Brachytherapy - (2011) -

Moderate dose escalation with single-fraction highedose ratebrachytherapy boost for clinically localized intermediate- and high-risk

prostate cancer: 5-year outcome of the first 100 consecutivelytreated patients

P�eter �Agoston1,*, Tibor Major1, Georgina Fr€ohlich1, Zolt�an Szab�o1, J�ozsef L€ovey1,J�anos Fodor1, Mikl�os K�asler2, Csaba Polg�ar1

1Department of Radiotherapy, National Institute of Oncology, Budapest, Hungary2National Institute of Oncology, Budapest, Hungary

ABSTRACT PURPOSE: To analyze the clinical outcome a

Received 16 Nove

* Corresponding a

tute of Oncology, R�a

þ36-1-224-8600; fax:

E-mail address: a

1538-4721/$ - see fro

doi:10.1016/j.brach

nd toxicity data of the first 100 consecutive patientstreated with a single-fraction highedose rate brachytherapy (HDR-BT) and external beam radio-therapy (EBRT).METHODS AND MATERIALS: Two-hundred eighty patients have been treated with HDR-BTboost for localized intermediate- to high-risk prostate cancer. Among these, the outcome andtoxicity of the first 100 patients treated with a single HDR-BT fraction were assessed. A mediandose of 60 Gy EBRTwas given to the prostate and vesicles. Interstitial HDR-BT of 10 Gy was per-formed during the course of EBRT.RESULTS: Median followup time was 61.5 months. The 5-year actuarial rates of overall survival,cause-specific survival, disease-free survival, and biochemical no evidence of disease (bNED) forthe entire cohort were 93.3%, 99.0%, 89.3%, and 85.5%, respectively. The 7-year actuarial rateof bNED was 84.2% for the intermediate-risk group and 81.6% for the high-risk group( p5 0.8464). The 7-year actuarial rates of bNED for Grade 1, 2, and 3 tumors were 97.5%,80.0%, and 67.1%, respectively. The 5-year probability for developing late Grade 3 gastrointestinaland genitourinary (GU) toxicity was 2.1% and 14.4%, respectively. Grade 3 GU complicationsoccurred significantly more frequently in patients with a history of preirradiation transurethralresection (29.1% vs. 8.8%; p5 0.0047).CONCLUSIONS: Five-year outcome after 60 Gy EBRT plus a single fraction of 10 Gy HDR-BTboost is encouraging. Preradiation transurethral resection significantly increases the risk of latesevere GU complications. � 2011 American Brachytherapy Society. Published by Elsevier Inc.All rights reserved.

Keywords: Prostate cancer; Highedose rate brachytherapy; Boost; External beam radiotherapy

Introduction

The optimal treatment for intermediate- and high-riskclinically localized or locally advanced prostate cancerremains undefined. Studies using dose escalation withexternal beam radiotherapy (EBRT) showed that doses

mber 2010; accepted 4 January 2011.

uthor. Department of Radiotherapy, National Insti-

th Gy. u. 7-9., H-1122 Budapest, Hungary. Tel.:

þ36-1-224-8680.

goston.p@oncol.hu (P. �Agoston).

nt matter � 2011 American Brachytherapy Society. Publis

y.2011.01.003

more than 70 Gy in 2 Gy fractions significantly increasedbiochemical and clinical freedom from failure in T1eT3localized prostate cancer (1). Other investigators usinghighedose rate brachytherapy (HDR-BT) as a boostshowed that there is a strong doseeresponse relationshipfor intermediate- to high-risk prostate cancer patients, andimproved locoregional control with higher radiation dosesalone can significantly decrease the incidence of biochem-ical and clinical failures (2). Use of HDR-BT as a means ofdose escalation in prostate cancer is based on the hypoth-esis that treatment delivery with high fractional doses willexploit the presumed fractionation sensitivity of prostate

hed by Elsevier Inc. All rights reserved.

Table 2

Patients’ baseline characteristics

Characteristic n

T stage UICC, 2002

T1 43

T2aec 25

T3aeb 32

Pretreatment PSA (ng/mL)

!10 35

10e20 36

O20e60 29

Histologic grade

1 42

2 35

3 19

UK 4

Risk group

Intermediate-risk 39

High-risk 61

UICC5Union for International Cancer Control; PSA5 prostate-

specific antigen; UK5 unknown.

2 P. �Agoston et al. / Brachytherapy - (2011) -

cancer (3). Recent data suggest a low a/b ratio for prostatecancer, implicating higher tumor sensitivity to higher doseper fraction (4).

Hypofractionated HDR-BT could consequently be ofadvantage with the possibility of higher local tumor controlwithout increasing normal tissue toxicity (5). Differentcombined fractionation schedules, HDR-BT techniques,and planning methods have been published in the literature(6e11). An HDR-BT boost protocol for patients havingintermediate- and high-risk clinically localized prostatecancer was implemented at the Hungarian National Insti-tute of Oncology, Budapest in December 2001. UntilOctober 2010, overall 280 patients have been treated. AnEBRT dose of 60 Gy (with conventional fractionation)combined with a single-fraction HDR-BT boost of 8 Gy(n5 6) or 10 Gy (n5 258) was given to the prostate. Theother 16 patients were treated with 50 Gy EBRT followedby two separated highedose rate (HDR) implants of10 Gy 2e3 weeks apart. In this article, we analyze thesurvival outcome and toxicity data for the first 100 consec-utive patients treated with a single-fraction HDR-BT whohad a long enough followup to assess the biochemicaland clinical outcome and late treatment toxicity.

