International Journal of

Radiation Oncology

biology physics

www.redjournal.org

Clinical Investigation

Role of the Technical Aspects ofHypofractionated Radiation Therapy Treatmentof Prostate Cancer: A ReviewStefania Clemente, PhD,* Roberta Nigro, PhD,y Caterina Oliviero, PhD,*Chiara Marchioni, PhD,y Marco Esposito, PhD,z

Francesca Romana Giglioli, PhD,x Pietro Mancosu, PhD,jj

Carmelo Marino, PhD,{ Serenella Russo, PhD,z Michele Stasi, PhD,#

Lidia Strigari, PhD,** Ivan Veronese, PhD,yy and Valeria Landoni, PhD**

*Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della BasilicataRionero in Vulture, Potenza, Italy; yAzienda Sanitaria Locale Rieti, Roma, Italy; zAzienda Sanitaria,Firenze, Italy; xAzienda Ospedaliera Citta della Salute e della Scienza di Torino, Torino, Italy;kHumanitas Clinical and Research Hospital, Rozzano, Milano, Italy; {Humanitas Centro Catanese diOncologia, Catania, Italy; #Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy;**Istituto Nazionale Tumori Regina Elena, Roma, Italy; and yyUniversita’ degli Studi di Milano,Milano, Italy

Received Jun 30, 2014, and in revised form Aug 1, 2014. Accepted for publication Aug 4, 2014.

The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostatecancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation(HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniquesused to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HFregimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Asso-ciation of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, andrectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and fre-quency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneityof the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy.� 2015 Elsevier Inc.

Reprint requests to: Stefania Clemente, PhD, Istituto di Ricovero e Cura

a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata

(IRCCS CROB), Service of Medical Physics, 1 Padre Pio St, 85028, Rionero

in Vulture, Potenza, Italy. Tel: (þ39) 0972-726373; E-mail: clemente_

stefania@libero.it

Conflict of interest: none.

Supplementary material for this article can be found at

www.redjournal.org.

AcknowledgmentsdThe authors thank Simona Marzi; Raffaella

Marconi for the English revision of the manuscript; and the staff of the

Library of the National Cancer Institute Regina Elena (Gaetana Cognetti,

Fabio D’Orsogna, and Francesca Servoli) for helping in the PubMed

search.

Int J Radiation Oncol Biol Phys, Vol. 91, No. 1, pp. 182e195, 20150360-3016/$ - see front matter � 2015 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.ijrobp.2014.08.006

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 183

Introduction

Hypofractionated (HF) radiation therapy of prostate cancerhas garnered increasing attention owing to its proposed lowa/b value, which is close to 1.5 Gy (1, 2). Hypofractionatedtreatments increase the therapeutic ratio and amelioratelogistical inconveniences for both patients and their pro-viders (2-4).

Supporting data have recently been summarized in asystematic review by Tree et al (5). Importantly, extreme(EHF) and moderate (MHF) hypofractionated regimens donot lead to higher toxicity to the nearby rectum and bladderthan conventional regimens (2 Gy per fraction) and havethe additional benefit of biochemical control.

The effect of geometric uncertainties is known to beone of the major concerns in radiation dose delivery inprostate cancer (6). These uncertainties are mostly due topatient setup errors and extensive motion of the rectumand bladder that is dependent on organ filling. In thisregard, an augmented impact of geometric uncertainties isexpected when high doses per fractions are adopted. Thiscould occur because in HF treatments, any single target-ing error causes a greater biologic impact by consistentlyunderdosing the target organ at greater expense of theorgans at risk (OARs) (7).

Several technological innovations have boosted thehigh-precision localization of the prostate during treatment,allowing the delivery of highly conformed dose fractions toa well-defined target with sharp dose fall-off toward thebladder and rectum (8). However, multiple technical pa-rameters and operational variables can affect the correctlocalization of the prostate and the reproducibility of theprocedures. For this reason, we focused our attention onthese features to investigate the potential correlation/asso-ciation with clinical outcome in prostate cancer patientstreated with EHF and MHF schemes.

