Table Of ContentJuetal.RadiationOncology2013,8:30
http://www.ro-journal.com/content/8/1/30
RESEARCH Open Access
Hypofractionated stereotactic body radiation
therapy as monotherapy for intermediate-risk
prostate cancer
Andrew W Ju1, Hongkun Wang2, Eric K Oermann1, Benjamin A Sherer3, Sunghae Uhm1, Viola J Chen1,
Arjun V Pendharkar3, Heather N Hanscom1, Joy S Kim1, Siyuan Lei1, Simeng Suy1, John H Lynch3,
Anatoly Dritschilo1 and Sean P Collins1*
Abstract
Background: Hypofractionated stereotactic body radiation therapy (SBRT) has been advanced as monotherapy for
low-risk prostate cancer. We examined the dose distributionsand early clinical outcomes using this modality for the
treatment ofintermediate-risk prostate cancer.
Methods: Forty-one sequential hormone-naïve intermediate-risk prostate cancer patients received 35–36.25Gy of
CyberKnife-deliveredSBRT in 5fractions. Radiation dose distributions were analyzed for coverage ofpotential
microscopic ECE by measuringthe distance from theprostatic capsule to the33 Gy isodose line. PSA levels,
toxicities, and quality oflife (QOL) measures were assessed at baseline and follow-up.
Results: Allpatients completed treatment with a mean coverage by the33 Gyisodose line extending >5 mm
beyond the prostatic capsule in all directions except posteriorly. Clinical responses were documented bya mean
PSA decrease from 7.67 ng/mL pretreatment to 0.64 ng/mL atthemedian follow-upof 21 months. Forty patients
remain freefrom biochemical progression.No Grade 3 or 4 toxicities were observed.Mean EPIC urinary irritation/
obstruction and bowel QOL scores exhibited a transient decline post-treatment with a subsequent return to
baseline. No significant change in sexual QOL was observed.
Conclusions: In this intermediate-risk patient population,an adequate radiation dose was delivered to areasof
expected microscopic ECE in the majority of patients. Althoughprospective studies are needed to confirm
long-term tumor control and toxicity, theshort-termPSA response, biochemical relapse-free survival rate, and QOL
inthis interim analysis are comparable to results reported for prostate brachytherapy or external beam radiotherapy.
Trial registration: TheGeorgetownInstitutionalReviewBoardhasapprovedthisretrospectivestudy(IRB2009–510).
Keywords:Stereotacticbodyradiotherapy,Prostatecancer,SBRT,CyberKnife,Intermediate-risk,Monotherapy,
Hypofractionation
Background complications, the linear-quadratic model predicts a
The treatment of prostate cancer has evolved to include greater therapeutic gain for hypofractionated courses of
optimization of radiation dose distributions and radiobi- radiotherapy over conventionally fractionated treatment
ological effectiveness. Clinical evidence suggests that the regimens. Early experience with investigations of limited
α/β ratio of prostate cancer is perhaps as low as 1.5-2 hypofractionation (fraction sizes from 2.5 to 3.5 Gy) has
Gy [1]. Given an α/β ratio for prostate cancer that is less revealed that such regimens are effective without undue
than the generally accepted value of 3 Gy for late rectal toxicity [2]. One Phase III trial has shown comparable
toxicities and improved freedom from biochemical fail-
*Correspondence:[email protected] ure with a hypofractionated treatment regimen of 62 Gy
1DepartmentofRadiationMedicine,LLBlesBuilding,3800ReservoirRdNW, in 20 fractions compared to a conventionally fractio-
Washington,DC20007,USA
nated regimen of 80 Gy in 40 fractions [3]. The linear-
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Juetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Juetal.RadiationOncology2013,8:30 Page2of10
http://www.ro-journal.com/content/8/1/30
quadratic model predicts that even larger fraction sizes risk was defined using the National Comprehensive Can-
mayprovideadditionalimprovementsincontrol. cerNetwork(NCCN)criteriaofpatientswithatleastone
Large radiation fractions have been successfully used of the following risk factors: Stage T2b - T2c disease, a
as a boost to escalate the dose to the prostate and se- Gleasonscoreof7,oraPSAof10–20ng/mL[26].Clin-
minal vesicles (SV). The hypofractionated boost is used icalstagewasassignedaccordingtothe6theditionofthe
to supplement a course of conventionally fractionated American Joint Committee on Cancer definitions. Ex-
external-beam radiotherapy (EBRT) designed to treat a clusion criteria included less than one year of clinical fol-
larger volume encompassing the microscopic disease ad- low-up, clinical involvement of lymph nodes or distant
jacenttotheprostateandseminalvesicles.Studiesinves- metastases on pre-treatment imaging, prior prostate can-
tigating a high dose-rate (HDR) brachytherapy boost cer-directed therapy, or prior pelvic irradiation. Patients
delivering 4–11.5 Gy/fraction over 2 to 4 sessions com- who received androgen deprivation therapy (ADT) were
bined with EBRT report five-year biochemical control excluded. Institutional review board approval was obtai-
rates in excess of 85% for intermediate-risk prostate nedforthisanalysis.
