostate glands. J Urol. 2006;175:505-509.

4. Turley RS, Hamilton RJ, Terris MK, et al. Small transrectal ultra-sound volume predicts clinically significant Gleason score upgrad-ing after radical prostatectomy: results from the SEARCH database.J Urol. 2008;179:523-528.

5. Freedland SJ, Isaacs WB, Platz EA, et al. Prostate size and risk ofhigh-grade, advanced prostate cancer and biochemical progressionafter radical prostatectomy: a SEARCH database study. J ClinOncol. 2005;23:7546-7554.

6. Klotz L, Zhang L, Lam A, et al. Clinical results of long-termfollow-up of a large, active surveillance cohort with localized pros-tate cancer. J Clin Oncol. 2010;28:126-131.

7. Morris WJ, Keyes M, Palma D, et al. Population-based study ofbiochemical and survival outcomes after permanent 125-I brachy-therapy for low- and intermediate-risk prostate cancer. Urology.2009;73:860-865.

8. Potters L, Morgenstern C, Calugaru E, et al. 12-year outcomesfollowing permanent prostate brachytherapy in patients with clin-ically localized prostate cancer. J Urol. 2005;173:1562-1566.

9. Taira AV, Merrick GS, Butler WM, et al. Long-term outcome forclinically localized prostate cancer treated with permanent inter-stitial brachytherapy. Int J Radiat Oncol Biol Phys. 2011;79:1336-1342.

0. Stone NN, Stock RG, Cesaretti JA, et al. Local control followingpermanent prostate brachytherapy: effect of high biologically effec-tive dose on biopsy results and oncologic outcomes. Int J RadiatOncol Biol Phys. 2010;76:355-360.

EDITORIAL COMMENTThe authors of this study aimed to examine a common criticismof any radiation technique: one does not acquire whole prostatepathologic information as a byproduct of treatment. The pro-ponents of RP cite the RP specimen’s pathologic assessment, tobe used in guiding adjuvant/salvage therapy after initial treat-ment, as 1 of its major advantages. Radiotherapy supporters citethe outcome data that show equivalence across all modalities(RP, EBRT, and BT) in multiple endpoints, such as biochem-ical relapse-free survival and metastases-free survival when pa-tients are stratified by pretreatment variables.

The authors focused their study specifically on BT patientswith “favorable-risk” disease treated from 2006 to 2007. Theyapplied a nomogram designed to predict pathologic GSU afterRP to this BT cohort and estimated that �50% of thesepatients would have been upgraded after whole prostate patho-logic examination of a RP specimen. Despite this potential forupgrading, the biochemical response at a median follow-up of4.2 years was consistent with the reported outcomes for “favor-able-risk” patients treated with any modality.

This study leads to one to question of the utility of calcu-lating the risk of GSU. Several studies comparing biopsy andsurgical specimens have shown that 25%-40% of biopsyGleason score 6 cancers are upgraded after review of thesurgical specimen.1-3 Studies have also shown that the biopsy

leason score remains a strong predictor of disease outcome,

ven after adjusting for the surgical Gleason score.4,5 In

54

clinical practice, rarely is a patient who presents with low-risk disease treated as if he has intermediate- or high-riskdisease based on the likelihood of GSU.

Possibly the most intriguing finding from this study is that itprovides information to support the offering of BT for nonfa-vorable risk (ie, intermediate-risk) patients. Data from our owninstitution have shown that the outcomes after BT mono-therapy for intermediate-risk disease are equivalent to thoseafter RP or EBRT.6 As the authors have noted, this question isurrently under investigation in a randomized trial.

There are 2 main criticisms of this study. First, the medianollow-up was relatively short. This allowed only the reportingf intermediate-term results. Second, the authors did not reportn the number of PSA tests per patient during follow-up, aeasure of how closely the patients are followed up after treat-ent. Although they did report on the planned PSA follow-up

ntervals, the actual number of PSA tests completed was nottated. Although it might seem trivial, the frequency of PSAesting is as significant as the Gleason score in its influence onhe biochemical endpoints.7

Despite the study’s potential weaknesses, it has demonstratedthat patients can achieve similar intermediate-term biochemi-cal outcomes when treated with BT, regardless of whether theyhave a high potential for upgrading, as assessed by a preopera-tive nomogram.

Jay P. Ciezki, M.D., and Chandana A. Reddy, M.S.,Cleveland Clinic, Cleveland, Ohio

References1. Berg KD, Toft BG, Røder MA, et al. Prostate needle biopsies:

interobserver variation and clinical consequences of histopatholog-ical re-evaluation. APMIS. 2011;119:239-246.

2. Serkin FB, Soderdahl DW, Cullen J, et al. Patient risk stratificationusing Gleason score concordance and upgrading among men withprostate biopsy Gleason score 6 or 7. Urol Oncol. 2010;28:302-307.

