Prognostic Factors for Newly DiagnosedProstate Cancer and Their Role in Treatment SelectionJuanita Crook, MD, and Ana Fernandez Ots, MD

Adenocarcinoma of the prostate is extremely heterogeneous, ranging from an indolentchronic illness to an aggressive rapidly fatal systemic malignancy. The classic prognosticfactors of tumor stage, prostate specific antigen level, and Gleason score have been usedfor over a decade to categorize patients at the time of diagnosis into broad risk groups thathelp to determine appropriate management. Although the grouping of patients into favor-able, intermediate, and high-risk categories has become standard, and the categoriescontinue to define distinct prognostic subgroups, considerable heterogeneity exists withineach risk group. As a range of management options are available, additional prognosticfactors can be considered when determining the treatment approach for an individualpatient. We review these additional prognostic variables under the headings of patient-related, tumor-related, and treatment-related. The influence of each of these factors mayvary depending on treatment factors such as dose, the radiation modality, or the use ofconcomitant androgen ablation.

Semin Radiat Oncol 23:165-172 © 2013 Elsevier Inc. All rights reserved.

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The range of management options for prostate cancer re-flects the heterogeneity of the disease. Although active

surveillance is very appropriate under some circumstances,definitive monotherapy (surgery, radiation, or brachyther-apy) is often selected for favorable or intermediate risk can-cers. More advanced and aggressive cancers generally receivea multimodality approach consisting of a combination of ra-diation and androgen ablation, or surgery with the additionof postoperative radiation and/or androgen deprivation, de-pending on final pathology. The addition of systemic chemo-therapy is considered investigational. To select the best treat-ment for a patient, a large number of factors must beconsidered. Since the mid-1990s, tumor stage, prostate spe-cific antigen (PSA) level, and Gleason score (GS) have beencombined to classify patients into 3 distinct risk groups toassist in determining the most appropriate treatment.

In the past decade, many other factors have been examinedfor prognostic significance but have not been incorporatedinto a formal risk group classification. The most promising ofthese are features such as pretreatment PSA velocity,1 the

Department of Radiation Oncology, British Columbia Cancer Agency, Cen-ter for the Southern Interior, Kelowna, British Columbia, Canada.

The authors declare no conflict of interest.Address reprint requests to Juanita Crook, MD, FRCPC, Department of

Radiation Oncology, British Columbia Cancer Agency, Center for theSouthern Interior, 399 Royal Avenue, Kelowna, British Columbia, Can-

ada, V1Y 5L3. E-mail: jcrook@bccancer.bc.ca

1053-4296/13/$-see front matter © 2013 Elsevier Inc. All rights reserved.DOI: 10.1016/j.semradonc.2013.01.002

presence of tertiary Gleason pattern 5 and percentage of high-grade disease (Gleason patterns 4 and 5 combined),2-4 thepercentage of positive biopsies,5,6 the presence of perineuralnvasion (PNI),7 and the presence of multiple adverse fac-tors.8 As the current broad risk group categories are very

eterogeneous, these additional factors may help to furthertratify patients within the same risk group to select appro-riate management. In addition to these factors, many noveliomarkers have been studied, including E-cadherin, p53,NA ploidy, CYP3A4 genotype, androgen receptor CAG re-eats, among others. The prognostic value of these noveliomarkers, however, is not yet clearly established.9 A fulleview is available from Sutcliffe et al, performed for theealth Technology Assessment Program.9

Sutcliffe et al9 acknowledge that although the terms “prog-nostic” and “predictive” are often used interchangeably,prognostic factors are markers for disease severity, whereaspredictive markers forecast outcome of a specific treatment.This review will deal with both types, as the interplay oftumor-related prognostic factors and treatment-related pre-dictive factors further complicates decision-making for theindividual patient. When formulating a treatment plan, thequestions of dose, radiation modality, and incorporation ofandrogen deprivation therapy (ADT) must be addressed.Multiple mature randomized trials10-15 show the benefits ofdose-escalated radiotherapy in terms of biochemical disease-free survival (DFS), local eradication of tumor, and improved

freedom from distant metastases (Table 1). The benefits of

165

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cil; PS

166 J. Crook and A. Fernandez Ots

neoadjuvant, concurrent, or adjuvant ADT have also beenwidely investigated in phase III trials.17-19 The role of ADT hasbeen well-established in intermediate and high-risk diseasemanaged with conventional dose external beam radiotherapy(EBRT: 65-70 Gy) (Table 2), but remains to be defined whencombined with optimal dose escalation.