Patients and methods

Patients

Between December 2001 and October 2010, 280patients with intermediate- and high-risk prostate cancer,without lymph node or distant metastases, were treatedusing the combination of three-dimensional conformalexternal beam radiotherapy (3D-CRT) and HDR-BT asa boost treatment. Data from the first 100 consecutivepatients treated between 2001 and 2005 with a single-fraction HDR-BT boost were analyzed. Patients weredivided into risk groups using D’Amico’s (12) risk groupstratification (Table 1). Patients’ baseline characteristicsare summarized in Table 2. Patients’ median age was 65years (range, 50e80 years). Sixty-one percent of thepatients were stratified as high risk. Initial prostate-specific antigen (iPSA) was available in all but 1 patient(99%). The mean and median iPSA values before any treat-ment were 18 ng/mL (range, 4e58 ng/mL) and 15 ng/mL,respectively. Patients with iPSAO60 ng/mL were excludedfrom this analysis as they have a very high risk of relapseafter treatment, and their results will be reported separately.

Table 1

Risk group definitions by D’Amico et al. (12)

Low-risk Intermediate-risk High-risk

PSA!10 ng/mL and

GS 2e6 and

Stage T1eT2a

PSA $10e20 ng/mL

and/or GS 7 and/or

Stage T2b

PSAO20 ng/mL and/

or GS 8e10 and/or

Stage $T2c

PSA5 prostate-specific antigen; GS5Gleason score.

Histologic diagnosis was based on transrectal ultrasound(TRUS)eguided core biopsy. Pretreatment clinical investi-gations included physical examination, rectal digital exam-ination (RDE), TRUS, and pelvic CT or MRI. Bone scanwas done in all patients to exclude bone metastases.Patients were clinically staged according to the AmericanJoint Committee on Cancer and the Union for InternationalCancer Control TNM classification system (13). In case ofdiscrepancy in T status detected by different diagnosticmethods, the worse was registered. The World Health Orga-nization (WHO) classification system was used for histo-pathologic grading, because Gleason score was notavailable for all patients. If Gleason score or grade wasgiven, it was corresponded to WHO grade as it is shownin Table 3.

Treatment

Endocrine therapyInstitutional protocol for endocrine therapy included neo-

adjuvant and concurrent (3e6 months) androgen deprivation(AD) for intermediate-risk patients. For high-risk patients,endocrine treatment was suggested to be continued for2e3 years after the completion of radiotherapy (RT).Eighty-four patients received AD added to RT. The meanduration of hormonal treatment for these patients was 17.7

Table 3

Gleason score and grade according to WHO grade

WHO grade Gleason grade Gleason score

1 1e2 2e62 3 7

3e4 4e5 8e10

WHO5World Health Organization.

3P. �Agoston et al. / Brachytherapy - (2011) -

months (range, 4e60 months). The duration of AD was lessthan 12 months in 38 patients. For the other 46 patients,long-term (O12 months) AD was given. The median follow-up after the end of ADwas 50 months (range, 0e88months).

External beam radiotherapyEBRTwas performed in supine position; the patients were

immobilized with knee and ankle support system. PlanningCT images were entered into the three-dimensional planningsystem (Pinnacle; Philips, Amsterdam, The Netherlands) tooutline the prostate, seminal vesicles, bladder, rectum, andhip joints. For high-risk patients (n5 61), the pelvic lymphnodes were included in the clinical target volume (CTV).The applied margin around the CTV to obtain the planningtarget volume (PTV) was 1.5 cm in all directions, but poste-riorly a margin of 0.75 cm was used. Individual metal blocksor multileaf collimators were applied to design conformalfields. A four-field box technique with coplanar 18-MVphoton beams was used to treat all PTVs. EBRT was deliv-ered in daily fractions of 2 Gy, five times a week. Patientsin the high-risk group received a four-field whole-pelvicRT to a median dose of 46 Gy (range, 27e50 Gy), whichwas followed by a conformal irradiation via reduced portalsto the prostate and vesicles up to a median dose of 60 Gy(range, 40e61 Gy). In intermediate-risk patients, the pelviclymph nodes were not irradiated and the prostate and vesi-cles were given a median dose of 60 Gy (range, 40e61 Gy).

BrachytherapyTRUS-guided transperineal conformal interstitial HDR

192Ir implants were performed during the EBRT course.A preplanning TRUS (Sonoline; Siemens, Erlangen,Germany) was performed in each patients to detect anatom-ical contraindications of the procedure (i.e., shortestprostateerectum distance !0.5 cm or pubic arch interfer-ence). A single-fraction HDR-BT ‘‘boost’’ was given duringthe first 4 weeks of EBRT. The implant procedure was per-formed under spinal anesthesia, with the patient in thelithotomy position with extreme pelvic flexion. A 7.5-MHzbiplanar TRUS probe was fixed to a stepper, which wasmounted to the floor. The apex and base of the prostate glandwere identified using the transversal and longitudinal TRUSimages. The probe was positioned as parallel as possible tothe prostatic urethra. The treatment length was consideredas the distance from the base. The prostate glandwas scannedat 5-mm intervals from 2.0 cm above the base to 2.0 cmbelow the apex of the prostate gland. No margin betweenthe CTV and PTV was created. The reference plane wasselected at the largest cross section of the prostate. Theurethra was contoured on each 5-mm transverse image.Urethral reference points were placed into the center of theurethral catheter, and rectal reference points were placed at0.5 cm from the outer surface of the TRUS probe in the ante-rior direction on each transversal TRUS image.