cancer patients with acceptable toxicities [4]. The tight
margins and steep dose gradients delivered with HDR Treatmentplanninganddelivery
brachytherapy can be approximated with SBRT using The fiducial placement and CT/MRI simulation proce-
the CyberKnife (CK) system, [5,6] which uses real-time dures have been previously described in Lei et al. [27]
image guidance to account for intrafraction prostatic The gross tumor volume (GTV) was defined as the
motion[7].EBRTwithanSBRTboosthasbeenexplored prostatic capsule and the proximal seminal vesicles up
in intermediate-risk prostate cancer with favorable early to the point that the left and right seminal vesicles sepa-
results[8,9]. rated. To create the clinical target volume (CTV), this
Delivering an entire course of radiotherapy for pros- volume was further expanded 3 mm posteriorly and 5
tate cancer using large fractions rather than as a boost mm in all other directions to cover areas of potential
to a course of conventionally fractionated EBRT could ECE. The planning target volume (PTV) was equal to
be radiobiologically advantageous. The safety, efficacy, the CTV. No attempt was made to spare the neurovas-
and convenience of such monotherapy with hypofractio- cular bundles in treatment planning. Treatment plan-
nated courses of treatment at 6–9.5 Gy per fraction has ning was performed using Multiplan (Accuray Inc.,
been demonstrated for localized prostate cancer using Sunnyvale, CA). The prescription dose was either 35 or
HDR brachytherapy [10-15]. Initial published outcomes 36.25 Gy to the PTV in 5 fractions over 1–2 weeks.
for hypofractionated SBRT using the CK system as mo- Patients with an elevated pre-treatment AUA scores,
notherapy for patients with clinically localized prostate large prostates, or medical co-morbidities were pres-
cancer show PSA responses and toxicity profiles that are cribed the lower dose [20]. The target doses and dose
historically comparable to conventional external beam constraintshavebeen described inOermannet al.[28]
radiotherapy or HDR brachytherapy [16-24]. However, During treatment, paired orthogonal x-rays were taken
with the exception of the recent paper by Lee et al., the every 3–6 beams to adjust for the translational and rota-
majority of the patients in these studies have low-risk tional intrafraction movement of the prostate, with the
disease, and there is a concern that the tight margins goal of keeping the translational corrections between
required to limit the normal tissue doses to the rectum images to less than 2 mm, and the rotational corrections
and bladder in hypofractionated radiotherapy may not to less than 5 degrees. This corresponds to approxima-
be adequate to treat the microscopic disease from extra- tely every 30–60 seconds at the start of treatment, and
capsular extension (ECE) and SV involvement that is the time between images is varied during the course
present in 35–50% of intermediate-risk patients [25]. of treatment depending on amount of prostate motion
Here, we provide dosimetric data to support the ad- [7,27]. All plans were reviewed and approved by a single
equacy of such treatment and report the early outcomes experienced physician in our institution (S.C.). Figure 1
for intermediate-risk prostate cancer patients treated shows an axial view of a typical treatment plan. Quality
with hypofractionated SBRT monotherapy using the CK assurance for the SBRT plans was assured by a weekly
system. departmentalreview ofcases.
Methods Pretreatmentassessmentandfollow-up
This retrospective review of prospectively collected data A clinical examination including a digital rectal exam
from 41 consecutively treated patients receiving hypo- (DRE), a PSA level, and a quality of life (QOL) question-
fractionatedstereotacticbodyradiotherapyatGeorgetown naire were performed prior to the initiation of stereotac-
UniversityHospitalasmonotherapyforhistologically-con- tic bodyradiotherapy, at 1and 3monthspost-treatment,
firmed intermediate-risk prostate cancer. Intermediate and every 3 months thereafter. The QOL questionnaires
Juetal.RadiationOncology2013,8:30 Page3of10
http://www.ro-journal.com/content/8/1/30
Figure1Exampletreatmentplanshowinganaxialview.ThevolumesrepresenttheGTV(red),PTV(blue)andrectum(lightgreen).The
prescriptionisodoseline(79%)isdenotedbythethicklightblueline.
evaluated urinary, bowel, and erectile functions using Statisticalanalysis
the International Prostate Symptom Score (IPSS), [29] Descriptive statistics were used to summarize the pa-
the Expanded Prostate Cancer Index Composite (EPIC) tients’ baseline clinicalcharacteristics,thedosimetriccha-
short form, [30] and the 12-item Medical Outcomes racteristics, as well as the rates of observed toxicities.
Study Short Form (SF-12) version 2 questionnaires [31]. QOL data from time points in which more than 80% of
Acute and late toxicities were scored using the Common patients completed the questionnaires were included in
Terminology Criteria for Adverse Events (CTCAE) Ver- the analysis. An QOL change of one-half standard devi-
sion 4.0. Acute toxicity is defined as occurring within 6 ation (SD) from the baseline QOL score, defined as the
months of completing treatment, and late toxicity as minimal important difference (MID), was used to denote
those events occurring later than 6 months. Biochemical a clinically significant change in the QOL score [36]. The
failure wasdefinedasa PSA rise of ≥ 2ng/mL above the two-sidedpairedWilcoxonrank-sumtestwasusedtocal-
nadir[32]. culate the significance of differences in the mean scores
on follow-up as compared to the baseline values. Pa-
rameters were identified as significant if the two-tailed
Dosimetricassessment p-valuewaslessthan0.05.MedCalcWversion11.6.1.0was
The coverage of potential extracapsular extension of dis- usedforthestatisticalanalyses.
ease with a dose sufficient to control gross and micro-
scopic disease was the focus of evaluation. The distance Results
fromtheGTVtothe33Gyisodoselineofthetreatment Patients
plans was measured in 45 degree increments on 3 axial Forty-one men were treated between October 1, 2008
planes: the plane 1 cm caudal from the base of the pros- and October 30, 2009 met the inclusion criteria. Their
tate, the plane 0.5 cm cranial from the apex, and the baseline characteristics are summarized in Table 1. The
plane in the mid-prostate halfway between the 2 other median clinical follow-up is 21 months (range 13 – 27.5
planes. This dosimetric analysis has been previously months). Eight patients received a total dose of 35 Gy,
described in brachytherapy implants [33,34]. The 33 Gy and 33 patients received 36.25 Gy. The median prescrip-
isodose line was chosen as the dose that would treat po- tion isodose line was 77% (range 75%–80%), which cov-
tential ECE. Conservatively assuming an α/β ratio of 3 ered a median 95.1% of the PTV (range 94.2%–96.4%).