We performed a search of the available literature onthe PubMed database, concentrating on technical anddosimetric aspects such as delivery techniques, immobi-lization devices, setup position, rectum and bladderpreparation, imaging, margins, localization imaging on-line systems, dose prescriptions, dose constraints, andclinical outcome.

Methods and Materials

Search strategy

An extensive PubMed search was performed on April 31,2014, including the search terms (((“Prostatic Neoplasms/radiotherapy”[Mesh] AND “Radiosurgery”[Mesh])) OR((Prostat* AND (hypofraction* OR SBRT OR “stereobodyradiotherap*” OR stereotactic OR radiosurger*))) NOTproton* NOT ion* NOT metastases) and using the filters:published in the last 10 years, English. A reference list of433 articles resulted from the database according to this

criterion. The list of articles was screened by 2 independentresearchers, and 158 articles were excluded because theyreferred to brachytherapy studies or where not strictly onhumans.

Studies referring to HF regimens (defined as more than2 Gy per fraction) were included if they containedbiochemical outcomes and/or standardized toxicity data.The bibliographies of the selected articles were alsoreviewed to identify additional references.

Data analysis

Because there was not weighting of group sizes or insti-tutional clustering of outcomes, a descriptive analysis thatfocused on contrasting and combining results from theselected studies was conducted to identify patterns amongthe study results or interesting relationships that mayappear in the context of multiple studies.

The biochemical relapse-free survival (bRFS) parameterat a median follow-up of 4.8 years and acute and late grade2 or higher (�G2) genitourinary (GU) and gastrointestinal(GI) toxicities were summarized according to treatmentvariables such as rectum and bladder preparation, targetvolume definition (with or without the inclusion of theseminal vesicle), magnetic resonance imaging (MRI)-basedcontouring, margins adopted, immobilization frames, fre-quency, and the kind of image guidance (IGRT) andtracking systems.

Results

In total, 275 reports were retrieved from the initial PubMedsearch. As a result of the abstracts reading, 236 wereexcluded because they did not fit exactly with the inclusioncriteria. There was no discrepancy between the 2 reviewers.

We reviewed the data from 733 and 3454 patients from15 EHF (9-23) and 24 MHF (24-47) reports, respectively.

Technical aspect of treatment

All treatment aspects, including delivery techniques, frac-tionation schemes, frames, OAR preparation, target volumedefinition, and IGRT strategies, are reported in Tables 1 and2 and Tables 3 and 4 for EHF and MHF studies,respectively.

Delivery techniques

In most studies, 3-dimensional conformal radiation therapyor intensity modulated radiation therapy treatments weredelivered using linear accelerators. Two (13%) and 10(67%) of the EHF studies used tomotherapy and Cyber-knife units, respectively, whereas the MHF studies usedlinear accelerator units.

Table 1 Summary of treatment characteristics from studies using extreme hypofractionation

Reference Device Technique Energy (MV) Frame Position

Madsen et al

2007 (9)

Linac 3D-CRT, 6 fields NR Specially

designed

cushion

Flex prone

Boike et al 2011 (10) Linac-Tomotherapy IMRT 6-15 NR Supine

Kim et al 2014 (11) Linac-Tomotherapy IMRT 6-15 NR Supine

Loblaw

et al 2013 (12)

Linac IMRT 6 Vacuum

custom

lock bag

Supine

Freeman

et al 2011 (13)

Cyberknife 150-200 fields 6 NR NR

King et al 2012,

2013 (14, 15)

Cyberknife NR 6 NR Supine

Jabbari et al 2012

(16)

Cyberknife NR 6 NR NR

Kang et al 2011 (17) Cyberknife NR 6 Thermoplastic

sheets

Supine

McBride

et al 2012 (18)

Cyberknife NR 6 Thermoplastic

sheets

Supine

Tang et al 2008 (19) Linac IMRT 6 Vacuum cushion Supine

Lee et al 2012 (20) Cyberknife NR 6 Vacuum cushion Supine

Katz et al 2010-14

(21-22)

