Single application of high-intensity focused ultrasound as primary therapy of localized prostate cancer:Treatment-related predictors of biochemical outcomes

Dietrich Pfeiffer＊,Juergen Berger,Andres Gross

aDepartment of Urology,Asklepios Hospital Hamburg-Barmbek,Hamburg,Germany

bCenter of Experimental Medicine,Institute of Medical Biometry and Epidemiology,University Medical Center Hamburg-Eppendorf,Hamburg,Germany

ORIGINAL ARTICLE

Single application of high-intensity focused ultrasound as primary therapy of localized prostate cancer:Treatment-related predictors of biochemical outcomes

Dietrich Pfeiffera,＊,Juergen Bergerb,Andreas Grossa

aDepartment of Urology,Asklepios Hospital Hamburg-Barmbek,Hamburg,Germany

bCenter of Experimental Medicine,Institute of Medical Biometry and Epidemiology,University Medical Center Hamburg-Eppendorf,Hamburg,Germany

Prostate cancer;

High-intensity

focused ultrasound;

Efficacy;

Biochemical failure;

Prostate edema;

Patient movement

Objective:Recent reports on high-intensity focused ultrasound(HIFU)treatment of localized prostate cancer suggest that preoperative risk groups of tumor recurrence are strong predictors of oncological outcomes.The purpose of this study is to determine the prognostic significance of treatment-related factors in relation to patient characteristics for biochemical outcomes after HIFU.

Methods:This retrospective single-center study included patients treated from December 2002 to December 2010 for localized prostate cancer with two generations of Ablatherm?HIFU devices(A1 and A2).All the patients underwent single HIFU treatment session under the concept of whole-gland therapy.Prostate surgery was performed before HIFU to downsize enlarged glands.Androgen deprivation therapy(ADT)was discontinued before HIFU.Biochemical failure(BCF)was defined as prostate specific antigen(PSA)nadir+1.2 ng/mL(Stuttgart definition).Predictors of BCF were determined using Cox regression models.As covariates, patient-related factors(age,tumor characteristics,ADT)were compared with treatmentrelated factors(prostate volume,HIFU device generation,conduct of therapy,prostate edema,patient movement,anesthetic modalities).

Results:Three hundred and twenty-three(98.8%)out of 327 consecutive patients were evaluable for BCF.Median(interquartile range)follow-up was 51.2(36.6—80.4)months.The overall BCF-rate was 23.8%.In multivariate analyses,higher initial PSA-values(Hazard ratio[HR]:1.03;p＜0.001)and higher D’Amico risk stages(HR:3.45;p＜0.001)were patient-related predictors of BCF.Regarding treatment-related factors,the A2 HIFU device was associated with a decreased risk of BCF(HR:0.51;p=0.007),while prostate edema had an adverse effect(HR:1.8;p=0.027).Short follow-up and retrospective study design are the primary limitations.

Conclusion:Success in a single HIFU session depends not merely on tumor characteristics,but also on treatment-related factors.Ablation is more efficacious with the technically advanced A2 HIFU device.Heat-induced prostate edema might adversely affect the outcome.

?2015 Editorial Office of Asian Journal of Urology.Production and hosting by Elsevier (Singapore)Pte Ltd.This is an open access article under the CC BY-NC-ND license(http:// creativecommons.org/licenses/by-nc-nd/4.0/).

1.Introduction

High-intensity focused ultrasound(HIFU)is a non-surgical, minimal invasive procedure that enables ablation of the prostatein situ.Extensive experience in treating clinically localized prostate cancer(PCa)has been gained using Ablatherm?HIFUdevices(EDAP-TMS,Vaulx-en-Velin, France).The curative potential was already recognized in 1996 with the use of a prototype[1].Since then,the oncologic efficacy has been evaluated with two commercially available devices.Recently,oncologic outcomes have beenreportedfromlargestudies[2—4].Allreports demonstrate that the efficacy of HIFU treatment is associated with the risk stages of tumor recurrence[5],which illustrates the strong influence of preoperative tumor characteristics.