Gy, the linear-quadratic equation would predict that this The dosimetric constraints to normal tissues were met
corresponds to a dose of 66 Gy delivered in 1.8 Gy daily inthemajority ofpatients.
fractions, which is the dose considered sufficient for
treating microscopic residual disease in the prostatic Dosimetricanalysis
fossa after prostatectomy [35]. In our SBRTstudy 33 Gy The mean 33 Gy isodose line extends beyond 5 mm
isgreater than 90%oftheprescription dose. from the prostate capsule in the anterior, lateral and
Juetal.RadiationOncology2013,8:30 Page4of10
http://www.ro-journal.com/content/8/1/30
Table1Patientcharacteristics transurethral microwave therapy prior to initiating radio-
Numberofpatients n=41 therapy. He had a baseline PSA of 6.9 ng/mL which
decreased to a nadir of 2.0 ng/mL at 9 months, and then
Age Median Range
rose to 3.9 and 4.2 ng/mL in the next 2 follow-up visits
69 60–92
while he was experiencing worsening urinary obstructive
Race n %
symptoms, before decreasing again to 2.1 ng/mL on sub-
Caucasian 26 63%
sequentfollow-up.ThepatientwasneverstartedonADT.
African-American 15 37% Given the possibility that his rise in PSA was a benign
Prostatevolume(cc) Median Range bounce’ due to his urinary symptoms, [37] the patient is
37 20–63 not considered to have clinically failed treatment and is
PSA(ng/mL) Median Range currentlyunderobservation.
6.9 3.5–18.3
Toxicityandqualityoflife
TStage n %
As previously reported, low grade urinary and rectal
1b 1 2%
toxicities were common following prostate SBRT [28].
1c 28 68% Themostcommonurinarytoxicities were frequencyand
2a 6 15% urinary obstructive symptoms. The course of symptoms
2b 4 10% peaked 1–2 weeks following completion of SBRT, fol-
lowed by an improvement within 2–3 months. Forty-
2c 2 5%
four percent of patients experienced a late Grade 2 urin-
Gleasonscore n %
ary toxicity. These correlated with alpha receptor antag-
3+3 9 22%
onist utilization for low grade symptoms. The most
3+4 23 56%
common bowel toxicity was frequency of bowel move-
4+3 9 22% ments. Seven percent of patients experienced Grade 2
Numberofriskfactors* n % late bowel toxicity secondary to rectal bleeding due to
1 34 83% exacerbation of hemorrhoids that required ligation, ban-
ding, or laser coagulation. There were no Grade 3 or
2 7 17%
higher acute orlatetoxicities.
3 0 0%
Figure 3 summarizes the baseline and follow-up urin-
*FactorsincludePSA10–20ng/mL,Gleason7,orT2b-2c.
ary, bowel, and sexual QOL scores. Eighty percent of
patients completed their QOL questionnaires for at least
posterolateral directions in all 3 of the axial planes ana- 15 months. The mean IPSS (Figure 3a) and the mean
lyzed. The mean and range of these distances are listed EPICurinaryirritation/obstructivescores(Figure3b)sho-
in Table 2, along with the percent of patients who re- wed clinically significant (score decreased by >1/2 SD)
ceive 33 Gy at 3, 4, 5, 6, and 7 mm on the treatment and statistically significant (p<0.001 and p=0.035, respec-
plan. The mean distances posteriorly from the prostatic tively) transient decrements one month post-treatment
capsule to the rectum are also listed in Table 2. The that subsequently returned to baseline. The mean EPIC
mean distances of the 33 Gy isodose line with the 95% urinary incontinence score (Figure 3c) was statistically
confidence interval of the mean are graphed in a radar worse at 1 month (p=0.005), but improved by 3 months.
plot in Figure 2. For the majority of patients the cover- Additionaldeclinewasobservedat9months,butthishas
age of the 33 Gy isodose line is more than 5 mm in the not reached clinical or statistical significance. The EPIC
directions where ECE is a greater concern including the bowel score (Figure 3d) showed a clinically and statis-
posteriolateraldirections,whiletheextensionofthehigh tically significant (p<0.001) decline at 1 month post-
doseregion intotherectumisshortincomparison. treatment with recovery at 15 months post-treatment.
EPIC sexual scores (Figure 3e) showed a slow decline
Biochemicalresponse over the first year following treatment; however, the
PSA values declined from a baseline mean of 7.67 ng/ decline was not clinically or statistically significant. No
mL (SD 3.26 ng/mL) to a mean of 1.35 ng/mL (SD 1.08 clinically or statistically significant decrease occurred in
ng/mL) at 12 months, and 0.64 ng/mL (SD 0.40 ng/mL) the SF-12 physical or mental component QOL scores
at 21 months. There have been no deaths from any cause (datanotshown).