Cyberknife 152 fields 6 NR Supine

Chen et al 2013 (23) Cyberknife 247 fields

(range, 199-289)

6 NR Supine

Abbreviations: 3D-CRTZ 3-dimensional conformal radiation therapy; bSVZ base of seminal vesicles; CBCTZ cone beam computedtomography; CT Z computed tomography; EPID Z electronic portal imaging device; IMRT Z intensity modulated radiation therapy;Linac Z linear accelerator; MRI Z magnetic resonance imaging; MV Z megavoltage; NR Z not reported; PZprostate gland;post Z posterior; PTV Z planning target volume; SV Z seminal vesicles; US Z ultrasound.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics184

Immobilization frames and setup position

Immobilization frames were used in 6 EHF studies (40%)and 14 MHF studies (58%). Two MHF studies (8%) re-ported no immobilization. In EHF studies, a customizedvacuum-lock bag was usually used. In 8 MHF studies(33%), knee, foot, and ankle supports were also used. Pa-tients were placed in the supine position in 11 EHF studies(73%) and 17 MHF studies (79%). Patients were placed in

the prone position in only 1 EHF study (4%). The positionwas not specified in the remaining studies.

Bowel/rectum and bladder preparation

Recommendations for bowel/rectum preparation were givenin 6 EHF studies (40%) and 11 MHF studies (46%). Bladderpreparation occurred in 4 EHF studies (27%) and 15 MHFstudies (63%).Generally, patientswere treatedwith an empty

Preparation bowel Preparation bladder Imaging

Prostate

volume (cm3) Margin (mm) Markers Method Correction

Empty rectum (diet

and simethecone 3 d

before simulation

and each treatment)

NR CT & MRI P (56.4; range,

13.66-134.5)

0 3 markers EPID (daily) NR

Empty rectum (milk of

magnesia, 30 mL the

evening before). Fleet

enema 1 h before

simulation and each

treatment) Rectal

balloon (60-100 cm3)

Full (for simulation

and treatment)

CT or CT

& MRI

P (<60) 3 Gold seeds

or Calypso

transponders

MV or KV

CBCT

NR

Empty rectum (milk of

magnesia, 30 mL the

evening before). Fleet

enema 1 h before

simulation and each

treatment) Rectal

balloon (60-100 cm3)

Full (for simulation

and treatment)

CT or CT

& MRI

P (35.4; range

12.3-60)

3 Gold seeds or

Calypso

transponders

MV or KV

CBCT

NR

Empty rectum Full (250-500 mL

of water before

simulation and

treatment)

CT P (<90) 4 3 gold seeds EPID (daily) NR

NR NR CT (1.25 mm) or

CT & MRI

(1-2 mm)

NR 2 3 or 4 gold

seeds

KV & tracking NR

NR NR CT (1.25 mm) NR 5, 3 post 3 gold seeds KV & tracking NR

NR NR CT & 3T MRI

(3 mm)

P (47) 0/2, 0 post 3 gold seeds KV & tracking NR

NR NR CT (2 mm) NR 4, 2 post 6 gold seeds KV & tracking NR

NR NR CT & MRI

(1-1.5 mm)

P (80 at US) 5, 3 post 4 gold seeds KV & tracking NR

Empty rectum Full (250 mL

of water

1 h before

simulation)

CT P (<60) 4 3 gold seeds EPID (daily) NR

NR NR CT (1.5 mm) NR 5, 2/3 post 3 or 4 gold

seeds

KV & tracking NR

Empty rectum

(Dulcolax and

Fleet enema)

NR CT & MRI

(1.5 mm)

NR 5, 3 post 4 seeds KV & tracking NR

NR NR CT & MRI P þ bSV (PZ85 g;

PTV Z 135;

range, 61-258)

5, 3 post 4 gold seeds KV & tracking NR

Table 1 Summary of treatment characteristics from studies using extreme hypofractionation (continued)

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 185

rectum (enema preparation) and a moderately full or fullbladder. The use of an endorectal balloon was reported in 1EHF study, but no tissue spacers were used.