Treatment success is most often determined by biochem-ical disease-free status. Unfortunately, a rising PSA does notdistinguish between systemic and local failure. Radiation is alocal treatment modality, the success of which can really onlybe determined by postradiation prostate biopsies.16,23-25 Themportance of eradication of local tumor in ultimate DFS andrevention of subsequent distant metastases has been dem-nstrated.26,27

Table 1 Randomized Trials of Dose Escalation

nArms by Dose

in Gray Eligib

MDA15 301 70/78 T1-3

GETUG13 306 70/80 T1-3, PSA

Dutch multicenter10 669 68/78 T1-4, PSA

Royal Marsden14 126 64/74 T1-T3b

MGH proton12 393 70.2/79.2 T1-T2b, P

MRC RT0116 843 64/74 T1-3, PSA

Abbreviations: bNED, biochemical no evidence of disease; GETUG,Massachusetts General Hospital; MRC, Medical Research Coun

Table 2 Randomized Trials of Androgen Ablation Combined W

Trial ArmsDose

RT (Gy) Populatio

RTOG 8531(10 years)20

RT vs RT �ADT�)

65-70 HR n � 977

RTOG 8610(10 years)21

RT vs RT �4 mo

65-70 HR (bulky) n �

EORTC 22863(5 years)22

RT vs RT �3 years

65-70 HR (gr3 or T3;N0) n � 415

TROG 9601(5 years)19

RT vs RT �6 mo

66 HR15% IR N � 81

D’Amico(5 years)18

RT vs RT �6 mo

70 IR (80%) N �

RTOG 9202(10 years)17

RT � STADRT � LTAD

65-70 IR–HR

Abbreviations: ADT/STAD/LTAD, androgen deprivation therapy, shoEuropean Organization for Research and Treatment of Canc

metastases/overall survival; RT, radiotherapy; RTOG, Radiotherapy and

Patient-RelatedPrognostic FactorsAppropriate management of prostate cancer is not only influ-enced by tumor-related factors but also by the age and gen-eral health of the patient.28,29 Wilt et al30 published the resultsf a randomized comparison of radical prostatectomy againstbservation for 731 men. Comorbidities of the populationere such that median survival was only 12 years. Patientsere dying of other causes before prostate cancer had a

hance to exert its toll. Only 14.2% of the observed deathsere from prostate cancer. Thus, radical intervention wasery unlikely to benefit overall survival, although it did re-uce all-cause mortality in men with PSA �10 ng/mL (P �

MedianFollow-up

YearsbNED

Std Arm

bNEDHigh-Dose

Arm P Value

8.7 59% 78% P � 0.0048 years

5.1 68% 77% P � 0.095 years

6.8 45% 56% P � 0.037 years

6.2 59% 71% P � 0.105 years

5 5.5 79% 91% P < 0.0015 years

5.3 60% 71% P � 0.00075 years

e d’Études de Tumeurs Uro-génitales; MDA, MD Anderson; MGH,A, prostate-specific antigen.

onventional Dose External Beam Radiotherapy

bNED LF DM OS

38%23%

P < 0.0001

39%24%

P < 0.001

39%49%

P � 0.00220%35%

P < 0.0001

47%35%

P � 0.006

34%43%

P � 0.1245%76%

P < 0.0001

16%2%

P < 0.0001

29%10%

P < 0.0001

62%78%

P � 0.000238%56%

P < 0.001

28%12%

P < 0.001

19%13%

P � 0.04655%79%

P < 0.001

78%88%

P � 0.0468%52%

P < 0.0001

22%12%

P < 0.0001

23%15%

P < 0.001

51.6%53.9%

P � 0.36

and long-term; bNED, biochemical no evidence of disease; EORTC,/IR, high risk/intermediate risk; LF/DM/OS, local failure/distant

ility

<50

<60

SA <1

<50

Group

ith C

n

465

90%

8

206

rt-termer; HR

Oncology Group; TROG, Trans-Tasman Radiation Oncology Group.