todate.The2-yearKaplan-Meierbiochemicalrelapse-free
survivalrateis97.6%.Onepatientexperiencedabiochem- Discussion
ical failure 15 months after treatment. This patient had a Although IMRT is the standard external beam modality
priorhistoryofobstructiveurinarysymptomstreatedwith for clinically localized prostate cancer, hypofractionated
httpJue
://wwtal.R
Table2CoverageofpotentialECE wa
Axialplane1cm Mean Range Distance≥3 Distance≥4 Distance≥5 Distance≥6 Distance≥7 .ro-jodiatio
caudaltothebase (mm) (mm) mm(%) mm(%) mm(%) mm(%) mm(%) un
rnO
Anterior 7.82 1.10–14.42 95% 88% 85% 73% 61% al.cnco
Left 8.59 4.47–18.46 100% 100% 95% 85% 73% omlog
/cy
Right 8.41 4.62–18.15 100% 100% 95% 71% 59% on20
Leftposterolateral 11.42 3.11–27.02 100% 98% 88% 83% 76% ten13,
Rightposterolateral 11.03 3.12–27.02 100% 98% 88% 80% 73% t/8/18:30
/3
Posterior 1.92 −0.66–6.070 20% 7% 5% 2% 0% 0
Distancefromrectum 2.41 0–17.01
toprostatecapsule
Axialplaneat Mean Range Distance≥3 Distance≥4 Distance≥5 Distance≥6 Distance≥7
mid-prostate (mm) (mm) mm(%) mm(%) mm(%) mm(%) mm(%)
Anterior 9.01 4.42–17.32 100% 100% 98% 76% 68%
Left 8.48 4.47–16.12 100% 100% 98% 88% 66%
Right 7.57 3.53–15.20 100% 98% 90% 76% 49%
Leftposterolateral 7.87 2.04–26.86 98% 95% 83% 61% 51%
Rightposterolateral 7.60 0–20.10 95% 85% 78% 68% 51%
Posterior 1.97 −0.66–4.86 29% 12% 0% 0% 0%
Distancefromrectum 0.87 0–3.58
toprostatecapsule
Axialplane0.5cm Mean Range Distance≥3 Distance≥4 Distance≥5 Distance≥6 Distance≥7
cranialtoapex (mm) (mm) mm(%) mm(%) mm(%) mm(%) mm(%)
Anterior 9.53 3.56–15.38 100% 95% 95% 95% 83%
Left 13.40 7.64–22.09 100% 100% 100% 100% 100%
Right 12.28 5.55–21.36 100% 100% 100% 98% 95%
Leftposterolateral 7.25 0–17.34 93% 85% 73% 61% 44%
Rightposterolateral 7.27 0–15.81 98% 93% 85% 68% 51%
Posterior 2.86 0–6.83 41% 24% 12% 2% 0%
Distancefromrectum 0.79 0–3.50
toprostatecapsule
Meandistance(mm)withrangebetweentheprostaticcapsuleandthe33Gyisodoseline,withthepercentofpatientswherethedistanceisgreaterthanorequalto3,4,5,6,and7mm.Themeandistancebetween
P
theprostaticcapsuleandtherectumisalsonoted. a
g
e
5
o
f
1
0
Juetal.RadiationOncology2013,8:30 Page6of10
http://www.ro-journal.com/content/8/1/30
Figure2CoverageofpotentialECE.Radarplotsofthemeandistance(solidredline)inmillimetersofthe33Gyisodoselinefromanidealized
prostateGTV(solidblackline).The95%confidenceintervalofthemeanisshownindashedbluelines.Thedistancesareshownon(a)theaxial
plane1cmcaudaltobase,(b)theaxialplaneinmid-prostate,and(c)theaxialplane0.5cmcranialtoapex.
SBRT monotherapy has recently emerged as a poten- may provide similar clinical outcomes to IMRT, and re-
tial alternative [18]. The studies that have the longest port high biochemical control rates with acceptable tox-
follow-up use the CyberKnife machine for SBRT de- icity [5,16-24]. Recent updates have confirmed a 5-year
livery, but prostate SBRT can also be delivered using biochemical disease-free survival in low-risk patients is in
other systems that account for intrafraction motion, excessof90%[17,21].
suchastheelectromagneticCalypsosystemoratransperi- These SBRT monotherapy studies include mostly low-
nealultrasound system. Multiplesingleinstitution experi- risk patients, and there is limited data on the use of hy-
ences with SBRT monotherapy in favorable risk patients pofractionated radiotherapy in intermediate-risk patients,
use a regimen of 35–40 Gy is delivered to the prostate in where ECE is more common and the treatment margins
4–5 fractions. Their results suggest that this approach maynotadequatelycoverthisextraprostaticdisease.
Juetal.RadiationOncology2013,8:30 Page7of10
http://www.ro-journal.com/content/8/1/30
Figure3(a-e)Meanqualityoflifemeasuresatbaselineandfollow-up.AnalysisoftheQOLdataincludedalltimepointsthathadatleast
an80%patientresponserate,whichwasupto15monthsforallQOLmeasures.ShownareplotsforIPSS(a),EPICurinaryirritation/obstruction
domain(b),EPICurinaryincontinencedomain(c),EPICboweldomain(d),andEPICsexualdomain(e).Thethresholdsforclinicallysignificant
changesinscores(½standarddeviationaboveandbelowthebaseline)aremarkedwithdashedlines.IPSSscoresrangefrom0–35withhigher
valuesrepresentingworseningurinarysymptoms.EPICscoresrangefrom0–100withhighervaluesrepresentingamorefavorable
health-relatedQOL.
Pathologicreviewsofpost-prostatectomyspecimensshow prostate, and 7.26 mm at the apex. This is comparable to
that the extent of microscopic ECE in intermediate-risk the Merrick et al. study, where the distances from the
patientsisgenerallysmall(2–3mm)anda4to5mmmar- prostate to the 90% isodose line in their series of Pd-103
ginaroundtheprostaticcapsuleshouldcoverthisspreadof implants as 8.4 mm at the base, 5.9 mm at the mid-pros-
diseaseinanestimated90-99%ofintermediate-riskpatients tate, and 6.8 mm at the apex [34]. The coverage directly
[25,33,38-41]. We consider 33 Gy (94% of the prescription posteriorlytowardstherectum isless thaninotherdirec-
dosefor35Gyplansor91%ofthe36.25Gyplans)tobean tions, but the extent of ECE is smallest in this direction,
adequatedosefortreatingmicroscopicdisease.Inourstudy, where the rectoprostatic fascia limits the extent of inva-
the mean distance of the 33 Gy isodose line on the treat- sion[40].