Imaging for contouring

Coregistration of MRI and computed tomography (CT)images for target and OAR contouring was reported in 9EHF studies (60%) and 5 MHF studies (21%). Only CT

imagingebased contouring was performed in 6 EHFstudies (40%) and 17 MHF studies (71%). The slicethicknesses ranged from 1 to 3 mm for CT scans and from 2to 5 mm for MRI scans.

Volume definition and relative margins

In 8 EHF studies (53%), it was clearly stated that theclinical target volume (CTV) involved the prostate only or

Table 2 Summary of treatment characteristics from studies using extreme hypofractionation

Reference

Total

dose

(Gy)

Dose

per

fractions

(Gy)

No. of

fractions

Overall

treatment

(d)

PTV

coverage Rectum constraints

Bladder

constrainsts

Other

constraints

Madsen et al

2007 (9)

33.5 6.7 5 5 DGTV >90% V33.5 Z 1.06 cm3

V30.15 Z 3.66 cm3

V26.8 Z 5.20 cm3

V16.75 Z 10.63 cm3

V10.05 Z 18.09 cm3

NR NR

Boike et al

2011 (10)

45/45.7/50 9/9.14/10 5 8 D95% � 100% Dmax <47.25/47.98/52.5

(anterior wall)

Dmax (�3 cm3)

<40.50/41.13/45

(lat wall)

Dmax <20.25/20.57/

22.50 (posterior wall)

Dmax

<47.25/47.98/52.5

V18.3

< 10 cm3 (wall)

NR

Kim et al

2014 (11)

45/47.5/50 9/9.5/10 5 8 D95% � 100% Dmax

<47.25/47.98/52.5

(anterior wall)

Dmax (�3 cm3)

<40.50/41.13/45

(lat wall)

Dmax <20.25/20.57/

22.50 (posterior wall)

Dmax

<47.25/47.98/52.5

V18.3

< 10 cm3 (wall)

NR

Loblaw et al

2013 (12)

35 7 5 29 D99% > 95%

Dmax �105%

V28 � 40%

V32 � 33%

V32 � 40% Penile bulb

V20 � 90%

Freeman et al

2011 (13)

35/36.25 7/7.25 5 5 D95% � 100% V18 < 50%

V29 < 20%

V32.62 < 10%

V36.25 < 5%

V36 < 1 cm3

V37 < 10 cm3 NR

King et al 2012,

2013 (14, 15)

36.25 7.25 5 7.5 D95% � 100% V18.13 < 50%

V29.1 < 20%

V32.62 < 10%

V36.25 < 5%

V18.13 < 40%

V36.25 < 10%

Femoral heads

V14.5 < 5%

Jabbari et al

2012 (16)

38 9.5 4 NR NR V14.25 < 2 cm3 V14.25 < 2 cm3 Urethra

V22.8 < 10%

Kang et al

2011 (17)

32/34/36 8/8.5/9 4 4 D95% � 77-80% V(16,17,18) <50%

Dmax <(32,34,36) Gy

NR NR

McBride et al

2012 (18)

36.25/37.5 7.25/7.5 5 10 D95% � 100% V36 < 1 cm3 V37.5 Gy < 5 cm3 Urethra V49 < 10%

Penile bulb

V29.5 < 50%

Tang et al

2008 (19)

35 7 5 29 D95% � 99%

Dmax �105%

V28 � 40% and

V32 � 33%

V32 � 40% Penile bulb V20

� 90%

Lee et al

2012 (20)

36 7.2 5 29 D95% � 100% V18 < 50%,V36 < 5% NR NR

Katz et al 2010,

2014 (21, 22)

36.25/35 7.25/7 5 NR D95% � 100% V75 � 3 cm3 V75 � 4 cm3 Penile bulb

Dmean <40%

Femoral heads

Dmean <15%

Chen et al

2013 (23)