By contrast,the impact of treatment-related factors on cancer control is not well documented.

The principles of a complete prostate ablation(wholegland therapy)as a prerequisite of complete tumor eradication have been delineated recently[6,7].Whether the evolving HIFU technology is associated with improving outcomes in patients treated under these principles has still to be determined[2].Moreover,variations in planning and conducting whole-gland therapy might affect the outcomes.In addition,intraoperative prostate edema or unintentional patient movements might interfere with the treatment plan and influence the results of therapy.

The present retrospective single-center study reports on biochemical outcomes after whole-gland treatment of localized PCa involving two generations of Ablatherm?HIFU devices.We focused on the efficacy of a single HIFU application and determined whether treatment-related factors(prostatevolume,HIFUdevicegeneration, conduct of treatment,prostate edema,patient movement, anesthetic modalities)have prognostic significance as outcome predictors independent of preoperative patient characteristics.

2.Methods

2.1.Patients

The records of all patients with clinically localized PCa who underwent a single session of whole-gland HIFU treatment asa first-linetherapy withcurative intentbetween December 2002 and December 2010 were assessed retrospectively.All men were unsuitable candidates for radical prostatectomy because of age or comorbidity and were unwilling to undergo radiotherapy.Extracapsular tumor extension and lymph node status was assessed with pelvic CT or MRI.Staging included a bone scan in patients with prostate speci fic antigen(PSA)≥10 ng/mL,and laparoscopic lymphadenectomy was recommended in patients with PSA＞20 ng/mL.Androgen deprivation therapy(ADT) was discontinued at the time of HIFU therapy.

Excluded from the study were patients with nervesparing HIFU ablation(preserving the neurovascular bundles by sparing the lateral prostate regions[8]),and patients with nodal extension or metastatic disease.

2.2.HIFU technology

Treatment involved two gen?erations of Ablatherm?devices,the Ablatherm Maxisand Ablatherm Integrated Imaging?(afterFebruary2006),hereafteraddressed respectively as device A1 and A2.Both devices comprised a 3 MHz therapeutic and a 7.5 MHz imaging transducer.The treatment transducer generates a focused ultrasound field and creates spindle-shaped elementary lesions of 1.7 mm in diameter by heat(85—100°C)and cavitation.By variable focusing,the focal length is adjustable(19—26 mm) together with the rectum distance length(3—8 mm).The maximum penetration depth in prostatic tissue is limited to 30 mm[3].The treatment-head moves computer-driven andlargertargetvolumescanbeablatedthrough repeated shots in juxtapositions.With the more advanced A2 device a new electronic probe with optimized treatment parameters was introduced which allows direct visual control of the procedure via transrectal ultrasound(TRUS) [9].Local movements of the applicator system were reduced,thus providing a more accurate targeting of the prostate[10].

2.3.Standard planning and conduct of treatment

The intention of whole-gland therapy is destruction of the prostate with a safety margin of 6 mm from the apex to preserve the urethral sphincter.The ablation technique should avoid leaving gaps of untreated tissue at prostate margins and within the gland[6].In patients at risk of extracapsular tumor extension,the treatment can be extendedbymillimetersbeyondthelateralorgan boundaries[7].A safety margin of at least 3 mm is maintained around the rectum.In patients with enlarged prostate glands,prostate surgery is performed prior to HIFU in order to ensure that the anterior prostate margins are within the limited spatial span of the ultrasound focus[3].

In treatment planning,the prostate is divided into several cranio-caudal blocks which are planned and treated separately[7].Within each block the apical safety margin and the treatment boundaries are de fined using transverse and longitudinal ultrasound images.Planning proceeds stepwise from the apex to the bladder neck.Within each step the corresponding transverse ultrasound image is used to determine the number of target lesions,to adjust the focal length to the anterior-posterior prostate diameter and to de fine the distance from the rectal wall.The blocks are planned with overlapping target lesions.The conduct of the procedure is automated and follows the plan accurately [11].