ment plans extends >5 mm beyond the prostate capsule in The mean pre-treatment PSA was 7.67 ng/mL and it
all directions except directly posteriorly into the rectum, decreased to a mean of 1.35 ng/mL by one year post-treat-
with generous coverage in the posterolateral directions ment.PSAdatafrompatientstreatedwithconventionalex-
whereECEmorecommonlyoccurs. ternal beam radiation therapy suggest that patients with
The actual dose delivered to the surrounding margin of PSA nadirs <2 ng/ml atone year following treatment have
theprostatecanbelessthantheplanneddoseduetointra- a high rate of long-term disease control, [42,43] and we
fractionmotionoftheprostate.Xieetal.calculatedthator- could predict a similarly high rate of long-term control in
thogonal imaging every 30–60 seconds would allow 95.6% thepatientstreatedinourseries.Giventhatthemajorityof
and92.5%ofthebeamstobedeliveredwithin2mmofthe biochemicalfailuresforintermediate-riskpatientsoccursev-
target during CyberKnife treatments of the prostate [7]. eral years after treatment, the median follow-up of 21.5
After taking this 1–2 mm of uncertainty into account, the months in the current study is inadequate to establish the
ECE coverage with CyberKnife SBRT is comparable to long-term efficacy of CK monotherapy in intermediate-risk
the coverage achieved in low-doserateprostatebrachy- patients.However,our97.6%2-yearbiochemicalfailure-free
therapy. The average distance from the prostatic capsule survival rate is consistent with the limited literature on
ofthe33Gyisodoselineinourstudyintheposteriolateral hypofractionated radiotherapy for intermediate-risk disease.
direction was11.23 mm atthebase,7.74mm atthe mid- For HDR monotherapy, which the dose distribution of
Juetal.RadiationOncology2013,8:30 Page8of10
http://www.ro-journal.com/content/8/1/30
SBRTmonotherapyisbasedon,thetwostudiesthatreport radiotherapy delivered with the CyberKnife as mono-
the biochemical control rate specifically for intermediate- therapy for intermediate-risk prostate cancer patients.
risk patients show excellent 5-year PSA failure-free rates of On dosimetric evaluation, the treatment plans provide
93% in Yoshioka et al. and 94% for Rogers et al. [14,15] In adequate coverage of potential extracapsular extension
the fractionated SBRT monotherapy literature, only Lee of disease and limits the dose to the adjacent rectum.
et al. [24], Bolzicco et al. [16], Katz et al. [20] included a Our early results show that the PSA response, absence
large percentage of intermediate-risk patients. Lee et al. re- of Grade 3 toxicity, and favorable QOL support SBRT
port their series of 29 patients treated with SBRT to a dose deliveredasCyberKnifemonotherapyasasafeandpoten-
of35to37.5Gyin5fractions.Nineteenof these patients tially effective treatment for intermediate-risk prostate
had intermediate-risk disease, the others had low or cancer.Longerfollow-upisneededtomoreaccuratelyas-
highriskdisease.The4-yearbiochemicalrelapse-freesur- sess late toxicities and biochemical failure rates of SBRT
vival was 86%. There were no Grade 3–4 acute toxicities, monotherapyinthispatientpopulation.
and one patient experienced a late Grade 3 urinary tox-
icity. These results are encouraging, but the results of the Abbreviations
(SBRT):Stereotacticbodyradiationtherapy;(SV):Seminalvesicles;
intermediate-risk cohort are not reported independently.
(EBRT):External-beamradiotherapy;(HDR):Highdose-rate;(CK):CyberKnife;
Katzet al.reporteda separatebiochemical failureratefor (ECE):Extracapsularextension;(NCCN):NationalComprehensiveCancer
their 81 intermediate-risk patients of 0%, but the follow- Network;(ADT):Androgendeprivationtherapy;(GTV):Grosstumorvolume;
(CTV):Clinicaltargetvolume;(PTV):Planningtargetvolume;
upperiodoftheirstudywasshort,witharangeof8to37
(IPSS):InternationalProstateSymptomScore;(DRE):Digitalrectalexam;
monthsfor all the patients inthe study. Longer follow-up (QOL):Qualityoflife;(EPIC):ExpandedProstateCancerIndexComposite;
is needed to validate the observations made in our study (SF-12):MedicalOutcomesStudyShortForm;(CTCAE):Common
TerminologyCriteriaforAdverseEvents;(SD):Standarddeviation;
and prospective studies are necessary for comparison to
(MID):Minimalimportantdifference;(IMRT):Intensitymodulated
the reported 70-80% 10-year biochemical failure-free sur- radiotherapy.
vivals obtained using conventionally fractionated external
beamradiotherapyandlowdose-ratebrachytherapy[4]. Competinginterests
TheDepartmentofRadiationMedicineatGeorgetownUniversityHospital
Our study suggests that clinically significant late Grade receivesaneducationalgrantfromAccuraytosupportaresearch
3toxicitiesareinfrequentfollowingCKmonotherapy,and coordinator.Dr.SeanCollinsisaclinicalconsultantforAccuray.