After scanning the prostate with TRUS, a virtual preim-plant treatment plan was generated using the PLATO

Brachytherapy Planning System v14.2.6 (Nucletron,Veenendaal, The Netherlands). Geometrical optimizationfollowed by graphical optimization was used, and theprescribed dose (PD) was 8 Gy in 6 and 10 Gy in 94patients given to the surface of the prostate. Treatment planwas accepted if the whole prostate volume received at least95% of the PD and the maximum of the reference pointdose of the urethra and rectum was below 125% and 80%of the PD, respectively.

After acceptance of the preimplant treatment plan, metalneedles were inserted into the prostate through a templateunder TRUS guidance according to their positions on thevirtual plan. During insertion, positions of the needles wereupdated on the reference plane. The insertion depth of nee-dles was adjusted one by one using longitudinal images ofthe TRUS. Optimization procedure was used again for theinserted needles to achieve the final dose distribution (14).Anteroposterior and lateral X-ray images were taken toverify the positions of needles, and the bladder balloon cath-eter (Foley catheter) was filled with contrast medium.Patients were treated with an HDR remote afterloadingequipment (microSelectron; Nucletron, B. V.) using a 192Irstepping source with an initial activity of 370 GBq. The totaltreatment time of EBRTand HDR-BTwas 6.5 weeks (range,44e54 days).

Followup

The median followup time (calculated from the last RTfraction) was 61 months (range, 7e94 months). A total of60 patients have been followed up for a minimum of 5 years.All 100 patients were eligible for evaluation of biochemicaland clinical outcomes, toxicity, and implant quality. Twopatients were lost to followup at 29 and 50 months afterRT. Followup examinations included prostate-specificantigen (PSA) test every 3 months in the first year, every6 months in the second to fifth years, and yearly thereafter.RDE was done at least annually or if complaints appearedor PSA elevation occurred. Overall survival (OS) reflectedall deaths, cancer related or otherwise. Cause-specificsurvival (CSS) was based on deaths that could be attributedto prostate cancer. Biochemical failure was defined accord-ing to the Phoenix consensus criteria: PSA nadirþ 2 ng/mL(15). Clinical disease-free survival (DFS) was calculated forall living patients and reflected all clinical events (local,regional, or distant failure, whichever came first). Localrecurrence was defined as local progression detected byRDE or MRI. Acute and late side effects were prospectivelyfollowed and recorded using the Radiation TherapyOncology Group/European Organization for Research andTreatment of Cancer acute and late toxicity scales (16).

Statistics

All time intervals were calculated from the last day ofRT to failure, death, or the last followup visit. The actuarial

Table 5

Five-year actuarial results by risk groups

End point

All patients

(%)

High-risk group

(%)

Intermediate-

risk group (%)

Log-

rank p

OS 93.3 92.8 94.2 NS

CSS 99.0 98.3 100 NS

DFS 89.3 86.2 94.0 NS

LRFS 97.7 98.3 96.6 NS

RRFS 100 100 100 NS

DMFS 89.3 86.2 93.9 NS

bNED (Phoenix) 85.5 86.4 84.2 NS

bNED (ASTRO) 80.3 80.6 79.5 NS

OS5 overall survival; CSS5 cause-specific survival; DFS5 disease-

free survival; LRFS5 local recurrenceefree survival; RRFS5 regional

recurrenceefree survival; DMFS5 distant metastasisefree survival;

bNED5 biochemical no evidence of disease; ASTRO5American

4 P. �Agoston et al. / Brachytherapy - (2011) -

rates of OS, CSS, DFS, local recurrenceefree survival,distant metastasisefree survival, biochemical no evidenceof disease (bNED), and complication rates were estimatedaccording to the KaplaneMeier method (17). UnivariateCox regression analysis was used to evaluate the possibleprognostic factors for different end points, including deathfrom any cause, cause-specific death, and biochemical andclinical failure (18). A p-value of #0.05 was consideredstatistically significant. A trend to significance was estab-lished at p-values between O0.05 and #0.10. The SOLOsoftware (Department of Biometrics, University ofCalifornia, Los Angeles, CA) was used for statistical anal-ysis. The time-to-event curves were compared using thetwo-sided log-rank test (19).

Society for Therapeutic Radiology and Oncology; NS5 not significant.

Results

Treatment outcome

At a median followup of 61.5 months, 4 local recur-rences (4%), 1 regional recurrence (1%), and 12 distantmetastases (12%) occurred. Fifteen patients (15%) devel-oped biochemical failure. Among these, six patients (6%)had a PSA relapse without clinical failure. To date, only4 patients (4%) died of prostate cancer. The crude ratesof specific events according to risk groups are summarizedin Table 4. The 5-year actuarial rates of OS, CSS, DFS, andbNED for the entire cohort were 93.3%, 99.0%, 89.3%, and85.5%, respectively. Actuarial 5-year estimates of differentend points for intermediate- and high-risk patients areshown in Table 5.

The probability of bNED in relation to risk groups isshown in Fig. 1. The 7-year actuarial rate of bNED was84.2% for the intermediate-risk group and 81.6% for thehigh-risk group ( p5 0.8464). However, patients withwell-differentiated (WHO Grade 1) tumors had a signifi-cantly better biochemical control rate compared with menhaving WHO Grade 2 or 3 tumors (Fig. 2.). The 7-yearactuarial rates of bNED for Grade 1, 2, and 3 tumors were97.5%, 80.0%, and 67.1%, respectively.