2.4.Data acquisition

All statistical analysis was performed using StataSE v.13 (StataCorp LP,College Station,USA).For the purposes of this retrospective study,patient characteristics and treatment data were analyzed using prospectively collected data of an Access database(since 2002)and the individual treatment protocols.Patients were strati fied into risk categories of tumor recurrence according to D’Amico et al.[5]. Criteria for the high-risk category were modi fied to include patients with pathological stages cT3A and cT3B(TNM 2002).Treatment protocols provided detailed information on the conduct of therapy with each procedure,including the block strategy(number of treated blocks)and the type ofapproach.Wedistinguishedbetweenastandard approach,following exactly the pre-plan,and an approach with adjustments of the plan to varying treatment conditions.Adjustments,madeeitheralongtheanteriorposterior,cranio-caudal or latero-lateral prostate axis, included the targeting of additional areas and modi fications in the length(reduction,extension)of the planned treatment blocks.The protocols were also assessed for records of prostate edema and patient movement.In patients with prostate edema the shift in prostate height and/or rectoprostatic distance was estimated by comparing ultrasound images taken at the beginning and the end of treatment near the mid-prostate.Measurements were made using ImageJ image processing software[12].

For this study all available postoperative PSA values were analyzed,which were either assessed in our clinic or by the referring urologists.Biochemical relapse was de fined as PSA nadir+1.2 ng/mL(Stuttgart de finition[13]).Followup period was de fined as the interval between HIFU treatment and the last available PSA values or death.

2.5.Statistical analysis

Patient characteristics and treatment variables(prostate measurements,conduct of therapy)were summarized in frequencytables,cross-tabulatedwithsubgroups,by Ablatherm?HIFU devices,occurrence of prostate edema, andpatientmovement.Categoricalvariableswere expressed as percentages and compared using Fisher’s exact test.Quantitative variables were reported as median and interquartile range(IQR)and compared with the Mann—WhitneyU-test.The Cox regression model was used in the univariate and multivariate analysis of the prognostic relevance of preoperative and intraoperative factors of biochemical progression.Backward elimination was used and only the final model is given.The Kaplan—Meier method was used to construct survival curves,which were compared using the log-rank test.Ap-value＜0.05 was considered statistically significant.

3.Results

Totally 327 consecutive patients underwent a single session of whole-gland HIFU therapy between December 2002 and December 2010.Median(IQR)age was 70(66.5—74.0) years.Baseline patient characteristics are summarized in Table 1.The number of patients treated with the HIFU devices A1 and A2 were 139(42.5%)and 188(57.5%), respectively.In all,112(34.2%)men received ADT prior to HIFU for a median(interquartile range,IQR)duration of 2.4(1.3—5.6)months.Two hundred and sixty-four(80.7%) patientswithenlargedprostateglands(anterior—posterior diameter＞3 cm[TRUS])underwent procedures to reduce the prostate size(TURP,n=258; adenomectomy,n=6).In the post-surgery group,the median(IQR)prostate volume at the time of HIFU treatment was lower(17[13—21]mL)than in the group without surgery(21[16—24]mL)(p=0.001).

Table 2 summarizes the treatment data of the whole study population and of subgroups,by generations of HIFU devices,occurrenceofprostateedema,andpatient movement,respectively.In general,prostate volumes had been reduced sufficiently by previous surgery to ensure that the prostate height(pre-plan)corresponded to the limited length of the ultrasound focus(26 mm)and anterior prostate margins were exposed to HIFU.With most patients a 2-block-strategy and standard approach was used.In 93 (28.4%)men,the operator decided for adjustments during the procedure,either ablation of additional areas(n=51) or modifications in the length of the treatment blocks (n=42).

With the A1 device,HIFU was more often delivered using a 3-to-4-block-strategy and the operator decided more often for adjustments,which explains the higher number of elementary lesions,the higher treatment volume(computed sum of single lesion volumes)and the longer treatment duration compared with that seen for the A2 device.