ourlowrateiscomparabletotheratesobservedfollowing
Authors’contributions
external beam radiotherapy,[44] HDR brachytherapy,
AJwastheleadauthor,whoparticipatedinthedesignoftheproject,
[10,11,13,15] or in other reported CK monotherapy series oversawandparticipatedinthedatacollectionanddataanalysis,andwho
[8,16,17,21-23].Ourpracticeallowsforprescribingselect- wrotetheprimarydrafts.HWisabiostatisticianwhoparticipatedinthe
statisticalanalysisandrevisedthestatisticalsectionsofthepaper.EOaided
ivealphablockersforrelativelyminorurinarycomplaints,
inthequalityoflifedatacollectionandstatisticalanalysis.BSaidedinthe
which may contribute to the higher rate of recorded clinicaldatacollection.SUaidedinthequalityoflifedatacollection.VC
Grade 2 late urinary toxicity seen in our series compared aidedinthequalityoflifedatacollection.APaidedintheclinicaldata
collection.HHandJKjointlymaintainedthepatientdatabase,aidedindata
to the rates reported in these other series. However, this
collection,andparticipatedininitialdatainterpretation.SListhedosimetrist
increased higher rate of recorded low grade urinary tox- whodevelopedthemajorityofthepatients’treatmentplans,and
icityisnotreflectedinourQOLresults. contributedtothedosimetricdataanalysisandinterpretation.SSisasenior
authorwhocollectedthedosimetricdata,participatedinitsanalysis,and
The QOL data indicate that CK monotherapy is well tol-
helpeddraftthemanuscript.JLisaseniorauthorwhoaidedindraftingthe
erated, with declines in patient reported urinary, bowel and manuscript.ADisaseniorauthorwhoaidedindraftingthemanuscriptand
sexual function that are similar to those seen in low-risk revisingitscontent.SCwastheprincipleinvestigatorwhoinitiallydeveloped
theconceptofthestudyandthedesign,aidedindatacollection,and
patientstreatedwithCKSBRTmonotherapy,[28]andcom-
helpedinrevisingthemanuscript.Allauthorsreadandapprovedthefinal
parable to the trends seen with conventionally fractionated manuscript.
external beam radiotherapy and brachytherapy [45-47].
Urinarysymptomspeakedinthe1–2weeksafterSBRT,and Authordetails
1DepartmentofRadiationMedicine,LLBlesBuilding,3800ReservoirRdNW,
were generally followed by improvement to pre-treatment Washington,DC20007,USA.2DepartmentofBiostatistics,Bioinformatics,and
levels within 2–3 months. Bowel function declined after Biomathematics,GeorgetownUniversity,Washington,DC,USA.3Department
ofUrology,GeorgetownUniversityHospital,Washington,DC,USA.
treatmentandslowlyrecoveredtonearbaselineatoneyear.
As reported by others, sexual QOL declined slowly over Received:7September2012Accepted:20December2012
time without recovery [47]. Longer follow up is needed to Published:31January2013
fully assess the late impact of CyberKnife monotherapy on
References
QOL.
1. MiralbellR,RobertsSA,ZubizarretaE,HendryJH:Dose-Fractionation
SensitivityofProstateCancerDeducedFromRadiotherapyOutcomesof
Conclusions 5,969PatientsinSevenInternationalInstitutionalDatasets:α/β=1.4
(0.9–2.2)Gy.IntJRadiatOncolBiolPhys2012,82:e17–e24.
This analysis assesses the dosimetric feasibility and early
2. RitterM,FormanJ,KupelianP,LawtonC,PetereitD:Hypofractionationfor
clinical outcomes of hypofractionated stereotactic body prostatecancer.CancerJ2009,15:1–6.
Juetal.RadiationOncology2013,8:30 Page9of10
http://www.ro-journal.com/content/8/1/30
3. ArcangeliG,FowlerJ,GomelliniS,ArcangeliS,SaracinoB,PetrongariMG, 22. McBrideSM,WongDS,DombrowskiJJ,HarkinsB,TapellaP,HanscomHN,
BenassiM,StrigariL:AcuteandLateToxicityinaRandomizedTrialof CollinsSP,KaplanID:Hypofractionatedstereotacticbodyradiotherapyin
ConventionalVersusHypofractionatedThree-DimensionalConformal low-riskprostateadenocarcinoma:preliminaryresultsofamulti-
RadiotherapyforProstateCancer.IntJRadiatOncolBiolPhys2011, institutionalphase1feasibilitytrial.Cancer2012,118:3681–3690.
79:1013–1021. 23. TownsendNC,HuthBJ,DingW,GarberB,MoorevilleM,ArrigoS,LamondJ,
4. CollinsSP,McRaeD,GagnonG,DritschiloA:Newdirectionsinradiation BradyLW:Acutetoxicityaftercyberknife-deliveredhypofractionated
therapyinprostatecancer,In:Pestell,RichardG.,Nevalainen,MarjaT.editors. radiotherapyfortreatmentofprostatecancer.AmJClinOncol2011,
Prostatecancer:signalingnetworks,genetics,andnewtreatmentstrategies. 34:6–10.
Totowa,NJ:HumanaPress;2008:323–338. 24. LeeYH,SonSH,YoonSC,YuM,ChoiBO,KimYS,JangHS,LeeSN,JangJS,
5. FullerDB,NaitohJ,LeeC,HardyS,JinH:VirtualHDRSMCyberKnife HwangTK:Stereotacticbodyradiotherapyforprostatecancer:A
TreatmentforLocalizedProstaticCarcinoma:DosimetryComparison preliminaryreport.AsiaPacJClinOncol2012,doi:10.1111/j.1743-
WithHDRBrachytherapyandPreliminaryClinicalObservations. 7563.2012.01589.x.
IntJRadiatOncolBiolPhys2008,70:1588–1597. 25. ChaoKK,GoldsteinNS,YanD,VargasCE,GhilezanMI,KormanHJ,Kernen
6. HossainS,XiaP,HuangK,DescovichM,ChuangC,GottschalkAR,RoachIiiM, KM,HollanderJB,GonzalezJA,MartinezAA,etal:Clinicopathologic
MaL:DoseGradientNearTarget–NormalStructureInterfacefor analysisofextracapsularextensioninprostatecancer:Shouldtheclinical
NonisocentricCyberKnifeandIsocentricIntensity-ModulatedBody targetvolumebeexpandedposterolaterallytoaccountformicroscopic
RadiotherapyforProstateCancer.IntJRadiatOncolBiolPhys2010,78:58–63. extension?IntJRadiatOncolBiolPhys2006,65:999–1007.