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Prognostic factors for newly diagnosed prostate cancer 167

0.04). This finding, that intervention in elderly men withsignificant comorbidities may be unnecessary, is supportedby Albertsen et al,29 who performed a 10-year competing risknalysis on 19,639 men aged 66 and older. Comorbiditiesere classified by the Charlson index, and patients receivedo surgery or radiation within 180 days of diagnosis. Menying in the first 10 years after diagnosis were more likely toie of other causes, even if they had a moderately or poorlyifferentiated prostate cancer.Crawford et al28 analyzed the data of the Prostate, Lung,

Colorectal, and Ovarian Cancer Screening Trial of 76,693men according to comorbidities. In men with no or minorcomorbidities assigned to intervention, prostate cancerscreening led to a significantly decreased risk of prostate can-cer-specific mortality. The number of healthy men which oneneeded to treat to prevent 1 death from prostate cancer wasreduced to only 5 (hazard ratio [HR]: 0.56; 95% confidenceinterval [CI]: 0.33-0.95; P � 0.03). In men with only 1 sig-nificant comorbidity, intervention no longer decreased pros-tate cancer mortality (HR: 1.43; 95% CI: 0.96-2.11; P �0.08), underlining the importance of careful assessment of apatient’s general health status before deciding on manage-ment. Older patients should be managed according to theirindividual health status and comorbidities and not accordingto chronologic age. The likelihood of a survival benefit mustbe weighed against the potential for treatment toxicity.

Comorbidities are also a consideration in systemic treat-ment with ADT. Keating et al31 performed a population-

ased observational study of 185,106 men aged 66 years andlder with local/regional prostate cancer over a 15-year pe-iod. ADT was used in 49.5% and was associated with anncrease in the adjusted hazard of myocardial infarction (HR:.09; 95% CI: 1.02-1.16) and diabetes (HR: 1.33; 95% CI:.27-1.39). This effect was seen similarly across groups withnd without comorbidities.

Tumor-RelatedPrognostic FactorsStagingThe widely used staging system developed jointly by theAmerican Joint Committee on Cancer and the InternationalUnion for Cancer Control was updated in 2010 to incorpo-rate both GS and PSA with the traditional anatomic factors ofprimary tumor stage (T), lymph node status (N), and thepresence of distant metastases (M)32 (Table 3).

● Group I: Low risk, localized tumors: T1 or T2a ANDPSA �10 ng/mL AND GS �6.

● Group IIA: Localized tumors with at least 1 feature as-sociated with an intermediate level of risk: T2b OR serumPSA �10 and �20 ng/mL OR GS 7.

● Group IIB: Localized tumors with at least 1 feature as-sociated with a high risk for recurrence: T2c OR serumPSA �20 ng/mL OR GS �8.

● Group III: Locally advanced tumors with extracapsular

extension (T3), any PSA level or GS.

● Group IV: Any T4 cancer OR positive lymph nodes (N1)OR distant metastases (M1).

The addition of pretreatment serum PSA level and GS tonatomic TNM staging to create these prognostic groups isased on multiple studies that demonstrate the importance ofhese parameters in determining outcome.21,33 However,

even within these refined groups, there is substantial hetero-geneity that has implications for patient management. Addi-tional tumor-related features with prognostic significance arepretreatment PSA kinetics,1 the number and percentage ofpositive biopsy cores,5,6 the percentage of high-grade cancer,4

and the presence of PNI.7 Although the 2010 TNM risk as-essment classification system does not take these measuresnto account, other prognostic models incorporate selecteddditional factors. The National Comprehensive Cancer Net-ork Guidelines34 define a very low-risk group based on

tumor volume, as assessed by number of positive cores andpercentage involvement of the individual cores. The Memo-rial Sloan-Kettering nomogram35 includes data for risk as-sessment based on the number of positive cores and thelength of tumor involvement in each core.

PSAPSA is a 30-33-kDa protease of the kallikrein family firstisolated from seminal plasma and now widely used in pros-tate cancer screening. In addition to baseline PSA, which is awell-established prognostic factor,24,33 PSA kinetics havebeen studied extensively in the past 2 decades, specificallyPSA velocity and doubling time. Increasing evidence suggeststhat PSA velocity is prognostic for prostate cancer aggressive-ness. The velocity is determined using the PSA value nearestto diagnosis and previous PSA values in the year before diag-nosis separated by at least 6 months (minimum number ofvalues: 2, maximum number of values: 3). D’Amico et al1

have shown that men with an annual PSA velocity �2 ng/mLin the year before diagnosis have a 12-fold increased risk ofprostate cancer mortality after EBRT, despite a favorable dis-ease category.