Table 4

Incidence of events by risk groups

Event

High-risk,

n (%)

Intermediate-risk,

n (%)

All patients,

n (%)

Local recurrence 3 (4.9) 1 (2.6) 4 (4)

Regional recurrence 0 (0) 1 (2.6) 1 (1)

Distant metastasis 9 (14.8) 3 (7.7) 12 (12)

Any first clinical relapsea 10 (16.4) 3 (7.7) 13 (13)

Biochemical failure

(Phoenix)

9 (14.8) 6 (15.4) 15 (15)

Biochemical failure

(ASTRO)

12 (19.7) 7 (17.9) 19 (19)

Prostate cancer death 4 (6.6) 0 (0) 4 (4)

Noneprostate cancer death 4 (6.6) 2 (5.1) 6 (6)

ASTRO5American Society for Therapeutic Radiology and Oncology.a Local, regional, or distant failure, whichever came first.

Interestingly, hormonally untreated patients had a trendfor a better 5-year biochemical control rate compared withmen receiving AD (100% vs. 83.4%; p5 0.0682). On theother hand, the 5-year probability for bNED after long-term (O12 months) AD was significantly higher than thatafter shorter (!12 months) duration of endocrine treatment(92.9% vs. 72.2%; p5 0.0237).

Early complications and late side effects

Early complications were few and reversible in all cases.Acute Grade 2 and 3 gastrointestinal (GI) side effectsoccurred in 15 and 1 patients, respectively. The correspond-ing rates of Grade 2 and 3 acute genitourinary (GU)complications were 37% and 3%. Late radiation side effectsare listed in Table 6. Only few (n5 2) severe late rectalcomplications were observed, with a 5-year actuarial rateof 2.1%. Grade 3 late GU side effects occurred in14 patients, with a 5-year actuarial rate of 14.4%. The mostfrequent Grade 3 GU complication was urethral stricture(n5 12) and hemorrhagic cystitis (n5 2). These patientsrequired endourethral incision or transurethral resection

Fig. 1. Time to biochemical failure according to risk group by Kaplane

Meier estimates. bNED5 biochemical no evidence of disease.

Fig. 2. Time to biochemical failure according to grade by KaplaneMeier

estimates. bNED5 biochemical no evidence of disease.Fig. 3. Time to G3 GU side effect according to pre-RT TURP by Kaplane

Meier estimates. G35 grade 3; GU5 genitourinary; RT5 radiotherapy;

TURP5 transurethral resection of the prostate.

5P. �Agoston et al. / Brachytherapy - (2011) -

of the prostate (TURP) after RT. Incontinence after postir-radiation TURP occurred in 4 patients (4%). The mediantime to late Grade 3 GU toxicity was 24 months (12e48months). Six of 14 patients with late Grade 3 GU toxicityhad undergone TURP before RT. The 5-year probabilityof developing Grade 3 late GU side effects with or withoutpre-RT TURP was 29.1% and 8.8% ( p5 0.0047), respec-tively (Fig. 3). However, the risk of developing late GIand/or GU side effects was similar in patients treated withor without endocrine therapy ( p5 0.5474).

Discussion

RT is one of the treatment choices for patients withlocalized intermediate- and high-risk prostate cancer. Thereare two main strategies to achieve better tumor control withRT: AD added to RT and dose escalation to the prostate (20,21). Hormone therapy combined with RT is associated withsignificant clinical benefits in patients with localized orlocally advanced prostate cancer (22). Not only adjuvanthormone therapy provides better local control, but alsothere is evidence for a significant survival advantage (23).In a meta-analysis of randomized trials, high-dose RT was

Table 6

Late radiation side effects

Side effect Cumulative toxicity Toxicity at the last followup

Late GI

Grade 0 37 67

Grade 1 42 25

Grade 2 19 7

Grade 3 2 1

Late GU

Grade 0 11 36

Grade 1 44 42

Grade 2 31 13

Grade 3 14 8

GI5 gastrointestinal; GU5 genitourinary.

found to be superior to conventional-dose (!70 Gy) RTin preventing biochemical failure in all risk groups;however, there was no significant difference in CSS andOS between high- and conventional-dose groups (24).

Boost dose can be given by particle beam (25), perma-nent seed implantation (26), 3D-CRT (27), intensity-modulated radiotherapy (IMRT) (28e30), and conformalHDR-BT (31e34). HDR-BT is a promising and safe solu-tion to deliver high biologically equivalent dose to the pros-tate, while keeping the dose to normal tissues low.Advantages of the HDR afterloading technique includeprecise irradiation without geographic miss of the tumorbecause of prostate fixation and image guidance. Placementof the needles is controlled real time by TRUS; thus, theplanned and delivered doses are virtually identical. Takingthe advantage of low a/b ratio of the prostate tissue(between 1.2 and 3 Gy), hypofractionated HDR-BT couldbe the most effective way to deliver high biologic equiva-lent dose. Cost-effectiveness is a great advantage ofHDR-BT over lowedose rate permanent seed implantationboost technique.

Different HDR-BT fractionation schedules are publishedin the literature (7e9). A single implantation using multiplefractions limits the harms of multiple invasive proceduresand anesthesia. However, movement of the implanted cath-eters can be significant, and position of the needles shouldbe checked before each fraction. Hoskin et al. (35) founda mean value of 11.5 mm interfraction movement of cathe-ters within the prostate away from the base of the prostate.This could lead to significant dosimetric changes, unlesscorrection is made.

The use of multiple implantations with single-fractionirradiation increases the consequence of multiple invasiveprocedures but has an advantage of real-time catheterplacement and precise dosimetry at each fraction.