Similarly,in 43(13.1%)patients with prostate edema, the therapy conducted was more extensive than that in the remainder(Table 2).The measured shift in prostate height was a median(IQR)of 5.2(3.6—7.3)mm and the prostatorectal shift was 3.6(0.4—5.3)mm,indicating both prostaticandperiprostaticswelling.Atmidprostate,the maximum diameter between the anterior prostate margin andtherectalwallwasamedian(IQR)of36.9(33.3—38.5)mm and the anterior gap not treatable by HIFU due to limited penetration depth of HIFU was 6.6(4.3—8.6)mm.These patients exhibited a significantly higher prostate volume and height at pre-plan(Table 2).Moreover,18.7%(21/ 112)of patients with previous ADT and 10.2%(22/215) without ADT exhibited prostate edema(p=0.038). Conversely,edema occured in 9.5%(25/264)of patients with previous prostate surgery and in 28.6%(18/63) without surgery(p＜0.001).

Table 1 Baseline characteristics in 327 patients and in subgroups by Ablatherm?HIFU devices A1 and A2.

Unintentional movement ocurred in 63(19.3%)patients and required intraoperative adjustments of the procedure more frequently(Table 2).Fifty-seven men exhibited movements under spinal anesthesia and i.v.sedation due to agitation or cough and six men moved under shallow general anesthesia.The procedure was discontinued in four men treated under spinal anesthesia and interrupted in the remainder for the purpose of re-planning the procedure.

With only four patients lost during follow-up,biochemical outcome data were available for 323(98.8%)men. Median(IQR)follow-up was 51.2(36.6—80.4)months with significant differences between the two generations of HIFUdevices(84.8[67.0—92.8]vs.42.3[32.4—51.2] months;p＜0.001)according to the later introduction of the A2 device.

Overall,77(23.8%)men exhibited biochemical relapse. Median(IQR)time to failure was 18.2(6.5—32.7)months.

Higher preoperative risk categories,the PSA value(at diagnosis),the A2 HIFU device and prostate edema were predictive factors of biochemical failure(Table 3),while multivariate analysis eliminated patient age,TNM-stages, Gleason sum,ADT,prostate volume(pre-plan),conduct of therapy(block strategies,type of approach),and spinal anesthesia as independent predictors(backward elimination).Notably,patientmovementswereneithera predictorinunivariateanalysisnorinmultivariate analysis.

The outcomes with both HIFU devices were further analyzed with a follow-up truncated to 50 months in order to adjust for different monitoring periods.The A2 device was associated with a decreased risk of biochemical failure (HR[95%CI]:0.415[0.253—0.672]).The biochemical failurefree survival rates with devices A1 and A2 were 70.3%and 82.3%,respectively(p＜0.001)(Fig.1).

4.Discussion

This study found that biochemical relapse is not excluded even if whole-gland treatment is performed to ensure completeeradicationoflocalizedPCa.Theoverall biochemical failure rate was 23.8%.Higher D’Amico risk stages proved to be strong predictors of adverse biochemical outcomes,as in previous reports[2—4].However,HIFU efficacy was not merely dependent on tumor characteristics,but also on treatment-related factors.

In our hands,single-session HIFU treatment proved to be more efficacious with the latest HIFU device than with the older model,as indicated by a decreased risk of biochemical recurrence.The differing results with both devices were not biased by different distributions of preoperative D’Amico risk stages or differing PSA levels at diagnosis. Although differences in the conduct of therapy(block strategies,type of approach)and administration of shortterm preoperative ADT were associated with the use of both devices,the changing practice in treating patients overtimewasnotresponsibleforthedecreasing biochemical failure rate,since these factors were not related to the outcomes on multivariate analysis.More likely,the increasing efficacy of HIFU treatment originated in technical advances.