Sutcliffe et al9 performed a systematic review of classicaland novel biomarkers, screening 4030 abstracts and 395 fullmanuscripts. Only 30 studies met the inclusion criteria re-quiring a minimum of 200 patients and a mean or medianfollow-up of 5 years. Although the quality of studies wasgenerally poor, of the 28 markers studied, the one with thestrongest evidence for significance was PSA velocity or dou-bling time. In the clinical model, the HR for death fromprostate cancer was 9.8 (95% CI: 2.8-34.3; P � 0.001) for

en with an annual PSA velocity �2 ng/mL. Similarly, in theathologic model, the HR was 12.8 (95% CI: 3.7-43.7; P �.001). Interestingly, another review of the literature over theame period36 was less selective and reached a contrary con-

clusion that pretreatment PSA dynamics are of limited clini-cal value. The selection criteria for inclusion of studies canclearly affect the conclusions of a review, especially if data are

included that are based on insufficient follow-up.

1

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168 J. Crook and A. Fernandez Ots

Gleason ScoreThe Gleason grading system, based on architectural featuresof malignant prostate glands, is consistently an independentprognostic factor for outcome, regardless of the treatmentmodality. For this reason, it has recently been incorporatedinto the previously purely anatomic American Joint Commit-tee on Cancer/International Union for Cancer Control stag-ing system. A higher GS is associated with a greater likelihoodof having non-organ-confined disease, as well as a greaterchance of biochemical failure after treatment of localized dis-ease by radical prostatectomy, EBRT, or combinations ofADT, EBRT, and brachytherapy.24,33,37 The importance of theGS is reflected by its key role in predictive nomograms andtables, such as the Memorial Sloan-Kettering Cancer Center(MSKCC) nomogram35 and the Partin tables.38

However, GS 7 prostate cancer remains a very heteroge-neous entity. Gleason 7 cancers with predominant pattern 4have a less favorable outcome than those that are predomi-nant pattern 3. Burdick et al39 reported a multivariate analysisfrom a prospective database of 705 men with Gleason 7 pros-

Table 3 TNM UICC AJC Staging Classification 201032

Primary Tumor (T)Clinical (cT)

TX Primary tumor cannot be assT0 No evidence of primary tumoT1 Clinically inapparent tumor nT1a Incidental histologic findingT1b >5% of tissue resectedT1c Identified by needle biopsy (T2 Confined within prostateT2a Involves < one-half of one loT2b >one-half of one lobe but noT2c Involves both lobesT3 Extends through the prostateT3a Extracapsular extension (unilT3b Invades seminal vesicle(s)T4 Fixed, or invades adjacent st

rectum, bladder, levator mPathologic (pT)

pT2 Organ confinedpT2a Unilateral, <one-half of onepT2b >one-half of one side but nopT2c Bilateral diseasepT3 Extraprostatic extensionpT3a Extraprostatic or microscopicpT3b Seminal vesicle invasionpT4 Invasion of rectum, levator m

Regional lymph nodes (N)NX Regional nodes cannot be asN0 No regional lymph node metN1 Metastasis in regional lymph

Distant metastases (M)M0 No distant metastasesM1 Distant metastasesM1a Nonregional lymph nodesM1b BoneM1c Other sites

tate cancer treated over a 9-year period. Three hundred ten

were treated with radical prostatectomy, 268 with EBRT, and127 with low-dose-rate (LDR) prostate brachytherapy. Thepredominant grade on biopsy was an independent predictorof biochemical relapse-free survival, with predominant grade3 better than grade 4. Khoddami et al40 analyzed 309 radicalprostatectomies with Gleason 7 tumors in the final pathol-ogy. Gleason 4 � 3 was associated with a greater percentageof positive biopsy cores (P � 0.006) and higher baseline PSA(P � 0.04), both seminal vesicle (P � 0.001) and regionalnode (P � 0.008) involvement, and positive surgical margins(P � 0.04). The 5-year risk of biochemical progression was

7% for 3 � 4 versus 35% for 4 � 3 (P � 0.002).When a small component of higher-grade tumor is found

n addition to the 2 predominant patterns, this minor com-onent is referred to as a tertiary Gleason grade and is present

n approximately 20% of radical prostatectomy specimens. In005, the International Society of Urologic Pathology con-ensus conference recommended that tertiary pattern 5, co-xisting with biopsy GS 3 � 4 or 4 � 3, should be classifieds GS 8 or 9, respectively.41 Tertiary pattern 5 is associated

palpable nor visible by imagingof tissue resected

cause of elevated PSA)