We have implemented a single-fraction HDR-BT boosttechnique to achieve moderate dose escalation after 60 GyEBRT (36). A dose of 10 Gy used as a single-fraction

6 P. �Agoston et al. / Brachytherapy - (2011) -

HDR-BT boost is in agreement with the European guidelinefor HDR-BT treatments (37). Encouraging 5-year biochem-ical and clinical tumor control could be achieved witha moderate dose escalation using a single HDR-BT fractionof 10 Gy. The 5-year actuarial bNED rate for the entire cohortwas 85%, despite 61% of our patients had high-risk prostatecancer. Others reported lower rates of 5-year bNED (73%bNED for the group treated by 74 Gy) by dose escalationusing 3D-CRT (38). Furthermore, our results compare favor-ablywith bNED rates achieved by IMRT, delivering the high-est dose possible by EBRT (39). In a Dutch randomized doseescalation trial, the efficacy of 68 vs. 78 Gy was comparedin 699 patients (including 55% high-risk patients), andthe probability of 5-year bNED was reported as 74% forthe high-dose group (40). In a prospective trial from Massa-chusetts, 393 patients (including only 8% high-risk patients)were randomized to receive EBRT to a total dose of either70.2 or 79.2 Gy (41). The 5-year bNED rate was 61% forthe conventional-dose therapy and 80% for the high-dosetherapy ( p!0.001). In the largest European dose escalationtrial using 3D-CRT technique, 883 patients (including 45%high-risk patients) received either 64 or 74 Gy (27). The5-year actuarial bNED rate was 60% for the low-dose groupand 71% for the high-dose group. In a retrospective compar-ison from the Mayo Clinic, different forms of EBRT doseescalation were evaluated (39). The 5-year bNED rates were74% for 3D-CRTand 87% for IMRT. However, only 15% ofpatients had high-risk disease.

Results of HDR-BT boost series are summarized inTable 7. Comparison of the results between different seriesis difficult because of differences in the use of AD, EBRTdose, and HDR fractionation schedules. Furthermore, it isto be noted that our patient group consisted of morepatients (61%) with high-risk disease than in most otherseries. Galalae et al. (33) reported the results of 611patients (including similar, 61% proportion of high-riskpatients) treated in three prospective trials. The 5-yearbNED rate of 77% was reported using the first AmericanSociety for Therapeutic Radiology and Oncology definitionfor biochemical failure (three consecutive elevation of thePSA after the nadir). Only short course of AD was applied.Recently, authors from the Catalan Institute of Oncologyreported their result of 114 patients (including 86% withhigh-risk features) using a treatment protocol (60 GyEBRTþ 9 Gy HDR-BT) similar to ours (8). After a rela-tively short followup of 2.7 years, encouraging results(4-year bNED rate of 97.4%) were reported. However,90% of their patients received long-term (3 years) completeAD, which probably postpones the occurrence of biochem-ical failure. Authors from Taiwan published results of 85patients (including 50% high-risk patients) using AD in58% (48). Their 4-year bNED rate of 86% using thePhoenix definition compares favorably with our 5-yearbiochemical control rate of 85%.

In the present study, we did not find significant differ-ence between the 5-year bNED rates for intermediate-

and high-risk patients (84.2% vs. 86.4%). This can bepartially attributed to our clinical practice using routinelong-term AD for high-risk patients. Furthermore, pelviclymph node irradiation was given more often to high-risk patients compared with intermediate-risk patients(96.7% vs. 2.6%). Although, the benefit of treating pelviclymph nodes is debatable, published data suggest that itmay improve outcomes for patients with prostate cancerif the risk of lymph node involvement is significant (51).All major, prospective, randomized trials that have beencompleted to date suggest that long-term (O2 years) ADimproves survival in patients with locally advanced, high-risk prostate cancer that is managed with EBRT (23). Thisfinding was also confirmed by our study as the 5-yearbNED rate after long-term (O12 months) AD was signifi-cantly higher than that after shorter (!12 months) AD(92.9% vs. 72.2%; p5 0.0237).

Rare and reversible severe acute toxicity was found. Therates of late GI and GU side effects in other HDR-BT boostseries are summarized in Table 8. Late GI toxicity is lowand comparable with that reported by others (2, 6, 7).The 5-year actuarial rate (14.4%) of late GU side effectsin our series is somewhat higher compared with otherseries. However, interpretation and comparison of toxicitydata are difficult as most other series report only the cruderate of toxicity at a given time point (instead of actuarialfigures) or use different scoring systems (7, 47, 49). Fortu-nately, 6 of 14 patients (43%) developing Grade 3 GUcomplications were treated efficiently by minor surgicalintervention. Therefore, the ultimate rate of late Grade 3GU complications at the last followup was decreased to8%, which is fairly comparable with that reported by others(Table 8.). Four patients (4%) suffered from moderate orsevere incontinence during their followup. This rate is stillcomparable with the best toxicity data reported from lapa-roscopic radical prostatectomy series (52). In our series, theincidence of developing Grade 3 late GU side effects wassignificantly higher for patients having pre-RT TURP(29.1%) compared with those without pre-RT intervention(8.8%; p5 0.0047). This observation corresponds withothers’ experience (45).