7. XieY,DjajaputraD,KingCR,HossainS,MaL,XingL:IntrafractionalMotion 26. MohlerJL,ArmstrongAJ,BahnsonRR,BostonB,BusbyJE,D'AmicoAV,
oftheProstateDuringHypofractionatedRadiotherapy.IntJRadiatOncol EasthamJA,EnkeCA,FarringtonT,HiganoCS,etal:ProstateCancer
BiolPhys2008,72:236–246. version3.2012.NCCNClinicalPracticeGuidelinesinOncology2012,6.
8. KatzAJ,SantoroM,AshleyR,DiblasioF,WittenM:StereotacticBody 27. LeiS,PielN,OermannEK,ChenV,JuAW,DahalKN,HanscomHN,KimJS,
RadiotherapyasBoostforOrgan-confinedProstateCancer.Technol YuX,ZhangG,etal:Six-dimensionalcorrectionofintra-fractional
CancerResT2010,9:575–582. prostatemotionwithcyberknifestereotacticbodyradiationtherapy.
9. OermannEK,SlackRS,HanscomHN,LeiS,SuyS,ParkHU,KimJS,Sherer FrontOncol2011,1:48.
BA,CollinsBT,SatinskyAN,etal:Apilotstudyofintensitymodulated 28. OermannEK,SuyS,HanscomHN,KimJS,LeiS,YuX,ZhangG,EnnisB,
radiationtherapywithhypofractionatedstereotacticbodyradiation RohanJP,PielN,etal:Lowincidenceofnewbiochemicalandclinical
therapy(SBRT)boostinthetreatmentofintermediate-tohigh-risk hypogonadismfollowinghypofractionatedstereotacticbodyradiation
prostatecancer.TechnolCancerResTreat2010,9:453–462. therapy(SBRT)monotherapyforlow-tointermediate-riskprostate
10. CornerC,RojasAM,BryantL,OstlerP,HoskinP:APhaseIIStudyofHigh- cancer.JHematolOncol2011,4:12.
Dose-RateAfterloadingBrachytherapyasMonotherapyforthe 29. BarryMJ,FowlerFJJr,O'LearyMP,BruskewitzRC,HoltgreweHL,Mebust
TreatmentofLocalizedProstateCancer.IntJRadiatOncolBiolPhys2008, WK:Measuringdisease-specifichealthstatusinmenwithbenign
72:441–446. prostatichyperplasia.MeasurementCommitteeofTheAmerican
11. DemanesDJ,MartinezAA,GhilezanM,HillDR,SchourL,BrandtD, UrologicalAssociation.MedCare1995,33:AS145–155.
GustafsonG:High-Dose-RateMonotherapy:SafeandEffective 30. WeiJT,DunnRL,LitwinMS,SandlerHM,SandaMG:Developmentand
BrachytherapyforPatientsWithLocalizedProstateCancer.IntJRadiat validationoftheexpandedprostatecancerindexcomposite(EPIC)for
OncolBiolPhys2011,81:1286–1292. comprehensiveassessmentofhealth-relatedqualityoflifeinmenwith
12. GrillsIS,MartinezAA,HollanderM,HuangR,GoldmanK,ChenPY, prostatecancer.Urology2000,56:899–905.
GustafsonGS:Highdoseratebrachytherapyasprostatecancer 31. WareJJr,KosinskiM,KellerSD:A12-ItemShort-FormHealthSurvey:
monotherapyreducestoxicitycomparedtolowdoseratepalladium constructionofscalesandpreliminarytestsofreliabilityandvalidity.
seeds.JUrol2004,171:1098–1104. MedCare1996,34:220–233.
13. MartinezAA,DemanesJ,VargasC,SchourL,GhilezanM,GustafsonGS: 32. RoachM,HanksG,ThamesH,SchellhammerP,ShipleyWU,SokolGH,
High-dose-rateprostatebrachytherapyanexcellentaccelerated- SandlerH:Definingbiochemicalfailurefollowingradiotherapywithor
hypofractionatedtreatmentforfavorableprostatecancer.AmJClin withouthormonaltherapyinmenwithclinicallylocalizedprostate
Oncol-Canc2010,33:481–488. cancer:RecommendationsoftheRTOG-ASTROPhoenixConsensus
14. RogersCL,AlderSC,RogersRL,HopkinsSA,PlattML,ChildsLC,CrouchRH, Conference.IntJRadiatOncol2006,65:965–974.
HansenRS,HayesJK:Highdosebrachytherapyasmonotherapyfor 33. ChoiS,WallnerKE,MerrickGS,CavanaghW,ButlerWM:Treatmentmargins
intermediateriskprostatecancer.JUrol2012,187:109–116. predictbiochemicaloutcomesafterprostatebrachytherapy.CancerJ
15. YoshiokaY,KonishiK,SumidaI,TakahashiY,IsohashiF,OgataT,KoizumiM, 2004,10:175–180.
YamazakiH,NonomuraN,OkuyamaA,InoueT:MonotherapeuticHigh- 34. MerrickGS,ButlerWM,WallnerKE,BurdenLR,DoughertyJE:Extracapsular
Dose-RateBrachytherapyforProstateCancer:Five-YearResultsofan radiationdosedistributionafterpermanentprostatebrachytherapy.Am
ExtremeHypofractionationRegimenWith54GyinNineFractions. JClinOncol2003,26:e178–189.