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Prognostic factors for newly diagnosed prostate cancer 169

biochemical and clinical recurrence.3 Although an importanttep, it should be noted that this reclassification creates stageigration where tumors previously considered to be inter-ediate risk are now included in the high-risk category.The percentage of high-grade prostate cancer in a speci-en (eg, combined Gleason patterns 4 and 5) may provide

dditional prognostic information. In a series of 227 consec-tive patients undergoing prostatectomy, an increasing per-entage of high-grade tumor was associated with a statisti-ally significant increase in non-organ-confined disease;owever, tertiary pattern 5 did not alter the outcome forumors where the only other Gleason present is pattern 4 (ie,S 4 � 4). In these cases, the tertiary pattern 5 did not

ncrease the total percentage of high-grade tumor. Conse-uently, the effect of tertiary pattern 5 is greatest when itoexists with a low primary or secondary pattern.2 A review

of 312 men with either GS 7 and tertiary pattern 5, or Gleason8, 9, or 10 treated by either radical prostatectomy or EBRT,with or without ADT, showed that the risk of PSA recurrencefor Gleason 7 with tertiary 5 was similar to that of GS 9 or 10.4

Percentage of Positive BiopsiesThe percentage of positive biopsies is an estimate of tumorvolume that can add relevant information to other factorssuch as T-stage and biopsy GS in predicting outcome. Thenumber of positive biopsy cores and the percentage of eachcore involved are directly proportional to the radical prosta-tectomy tumor volume. In a series of 605 radical prostatec-tomy pathology sets, a higher percentage of positive biopsieswere associated with established prognostic and pathologicfeatures such as higher baseline PSA, extracapsular disease,seminal vesicle and regional lymph node involvement, andPNI.5 D’Amico et al6 examined the influence of the percent-ge of positive biopsies (�50% or �50%) in 381 men treatedith EBRT. With a median follow-up of 4.3 years (range:.8-13.3), incorporation of the percentage of positive biop-ies (�50% vs �50%) into the established risk stratificationystem identified a minimal risk cohort (low or intermediateisk and �50% positive biopsies) with estimated 100% pros-ate cancer-specific survival (PCSS) at 10 years as comparedith high risk (intermediate or high risk and �50% positiveiopsies) with estimated PCSS of 55% at 10 years (P � 0.000). Overall survivals were 84% and 40%, respectively (P �.02). The 2012 National Comprehensive Cancer Networkuideline has incorporated cancer volume into the definitionf a very-low-risk group adding the criteria “fewer than 3iopsy cores positive and �50% involvement in each core” tohe standard low-risk criteria.34

Perineural InvasionPNI is defined as carcinoma tracking within the perineuralspace, along or around a nerve, and is a potential mechanismfor prostate cancer cells to spread beyond the prostate. In anexcellent review by Harnden et al,7 PNI was reported to be

resent in 7%-43% of prostate needle biopsy specimens that

ontained prostate cancer. The significance of PNI in prostate

iopsies, and its influence on biochemical outcomes afteradical treatment for prostate cancer, are controversial anday vary with the type of treatment. For men treated with

adical prostatectomy, PNI is associated, on multivariatenalysis, with an increased risk of extracapsular extensionnd higher pathologic stage, and the presence of seminalesicle and/or pelvic lymph node involvement. It may bessociated with a higher likelihood of local recurrence afterBRT even in the era of dose escalation. In a series of 651 men

reated with doses �75 Gy, the presence of PNI on biopsyas associated with an increased risk of metastatic failure

33% vs 11%; P � 0.02) and death from prostate cancer(31% vs 9%; P � 0.04), particularly in men with GS 8-10.42

The same effect has not been seen in men treated withbrachytherapy,43,44 although this may be related to the rarityof high-grade cancers in these reports. Weight et al44 re-viewed 651 men treated with brachytherapy, 55% favorablerisk and 38% intermediate. Sixty-three failures were matchedwith nonfailing controls and showed a similar percentage ofPNI (19.6% vs 14.3%; P � 0.45), which did not correlatewith biochemical DFS (P � 0.4). Piña et al43 reported a sim-ilar observation in a cohort of 339 men treated with brachy-therapy. PNI was found in 24% of biopsy samples. Five-yearbiochemical disease-free rates were 93% with PNI and 99%without (P � 0.06).