Conclusion

Our series proves that a single-implant, single-fractionHDR-BT boost added to EBRT using pelvic irradiationand long-term AD in case of high-risk prostate cancer isan effective treatment for patients suffering from localizedor locally advanced prostate cancer. Despite the highproportion of high-risk patients in the present study, the5-year actuarial biochemical control rate for the entirecohort was 85.5%. Acute and late GI toxicity were rareafter HDR-BT boost. However, pre-RT TURP significantlyincreases the risk of developing late Grade 3 GU sideeffects. Therefore, HDR-BT boost should be given with

Table 7

Results of prostate HDR-BT boost series

Institute

No. of

patients

High-risk

patients (%)

Median

FUP (yr)

EBRT

dose (Gy)

HDR-BT

dose (Gy)

5-yr bNED %

(Phoenix)

5-yr bNED %

(ASTRO) 5-yr LR (%)

5-yr DFS

(%)

5-yr CSS

(%)

5-yr OS

(%)

Kiel-WBH-SPI (33) 611 61 5 45.6e50 8e9� 2; 3e4� 4;

5.5e6� 3; 8.25e11.5� 2

NR 77 7.4 67 96 85

Univ. Berlin (42) 444 NR 3.3 45e50.4 9e10� 2 NR NR; T1: 100; T2:

70; T3: 65

4.7a 98 95 93

Univ. Gothenburg (43) 214 22 4 50 10� 2 NR 82 1.4a 91 97 89

CET (6) 209 22 7.25 36 5.5e6� 4 91 87 0.5a NR 97a 79a

Sao Paulo (44) 209 32 5.3 36e54 4e6� 4 95.7 NR NR NR NR 95.7

WBH (2) 197 !34 4.9 46 5e6.5� 3; 8.25e11.5� 2 NR 78.4 4.8 90.2 98.3 92.9

Radiumhemmet (31) 154 NR 6.1 50 10� 2 NR 84b 0 NR 94a 84a

Qu�ebec Univ.(45) 153 14 3.7 40e44 6e6.5� 3; 9e10� 2 95.8 96 6.4a NR NR 97.1

Catalan Inst. Oncol. (8) 114 86 2.7 60 9� 1 97.4c NR NR NR NR NR

Mount Vernon Hosp. (46) 109 NR 6.1 35.75 8.5� 2 80c NR NR NR NR 94c

Offenbach (7) 102 NR 2.6 39.6e45 5e7� 4 NR 82d 2a 95.1a 98d 90d

Chang Gung Univ. (47) 85 50 4.1 50.4 5.5� 3 86c NR 1.2a 96.5a NR NR

Kanazawa Univ. (48) 84 NR 1.7 44 6� 3 NR 82.6c NR NR NR 87.2c

Kawasaki Med. Sc. (49) 71 NR 3.7 41.8e45 5.5� 3e4 NR 93 0 98.6a 100 95

Wakayama Univ. (50) 53 58 5.1 50 7.5� 2 72d NR NR NR 100 88.1

Recent study 100 61 5.1 60 10� 1 85.5 80.3 2.3 89.3 99.0 93.3

All patients 2909 14e86 1.7e7.25 35.75e60 3e11.5� 1e4 80e97.4 77e96 0e7.4 67e98.6 94e100 79e97.1

HDR-BT5 highedose rate brachytherapy; FUP5 followup period; EBRT5 external beam radiotherapy; bNED5 biochemical no evidence of disease; ASTRO5American Society for Therapeutic Radi-

ology and Oncology; LR5 local recurrence; DFS5 disease-free survival; CSS5 cause-specific survival; OS5 overall survival; WBH5William Beaumont Hospital; SPI5 Seattle Prostate Institute; Univ.5

university; CET5California Endocurietherapy Cancer Center; Inst. Oncol.5 Institute of Oncology; Hosp.5 hospital; Med. Sci.5medical school; NR5 not reported.a Crude rate.b bNED was defined at prostate-specific antigen levels!2 mg/L.c 4-year actuarial rate.d 3-year actuarial rate.

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al./Brachyth

erapy

-(2011)-

Table 8

Late G3eG4 toxicity in HDR-BT boost series

Institute

No. of

patients

Median

FUP (yr)

EBRT

dose (Gy)

HDR-BT

dose (Gy)

5-yr G3eG4 GI

toxicity (%)

5-yr G3eG4 GU

toxicity (%)

Univ. Berlin (42) 444 3.3 45e50.4 9e10� 2 1.7 10.5a

Univ. Gothenburg (43) 214 4 50 10� 2 0 10

CET (6) 209 7.25 36 5.5e6� 4 0 6.7

Sao Paulo (44) 209 5.3 36e54 4e6� 4 0 0

WBH (2) 197 4.9 46 5e6.5� 3; 8.25e11.5� 2 2.3 4.5

Offenbach (7) 102 2.6 39.6e45 5e7� 4 1 4.9a

Chang Gung Univ. (47) 85 4.1 50.4 5.5� 3 0 5a

Kanazawa Univ. (48) 84 1.7 44 6� 3 NR 8.2

Kawasaki Med. Sc. (49) 71 3.7 41.8e45 5.5� 3e4 0 5.6a

Wakayama Univ. (50) 53 5.1 50 7.5� 2 0 0

Recent study 100 5.1 60 10� 1 2.1 14.4

All patients 1768 1.7e7.25 36e60 4e11.5� 1e4 0e2.3 0e14.4

HDR-BT5 highedose rate brachytherapy; FUP5 followup period; EBRT5 external beam radiotherapy; G5 grade; GI5 gastrointestinal; GU5 geni-

tourinary; Univ.5 university; CET5California Endocurietherapy Cancer Center; WBH5William Beaumont Hospital; Med. Sci.5medical school;

NR5 not reported.a Crude rate.

8 P. �Agoston et al. / Brachytherapy - (2011) -

caution to patients who underwent previous TURP. Correla-tions between dosimetric parameters and late GU complica-tions need further investigations.

References

[1] Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D.

Anderson randomized dose-escalation trial for prostate cancer. Int J

Radiat Oncol Biol Phys 2008;70:64e74.[2] Vargas CE, Martinez AA, Boike TP, et al. High-dose irradiation for

prostate cancer via a high-dose-rate brachytherapy boost: Results of

a phase I to II study. Int J Radiat Oncol Biol Phys 2006;66:416e423.