By contrast to our results,the latest Ablatherm?device did not prove to be more efficacious in a recent study by Crouzet et al.[2].However,their study included patients who received repeat HIFU treatments with retreatment rates differing between both devices.In addition,the Phoenix definition(PSA nadir+2 ng/mL)of PSA relapse was used,originally designed to monitor biochemical response following radiotherapy[14].We decided to focus on the efficacy of single-session HIFU treatment as in an earlierreport[15].Moreover,the Stuttgart definition of PSA failure (PSA nadir+1.2 ng/mL)was selected as it provides a more specific evaluation of HIFU outcome[13],which is meaningful for comparisons between HIFU devices.

Heat-induced prostate edema occurred in a small proportion of patients(13.1%)and was an independent predictor of HIFU outcomes.Prostate swelling was first described by Shoji et al.[16]in patients without previous ADT or TURP treated with the alternative Sonablate HIFU device(Focus surgery,Indianapolis,IN,USA).We demonstrate that edema may not only involve the prostate gland but also the periprostatic tissue,then widening the rectoprostatic space.Both effects contribute to an enlarged distance between the anterior prostate margin and the rectal wall which may result in an anterior gap of untreated tissue.In these cases,HIFU may fail due to the limited penetration depth of the ultrasound.In contrast to the findings of Shoji et al.[16],prostate glands with edema had a higher volume and AP-diameter on pre-plan.Moreover, previous ADT might have an adverse effect,while previous TURP reduces the risk of swelling.This can be explained consistently by an imbalance between release and drainage of intraprostatic fluids after tissue destruction,which ispronounced in larger glands and even more accentuated by an ADT-induced involution of the prostatic vasculature [17,18].TURP provides additional drainage via the prostate cavity instead.

This is the first report on unintentional patient movements during HIFU therapy.Movements occurred in 19%of the men and are a challenge to the operator.Most movements were noted under spinal anesthesia and supplementary i.v.sedation which was the predominant anesthetic modality,as also in other clinics[3,19].Accordingly,this regimen is not ideal to provide both analgesia and immobilization in all patients.As shown,movements may enforce a discontinuation of the procedure,although treatment could be completed in most patients after adjustments for prostate shifts.Most importantly,movements were not an independent predictor of biochemical outcome,suggesting that movements during HIFU procedures could be compensated sufficiently by the operator to avoid untreated gaps within the prostate tissue.

This study has limitations according to its retrospective nature.The follow-up period with the latest HIFU device was still too short to verify a definite advantage over the older model and more studies with a longer follow-up are needed in order to confirm the present results using the same criteria of PSA relapse.The biochemical outcomes were used as a surrogate parameter for treatment efficacy whereas local control was not analyzed.

5.Conclusion

HIFU efficacy is not only dependent on preoperative tumor characteristics,but also on treatment-related factors.Our data support the preliminary estimate that the efficacy increases with the technically advanced latest HIFU device. Prostate edema might adversely affect the outcome.

Conflicts of interest

Dietrich Pfeiffer acted as a trainer for EDAP-TMS.Juergen Berger and Andreas Gross declare no conflict of interest.

[1]Gelet A,Chapelon JY,Bouvier R,Souchon R,Pangaud C, Abdelrahim AF,et al.Treatment of prostate cancer with transrectal focused ultrasound:early clinical experience.Eur Urol 1996;29:174—83.

[2]Crouzet S,Chapelon JY,Rouvie`re O,Mege-Lechevallier F, Colombel M,Tonoli-Catez H,et al.Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound:oncologic outcomes and morbidity in 1002 patients. Eur Urol 2014;65:907—14.

[3]Thu¨roff S,Chaussy C.Evolution and outcomes of 3 MHz highintensity focused ultrasound for localized prostate cancer during 15 years.J Urol 2013;190:702—10.

[4]Ganzer R,Fritsche HM,Brandtner A,Bru¨ndl J,Koch D, Wieland WF,et al.Fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer.BJU Int 2013;112:322—9.

[5]D’Amico AV,Whittington R,Malkowicz SB,Schultz D,Blank K, Broderick GA,et al.Biochemical outcome after radical prostatectomy,external beam radiation therapy,or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969—74.