Summary ofTumor-Related Prognostic FactorsHow does one incorporate these tumor-related prognosticfactors into the established risk groups and use this informa-tion in determining treatment? Of the factors discussed, onlyPSA velocity in the year before diagnosis is strongly associ-ated with increased prostate cancer-specific mortality. Thepathologic factors (Gleason 7 with predominant pattern 4,the presence of tertiary pattern 5, percentage of positive bi-opsies, and the presence of PNI) largely predict for moreadvanced pathologic stage, and consequently, are associatedin many reports with increased biochemical failure. Theirutility in predicting outcome is enhanced when combinedwith other factors. For example, PNI may predict for in-creased prostate cancer-specific mortality in men with high-grade tumors. The percentage of positive biopsies can definea very-low-risk cohort when �50% in a patient who other-wise has a favorable or intermediate risk cancer, whereas if�50% in a patient with intermediate or high risk disease isassociated with decreased PCSS. The application of thesefactors can help in determining appropriate treatment in thelarge “grey zone” of intermediate risk disease, when to con-sider brachytherapy alone, when to add external beam, andwhen to add ADT and for how long.

Treatment-Related FactorsThe dose–response relationship for prostate cancer has beenwell-established by level 1 evidence from mature results of

numerous randomized trials.10-15 Although dose escalation

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170 J. Crook and A. Fernandez Ots

has been shown to improve biochemical DFS in all riskgroups,24 the optimal dose and the method to achieve it re-main to be determined. Table 1 shows an improvement ofapproximately 10% in biochemical DFS when the conven-tional dose of radiotherapy (64-70 Gy) is increased by as littleas 10 Gy.

A retrospective analysis by Zelefsky et al24 of 2551 patients(favorable risk: 22%, intermediate: 42%, and high: 36%)showed that dose levels �70.2 Gy and 70.2-79.8 Gy wereassociated with 2.3- and 1.3-fold, respectively, increased riskof biochemical recurrence compared with higher doses. Ra-diotherapy and Oncology Group 94-06 investigated sequen-tial dose escalation in intermediate- and high-risk patients.The estimated biochemical DFS using the nadir � 2 defini-tion for intermediate-risk patients receiving 78-79.2 Gy at 5years was approximately 70%, but by 10 years, had fallen to50%, underlining the importance of long-term follow up,and suggesting that this degree of dose escalation may not beadequate.45 Nonetheless, improvement in distant metastases-free survival has been reported with higher radiation dosesfor all risks groups by Zelefsky et al.24 Specifically for GS8-10, doses �80 Gy are associated in Cox regression withreduced overall mortality (P � 0.035) and improved distantmetastases-free survival (P � 0.007).26

To obtain optimal results, a biologically effective dose(BED) greater than this may be necessary but is difficult toachieve with EBRT alone. Results from a prospective databaseof 2250 patients treated at the Mount Sinai Hospital in NewYork with intermediate-risk cancer showed that the high BEDachieved with either the combination of EBRT and a LDRbrachytherapy boost, or a high-quality LDR implant alone,resulted in improved biochemical disease-free rates. A BED�150 Gy achieved a 92% freedom from biochemical failureversus 62% with BED �150 Gy. The difference betweenimplant alone and an implant � EBRT was not significantP � 0.23).46 Stock et al37 reported over a decade of experi-

ence with tri-modality therapy in high-risk prostate cancer,consisting of EBRT to the prostate and seminal vesicles, LDRbrachytherapy, and 9 months of ADT. Freedom from bio-chemical failure was 73%, freedom from distance metastases80%, and PCSS was 87% at 8 years.