3. Moreira Leite KR, Camara-Lopes LH, Dall’Oglio MF, et al. Upgrad-ing the Gleason score in extended prostate biopsy: implications fortreatment choice. Int J Radiat Oncol Biol Phys. 2009;7:353-356.

4. Fitzsimons NJ, Presti JC, Kane CJ, et al. Is biopsy Gleason scoreindependently associated with biochemical progression followingradical prostatectomy after adjusting for pathological Gleason score?J Urol. 2006;176:2453-2458.

5. Vira MA, Guzzo T, Heitjan DF, et al. Is the biopsy Gleason scoreimportant in predicting outcomes for patients after radical prosta-tectomy once the pathological Gleason score is known? BJU Int.2008;101:1232-1236.

6. Vassil AD, Murphy ES, Reddy CA, et al. Five-year biochemicalrecurrence free survival for intermediate risk prostate cancer afterradical prostatectomy, external beam radiation therapy or perma-nent seed implantation. Urology. 2010;76:1251-1257.

7. Ciezki JP, Reddy CA, Stephenson AJ, et al. The importance ofserum prostate-specific antigen testing frequency in assessing bio-chemical and clinical failure after prostate cancer treatment. Urol-ogy. 2010;75:467-471.

http://dx.doi.org/10.1016/j.urology.2012.03.056UROLOGY 80: 654, 2012. © 2012 Elsevier Inc.

REPLYAmong those with favorable-risk prostate cancer, there is awide range of perceived severity of disease according to the

known prognostic factors, such as tumor volume, percentage of

UROLOGY 80 (3), 2012

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positive cores, PSA level, and so forth. If the assessment ofthese factors has been formalized based on the final surgicalpathologic findings, it becomes a predictive nomogram.

The editorial comment is correct in that our study offers onlyintermediate-term follow-up; however, the follow-up was longenough to achieve a median PSA level of 0.07 ng/mL, a levelwell below that shown to be highly associated with long-termbiochemical freedom from failure. Both Hayden et al1 and

tock et al2 reported a �2% biochemical failure rate withlong-term follow-up in large series of patients who achieved aPSA level �0.2 ng/mL at 48-60 months after BT.

Ciezki et al3 have shown that performing 2 PSA tests annu-ally provides optimal sensitivity and specificity for detectingboth biochemical and clinical failure. Although we neglected toinclude the number of PSA tests per patient in our report, ourcohort analyzed for the risk of GSU had a median number ofPSA tests of 8 per patient (range 3-14) for the 4.2 years offollow-up (mean 8.2 � 2.3 tests per patient). This would fulfillthe recommendation of Ciezki et al3 for the ideal testing fre-quency.

We would argue against the statement that “. . . rarely is apatient who presents with low-risk disease treated as if he hasintermediate- or high-risk disease based on the likelihood ofGSU.” Certainly, one is not going to treat a patient assumingan upgrading of 2 risk categories; however, daily in clinicalpractice, one assesses the constellation of PSA level, digitalrectal examination findings, TRUS results, and the percentageof positive cores to determine whether a “low-risk” patient can

safely be offered active surveillance (ie, likely to have truly

UROLOGY 80 (3), 2012

low-risk disease) or should be offered definitive treatment (ie,likely to have significant or “serious” cancer). When an expe-rienced surgeon sees a high-volume, Gleason score 6 cancerwith a PSA level close to 10 ng/mL, the surgeon knows thelikelihood of finding some Gleason pattern 4 in the final patho-logic specimen is high. A nomogram, with all its faults, attemptsto formalize this process. Our study has shown that BT iseffective treatment despite these less favorable features.

Juanita Crook, M.D., and David Bowes, M.D.,Department of Radiation Oncology, British ColumbiaCancer Agency, Kelowna, British Columbia, Canada

References1. Hayden A, Morris W, Keyes M, et al. The PSA value at 4-5 years

after permanent prostate brachytherapy predicts for biochemicalfailure free survival. Radiother Oncol. 2010;96(suppl 2):S2.

2. Stock RG, Klein TJ, Cesaretti JA, et al. Prognostic significance of5-year PSA value for predicting prostate cancer recurrence afterbrachytherapy alone and combined with hormonal therapy and/orexternal beam radiotherapy. Int J Radiat Oncol Biol Phys. 2009;74:753-758.

3. Ciezki JP, Reddy CA, Stephenson AJ, et al. The importance ofserum prostate-specific antigen testing frequency in assessing bio-chemical and clinical failure after prostate cancer treatment. Urol-ogy. 2010;75:467-471.

http://dx.doi.org/10.1016/j.urology.2012.03.057

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