IntJRadiatOncolBiolPhys2011,80:469–475. 35. CoxJD,GallagherMJ,HammondEH,KaplanRS,SchellhammerPF:
16. BolziccoG,FavrettoMS,ScreminE,TamboneC,TascaA,GuglielmiR: Consensusstatementsonradiationtherapyofprostatecancer:
Image-guidedstereotacticbodyradiationtherapyforclinicallylocalized guidelinesforprostatere-biopsyafterradiationandforradiation
prostatecancer:preliminaryclinicalresults.TechnolCancerResTreat2010, therapywithrisingprostate-specificantigenlevelsafterradical
9:473–477. prostatectomy.AmericanSocietyforTherapeuticRadiologyand
17. FreemanDE,KingCR:Stereotacticbodyradiotherapyforlow-riskprostate OncologyConsensusPanel.JClinOncol1999,17:1155.
cancer:five-yearoutcomes.RadiatOncol2011,6:3. 36. NormanGR,SloanJA,WyrwichKW:Interpretationofchangesinhealth-
18. FriedlandJL,FreemanDE,Masterson-McGaryME,SpellbergDM: relatedqualityoflife:theremarkableuniversalityofhalfastandard
Stereotacticbodyradiotherapy:anemergingtreatmentapproachfor deviation.MedCare2003,41:582–592.
localizedprostatecancer.TechnolCancerResTreat2009,8:387–392. 37. CrookJ,GillanC,YeungI,AustenL,McLeanM,LockwoodG:PSAKinetics
19. JabbariS,WeinbergVK,KaprealianT,HsuIC,MaLJ,ChuangC,DescovichM, andPSABounceFollowingPermanentSeedProstateBrachytherapy.Int
ShiaoS,ShinoharaK,RoachM,GottschalkAR:Stereotacticbody JRadiatOncolBiolPhys2007,69:426–433.
radiotherapyasmonotherapyorpost-externalbeamradiotherapyboost 38. ButzbachD,WatermanFM,DickerAP:Canextraprostaticextensionbe
forprostatecancer:technique,earlytoxicity,andPsaresponse. treatedbyprostatebrachytherapy?Ananalysisbasedonpostimplant
IntJRadiatOncol2012,82:228–234. dosimetry.IntJRadiatOncolBiolPhys2001,51:1196–1199.
20. KatzAJ,SantoroM,AshleyR,DiblasioF,WittenM:Stereotacticbody 39. DavisBJ,PisanskyTM,WilsonTM,RothenbergHJ,PacelliA,HillmanDW,
radiotherapyfororgan-confinedprostatecancer.BMCUrol2010,10:1. SargentDJ,BostwickDG:Theradialdistanceofextraprostaticextension
21. KingCR,BrooksJD,GillH,PrestiJCJr:Long-TermOutcomesFroma ofprostatecarcinoma.Cancer1999,85:2630–2637.
ProspectiveTrialofStereotacticBodyRadiotherapyforLow-RiskProstate 40. SohaydaC,KupelianPA,LevinHS,KleinEA:Extentofextracapsular
Cancer.IntJRadiatOncolBiolPhys2012,82:877–882. extensioninlocalizedprostatecancer.Urology2000,55:382–386.
Juetal.RadiationOncology2013,8:30 Page10of10
http://www.ro-journal.com/content/8/1/30
41. TehBS,BastaschMD,WheelerTM,MaiW-Y,FrolovA,UhlBM,LuHH,
CarpenterLS,ChiuJK,McGaryJ,etal:IMRTforprostatecancer:Defining
targetvolumebasedoncorrelatedpathologicvolumeofdisease.
IntJRadiatOncolBiolPhys2003,56:184–191.
42. AlcantaraP,HanlonA,BuyyounouskiMK,HorwitzEM,PollackA:Prostate-
specificantigennadirwithin12monthsofprostatecancerradiotherapy
predictsmetastasisanddeath.Cancer2007,109:41–47.
43. RayME,LevyLB,HorwitzEM,KupelianPA,MartinezAA,MichalskiJM,
PisanskyTM,ZelefskyMJ,ZietmanAL,KubanDA:Nadirprostate-specific
antigenwithin12monthsafterradiotherapypredictsbiochemicaland
distantfailure.Urology2006,68:1257–1262.
44. KubanDA,TuckerSL,DongL,StarkschallG,HuangEH,CheungMR,LeeAK,
PollackA:Long-TermResultsoftheM.D.AndersonRandomizedDose-
EscalationTrialforProstateCancer.IntJRadiatOncolBiolPhys2008,
70:67–74.
45. SandaMG,DunnRL,MichalskiJ,SandlerHM,NorthouseL,HembroffL,Lin
X,GreenfieldTK,LitwinMS,SaigalCS,etal:Qualityoflifeandsatisfaction
withoutcomeamongprostate-cancersurvivors.NEnglJMed2008,
358:1250–1261.
46. SimoneNL,MenardC,SouleBP,AlbertPS,GuionP,SmithS,GodetteD,
CrouseNS,SciutoLC,Cooley-ZgelaT,etal:Intrarectalamifostineduring
externalbeamradiationtherapyforprostatecancerproducessignificant
improvementsinQualityofLifemeasuredbyEPICscore.IntJRadiat
OncolBiolPhys2008,70:90–95.
47. WiegnerEA,KingCR:Sexualfunctionafterstereotacticbodyradiotherapy
forprostatecancer:resultsofaprospectiveclinicaltrial.IntJRadiatOncol
BiolPhys2010,78:442–448.
doi:10.1186/1748-717X-8-30
Citethisarticleas:Juetal.:Hypofractionatedstereotacticbody
radiationtherapyasmonotherapyforintermediate-riskprostatecancer.
RadiationOncology20138:30.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submit