Similar results have been seen with high-dose-rate (HDR)brachytherapy. Deutsch et al47 compared 86.4-Gy intensity-modulated radiation therapy (n � 470) with intensity-mod-ulated radiation therapy (51 Gy) plus an HDR brachytherapyboost (7 Gy � 3) (n � 160) and demonstrated significantmprovement in biochemical no evidence of disease (bNED)ates for intermediate risk disease treated with the HDR boostP � 0.001). For the high-risk group, although the differencettained in biochemical disease-free rates was not statisticallyignificant, there was a striking elimination of local failures.artinez et al48 treated intermediate- and high-risk patients

with EBRT plus an HDR boost. Results for 452 patientsachieving a BED �268 Gy demonstrate reduced 10-year bio-chemical (P � 0.001) and clinical failure rates (P � 0.001)and improved metastatic DFS (P � 0.028), with a trend

toward improved overall survival (P � 0.131). o

The role of ADT with optimal dose escalation remains to bedefined. Multiple randomized trials (Table 2) show a benefitfor the addition of ADT to conventional dose radiotherapy inintermediate- and high-risk disease in terms of improvedfreedom from biochemical failure, distant metastases, andoverall survival.18,19,21,22 Potential benefits of ADT combinedwith dose-escalated radiotherapy remain to be quantified forboth intermediate- and high-risk disease. In conjunctionwith conventional dose radiotherapy, the recommended du-ration of ADT is established at 2-3 years. However, Stock et alhave reported excellent results with durations of ADT of 9-12months when combined with the high doses achieved withEBRT and the addition of a brachytherapy boost. The efficacyof this “tri-modality” treatment is substantiated by the changein the pattern of failure, with greatly reduced local failuresand elimination of the second wave of distant metastases thatemanate from uncontrolled local disease.46 Furthermore,looking solely at intermediate-risk patients treated with thecombination of EBRT and brachytherapy, the addition ofADT did not impact on 8-year bNED rates (92% with orwithout ADT).49 Similar results were reported by Martinez etl50 for 1260 men treated with EBRT and HDR brachyther-py. The bNED rates at 8 years were 85% and 81% with andithout a short course of ADT, respectively. The role of

hort-term (6 months) androgen deprivation with dose-esca-ated radiotherapy in intermediate-risk patients is being in-estigated in the current Radiotherapy and Oncology Group815 randomized trial.

Post-Treatment BiopsiesPostradiotherapy prostate biopsies are not a routine compo-nent of follow-up and are generally only indicated if theserum PSA is rising and local salvage therapy is being consid-ered. However, biopsy remains the only direct measure oflocal tumor response and efficacy of radiotherapy. Biopsystatus is not only a strong predictor of freedom from bio-chemical failure in multivariate analysis but is also predictiveof cause-specific survival and the development of subsequentdistant metastases and prostate cancer death.23,51,52 Zelefskyet al52 studied post-treatment biopsies in 339 men after 3Donformal radiotherapy. Median follow-up was 10 years afterompletion of treatment and over 6 years since the biopsy.ositive biopsies were found in 32% of patients overall, buthe incidence was dose-dependent, being 42% for doses

70.2 Gy and 24% for doses �75.6 Gy. Crook et al haveublished on the issues around timing and interpretation ofostradiotherapy prostate biopsies.16 Both Crook et al23 andelefsky et al52 have found that men with biopsies showingevere treatment effect have the same outcome as those withegative biopsies. Stock et al51 followed 446 men with post-reatment biopsies after LDR brachytherapy or tri-modalityreatment and found positive biopsies in only 2% receivingED �180 Gy compared with 24% with BED �100 Gy.reedom from disease at 10 years was 85% for negative bi-

psies compared with 59% for positive biopsies.

Prognostic factors for newly diagnosed prostate cancer 171

ConclusionsPretreatment clinical factors (T stage, serum PSA, and GS) areroutinely used to determine management. Additional factorssuch as PSA velocity and doubling time, the primary Gleasonpattern and percentage of high-grade disease, the percentageof positive biopsy cores, and the presence of PNI should alsobe considered to guide the therapeutic decision, especiallywithin the heterogeneous intermediate-risk group.

Improved biochemical response with dose escalation re-flects more effective local treatment with ablation of the pri-mary tumor. This is seen across all risk groups and is associ-ated with reduction in both distant metastases and cancer-related deaths. Combined radiation modalities that include acomponent of brachytherapy, either LDR or HDR, appearbetter able to achieve an optimal dose escalation. Post-treat-ment biopsies reflect this improved outcome. The indicationsfor, and optimal duration of, ADT remain to be clarified whencombined with optimal dose escalation.

In assessing a patient with newly diagnosed prostate can-cer, full appreciation of comorbidities, categorization by riskgroup, and then fine-tuning of the treatment approach ac-cording to the interplay of secondary prognostic factors willhelp to individualize management.

References1. D’Amico AV, Renshaw AA, Sussman B, et al: Pretreatment PSA velocity

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