[6]Blana A,Robertson CN,Brown SC,Chaussy C,Crouzet S, Gelet A,et al.Complete high-intensity focused ultrasound in prostate cancer:outcome from the@-registry.Prostate Cancer Prostatic Dis 2012;15:256—9.

[7]Ficarra V,Antoniolli SZ,Novara G,Parisi A,Fracalanza S, Martignoni G,et al.Short-term outcome after high-intensity focused ultrasound in the treatment of patients high-risk prostate cancer.BJU Int 2006;98:1193—8.

[8]Ward JF,Stephen Jones J.Classi fication system:organ preserving treatment for prostate cancer.Urology 2010;75: 1258—60.

[9]Pichardo S,Gelet A,Curiel L,Chesnais S,Chapelon JY.New integrated imaging high intensity focused ultrasound probe for transrectal prostate cancer treatment.Ultrasound Med Biol 2008;34:1105—16.

[10]Cordeiro ER,Cathelineau X,Thu¨roff,Marberger M,Crouzet S, de la Rosette JJ.High-intensity focused ultrasound(HIFU)for de finitive treatment of prostate cancer.BJU Int 2012;110: 1228—42.

[11]Rewcastle J.High intensity focused ultrasound for prostate cancer:a review of the scienti fic foundation,technology and clinical outcomes.Technol Cancer Res Treat 2006;5:619—25.

[12]Rasband WS.ImageJ.Maryland,USA:U.S.National Institutes of Health,Bethesda;1997-2012.http://imagej.nih.gov/ij/.

[13]Blana A,Brown SC,Chaussy C,Conti GN,Eastham JA, Ganzer R,et al.High-intensity focused ultrasound for prostate cancer:comparative de finitions of biochemical failure.BJU Int 2009;104:1058—62.

[14]Roach 3rd M,Hanks G,Thames Jr H,Schellhammer P, Shipley WU,Sokol GH,et al.De fining biochemical failure following radiation therapy with or without hormonal therapy in men with clinically localized prostate cancer:recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965—74.

[15]Pfeiffer D,Berger J,Gross AJ.Single application of highintensity focused ultrasound as a first-line therapy for clinically localized prostate cancer:5-yr outcomes.BJU Int 2012; 110:1702—7.

[16]Shoji S,Uchida T,Nakamoto M,Kim H,de Castro Abreu AL, Leslie S,et al.Prostate swelling and shift during high intensity focused ultrasound:implication for targeted focal therapy.J Urol 2013;190:1224—32.

[17]Shabsigh A,Chang DT,Heitjan DF,Kiss A,Olsson CA, Puchner PJ,et al.Rapid reduction in blood flow to the rat ventral prostate gland after castration:preliminary evidence that androgens in fluence prostate size by regulating blood flow of the prostate gland and prostatic endothelial cell survival.Prostate 1998;36:201—6.

[18]Wiart M,Curiel L,Gelet A,Lyonnet D,ChapelonJY, Rouvie`re O.In fluence of perfusion on high-intensity focused ultrasound prostate ablation:a first-pass MRI study.Magn Reson Med 2007;58:119—27.

[19]Pinthus JH,Farrokhyar F,Hassouna MM,Woods E,Whelan K, Shayegan B,et al.Single-session primary high-intensity focused ultrasonography treatment for localized prostate cancer:biochemical outcomes using the third generationbased technology.BJU Int 2012;110:1142—8.

Received 15 July 2014;received in revised form 12 August 2014;accepted 26 August 2014

Available online 16 April 2015

＊Corresponding author.

E-mail address:d.pfeiffer@asklepios.com(D.Pfeiffer).

Peer review under responsibility of Chinese Urological Association and SMMU.

http://dx.doi.org/10.1016/j.ajur.2014.08.009

2214-3882/?2015 Editorial Office of Asian Journal of Urology.Production and hosting by Elsevier(Singapore)Pte Ltd.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).