[3] Li XA, Zwang JJ, Stewart RD, et al. Designing equivalent treatment

regimens for prostate radiotherapy based on equivalent uniform dose.

Br J Radiol 2008;8:59e68.

[4] King CR, Fowler JF. A simple analytic derivation suggests that pros-

tate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001;

51:213e214.

[5] Kestin LL, Martinez AA, Stromberg JS, et al. Matched-pair analysis

of conformal high-dose-rate brachytherapy boost versus external-

beam radiation therapy alone for locally advanced prostate cancer.

J Clin Oncol 2003;18:2869e2880.

[6] Demanes DJ, Rodriguez RR, Schour L, et al. High-dose-rate

intensity-modulated brachytherapy with external beam radiotherapy

for prostate cancer: California endocurietherapy’s 10-year results.

Int J Radiat Oncol Biol Phys 2005;61:1306e1316.

[7] Martin T, R€oddiger S, Kurek R, et al. 3D conformal HDR brachyther-

apy and external beam irradiation combined with temporary

androgen deprivation in the treatment of localized prostate cancer.

Radiother Oncol 2004;71:35e41.

[8] Pistis F, Guedea F, Pera J, et al. External beam radiotherapy plus

high-dose-rate brachytherapy for treatment of locally advanced pros-

tate cancer: The initial experience of the Catalan Institute of

Oncology. Brachytherapy 2010;9:15e22.

[9] Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using

conformal high-dose-rate brachytherapy improves outcome in unfavor-

able prostate cancer. Int J Radiat Oncol Biol Phys 2002;53:316e327.

[10] Monroe AT, Faricy PO, Jennings SB, et al. High-dose-rate brachy-

therapy for large prostate volumes (O or 550cc)dUncompromised

dosimetric coverage and acceptable toxicity. Brachytherapy 2008;7:

7e11.

[11] Slessinger ED. Practical considerations for prostate HDR brachyther-

apy. Brachytherapy 2010;9:282e287.

[12] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical

outcome after radical prostatectomy external beam radiation therapy,

or interstitial radiation therapy for clinically localized prostate

cancer. JAMA 1998;280:969e974.

[13] American Joint Committee on Cancer. Prostate. In: Greene FL,

Page DL, Fleming ID, et al, editors. AJCC cancer staging manual.

6th ed. New York, NY: Springer-Verlag; 2002. p. 301e305.

[14] Fr€ohlich G, Agoston P, L€ovey J, et al. Dosimetric evaluation of high-

dose-rate interstitial brachytherapy boost treatments for localized

prostate cancer. Strahlenther Onkol 2010;186:388e395.

[15] Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical

failure following radiotherapy with or without hormonal therapy in

men with clinically localized prostate cancer: Recommendations of

the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat On-

col Biol Phys 2006;65:965e974.

[16] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy

Oncology Group (RTOG) and the European Organization for

Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol

Phys 1995;31:1341e1346.

[17] Kaplan EL, Meier P. Non-parametric estimation from incomplete

observation. J Am Stat Assoc 1958;53:457e481.

[18] Cox DR. Regression models and life tables. J R Stat Soc 1972;34:

187e220.

[19] Mantel N. Evaluation of survival data and two new rank order statis-

tics arising in its consideration. Cancer Chemother Rep 1966;50:

163e170.

[20] Lee AK. Radiation therapy combined with hormone therapy for pros-

tate cancer. Semin Radiat Oncol 2006;16:20e28.

[21] Mangar SA, Huddart RA, Parker CC, et al. Technological advances

in radiotherapy for the treatment of localised prostate cancer. Eur J

Cancer 2005;41:908e921.[22] Bolla M, Descotes JL, Artignan X, et al. Adjuvant treatment to radi-

ation: Combined hormone therapy and external radiotherapy for

locally advanced prostate cancer. BJU Int 2007;100(Suppl. 2):44e47.

[23] Kumar S, Shelley M, Harrison C, et al. Neo-adjuvant and adjuvant

hormone therapy for localised and locally advanced prostate cancer.

Cochrane Database Syst Rev 2006;(4). CD006019.

[24] Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radia-

tion doses in localized prostate cancer treatment: A meta-analysis

of randomized, controlled trials. Int J Radiat Oncol Biol Phys

2009;74:1405e1418.

[25] Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing

conventional-dose with high-dose conformal radiation therapy in

early-stage adenocarcinoma of the prostate: Long-term results from

9P. �Agoston et al. / Brachytherapy - (2011) -

Proton Radiation Oncology Group/American College of Radiology

95-09. J Clin Oncol 2010;28:1106e1111.

[26] Jabbari S, Weinberg VK, Shinohara K, et al. Equivalent biochemical

control and improved prostate-specific antigen nadir after permanent

prostate seed implant brachytherapy versus high-dose three-

dimensional conformal radiotherapy and high-dose conformal proton

beam radiotherapyboost. Int JRadiatOncol Biol Phys2010;76:36e42.

[27] Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus

standard-dose conformal radiotherapy in prostate cancer: First results

from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;

8:475e487.

[28] Al-Mamgani A, Heemsbergen WD, Peeters ST, et al. Role of

intensity-modulated radiotherapy in reducing toxicity in dose escala-

tion for localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;

73:685e691.

[29] Solaiappan G, Singaravelu G, Prakasarao A, et al. Influence of

photon beam energy on IMRT plan quality for radiotherapy of pros-

tate cancer. Rep Pract Oncol Radiother 2009;14:18e31.

[30] Derbyshire S, Morgan AM, Thompson RCA, et al. Optimal planning

parameters for simultaneous boost IMRT treatment of prostate cancer

using a beam modulator. Rep Pract Oncol Radiother 2009;14:

205e213.

[31] K€alkner KM, Wahlgren T, Ryberg M, et al. Clinical outcome in

patients with prostate cancer treated with external beam radiotherapy

and high dose-rate iridium 192 brachytherapy boost: A 6-year follow-

up. Acta Oncol 2007;46:909e917.

[32] Yoshioka Y, Konishi K, Oh RJ, et al. High-dose-rate brachytherapy

without external beam irradiation for locally advanced prostate

cancer. Radiother Oncol 2006;80:62e68.

[33] Galalae RM, Martinez A, Mate T, et al. Long-term outcome by risk

factors using conformal high-dose-rate brachytherapy (HDR-BT)

boost with or without neoadjuvant androgen suppression for localized

prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:1048e1055.

[34] Yamada Y, Bhatia S, Zaider M, et al. Favorable clinical outcomes of

three-dimensional computer-optimized high-dose-rate prostate bra-

chytherapy in the management of localized prostate cancer. Brachy-

therapy 2006;5:157e164.

[35] Hoskin PJ, Bownes PJ, Ostler P, et al. High dose rate afterloading

brachytherapy for prostate cancer: Catheter and gland movement

between fractions. Radiother Oncol 2003;68:285e288.

[36] Agoston P, Major T, Somogyi A, et al. [Brachytherapy boost irradi-

ation in the treatment of high risk, localised prostate cancer. Initial

national experience in Hungary]. Magy Onkol 2004;48:81e88.

[in Hungarian].

[37] Kov�acs G, P€otter R, Loch T, et al. GEC/ESTRO-EAU recommenda-

tions on temporary brachytherapy using stepping sources for local-

ised prostate cancer. Radiother Oncol 2005;74:137e148.

[38] Goldner G, Dimopoulos J, Kirisits C, et al. Moderate dose escalation in

three-dimensional conformal localized prostate cancer radiotherapy:

Single-institutional experience in 398 patients comparing 66Gy versus

70 Gy versus 74 Gy. Strahlenther Onkol 2009;185:438e445.

[39] Wong WW, Vora SA, Schild SE, et al. Radiation dose escalation for

localized prostate cancer: Intensity-modulated radiotherapy versus

permanent transperineal brachytherapy. Cancer 2009;115:

5596e5606.

[40] Peeters STH, Heemsbergen WD, Kope PCM, et al. Dose-response in

radiotherapy for localized prostate cancer: Results of the Dutch

multicenter randomized Phase III trial comparing 68 Gy of radio-

therapy with 78 Gy. J Clin Oncol 2006;24:1990e1996.

[41] Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of

conventional-dose vs high-dose conformal radiation therapy in clini-

cally localized adenocarcinoma of the prostate: A randomized

controlled trial. JAMA 2005;294:1233e1239.

[42] Deger S, Boehmer D, T€urk I, et al. High dose rate brachytherapy of

localized prostate cancer. Eur Urol 2002;41:420e426.

[43] Astr€om L, Pedersen D, Mercke C, et al. Long-term outcome of high

dose rate brachytherapy in radiotherapy of localised prostate cancer.

Radiother Oncol 2005;74:157e161.

[44] Pellizzon AC, Salvajoli J, Novaes P, et al. Updated results of high-

dose rate brachytherapy and external beam radiotherapy for locally

and locally advanced prostate cancer using the RTOG-ASTRO

Phoenix definition. Int Braz J Urol 2008;34:293e301.

[45] Bachand F, Martin AG, Beaulieu L, et al. An eight-year experience of

HDR brachytherapy boost for localized prostate cancer: Biopsy and

PSA outcome. Int J Radiat Oncol Biol Phys 2009;73:679e684.

[46] Hoskin PJ, Motohashi K, Bownes P, et al. High dose rate brachyther-

apy in combination with external beam radiotherapy in the radical

treatment of prostate cancer: Initial results of a randomised phase

three trial. Radiother Oncol 2007;84:114e120.

[47] Chen YC, Chuang CK, Hsieh ML, et al. High-dose-rate brachyther-

apy plus external beam radiotherapy for T1 to T3 prostate cancer: An

experience in Taiwan. Urology 2007;70:101e105.

[48] Shigehara K, Mizokami A, Komatsu K, et al. Four year clinical

statistics of iridium-192 high dose rate brachytherapy. Int J Urol

2006;13:116e121.[49] Hiratsuka J, Jo Y, Yoshida K, Nagase N. Clinical results of combined

treatment conformal high-dose-rate iridium-192 brachytherapy and

external beam radiotherapy using staging lymphadenectomy for

localized prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:

684e690.

[50] Sato M, Mori T, Shirai S. High-dose-rate brachytherapy of a single

implant with two fractions combined with external beam radio-

therapy for hormone-naive prostate cancer. Int J Radiat Oncol Biol

Phys 2008;72:1002e1009.

[51] Roach M III, DeSilvio M, Valicenti R, et al. Whole-pelvis, ‘‘mini-

pelvis,’’ or prostate-only external beam radiotherapy after neoadju-

vant and concurrent hormonal therapy in patients treated in the

Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol

Biol Phys 2006;66:647e653.

[52] Novara G, Ficarra V, D’elia C, et al. Evaluating urinary continence

and preoperative predictors of urinary continence after robot assisted

laparoscopic radical prostatectomy. J Urol 2010;184:1028e1033.