36.25/35 7.25/7 5 10.6 (mean) D95% � 100% V36 < 1 cm3

V36.25 < 5%

V32.63 < 10%

V29 < 20%

V27.19 < 25%

V18.13 < 50%

V36.25 < 10%

V18.13 < 40%

Penile bulb V29.5

< 50%

Membranous

urethra V37

< 50%

Sigmoid colon

V30 < 1 cm3

Testicles

V2 <20%

Abbreviations: D Z dose received by a given structure or a given percentage of structure; Dmax Z maximum dose to structure; Dmean Z mean dose

to the structure; GTV Z gross tumor volume; V Z volume receiving a given dose. Other abbreviation as in Table 1.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics186

the prostate plus seminal vesicles (SV), whereas in theremaining EHF studies the definition of the CTV volumewas not specified. In the MHF studies, the CTV involvedonly the prostate gland in 3 studies (13%) and the prostate

plus SV in 11 studies (46%). Margins to derive the planningtarget volume (PTV) were given isotropically in 6 EHFstudies (40%) (from 0 to 4 mm) and in 4 MHF studies(17%) (from 7 to 15 mm).

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 187

In the remaining studies, anisotropic volumetricexpansion was performed. A margin of 4 to 5 mm, reducedto 2 to 3 mm in the posterior direction, was used in theEHF studies, whereas a margin of 7 to 20 mm, reduced to 3to10 mm in the posterior direction, was used in the MHFstudies.

Localization systems and IGRT techniques

For treatment localization of the prostate, the use ofimplanted fiducial markers (from 3 to 6) was reported in theEHF studies. Fiducials were used in only 5 MHF studies(21%). Furthermore, 4 MHF studies (17%) used skinmarkers. A corrective action was generally taken whenmarker displacements of 2 to 3 mm were recorded.

Patient setup verification was performed with differenttiming using a 2-dimensional electronic portal imagingdevice, 3-dimensional cone beam CT (CBCT), or 3-dimensional ultrasound (US) localization methods. Local-ization using Cyberknife was accomplished using 2orthogonal kilovoltage x-ray images providing real-timestereoscopic image guidance and automatic correction formovements of the prostate throughout treatment.

Fractionation schemes and OAR dose constraints

The prescribed dose for EHF studies ranged from 33.5 to50 Gy, with a dose per fraction from 6.7 to 10 Gy given in atotal of 4 to 5 fractions. The overall treatment time was 4-29 days (Table 2). The prescribed dose for MHF studiesranged from 51 to 72 Gy, with a dose per fraction from 2.63to 3.64 Gy given in a total of 14 to 30 fractions. The overalltreatment time in these studies was 19-45 days (Table 4).The dose prescriptions and the applied dose constraints toOARs are also reported (Tables 2 and 4). No adaptivestrategy of replanning was adopted in any of the analyzedstudies.

Clinical outcome

In EHF studies, the reported median 4-year bRFS wasapproximately 86%-100% for low-risk, 86%-100% forintermediate-risk, and 78%-100% for high-risk disease.Acute � G2 GU and GI toxicity reported were 1%-45%and 0-21%, respectively. Late � G2 GU and GI toxicitywere 1-20% and 0-28%, respectively. The median 5-yearbRFS reported in MHF studies was approximately 50%-100%, 56%-100%, and 31%-99% for low-risk, intermedi-ate-risk, and high-risk disease, respectively. Acute � G2GU and GI toxicity were 0-47% and 4%-38%, respectively.Late � G2 GU and GI toxicity were 0-45% and 0-33%,respectively.

Tables 5 and 6 show the distribution of bRFS and �G2toxicity (acute and late GU and GI) as a function of rectumand bladder preparation, MRI contouring, target volume(only prostate or prostate plus SV), margins applied to

CTV, 2-dimensional or 3-dimensional imaging duringtreatment, imaging frequency, and tumor tracking.

Discussion

The aim of this study was to describe the state of the art ontechnical strategies used in HF radiation therapy treatmentsand their potential correlation with clinical outcome. Tar-geting this goal, a review of published studies on HF reg-imens in prostate cancer patients treated with EHF andMHF schemes was performed.

We would like to point out that our work may be not acomprehensive and exhaustive analysis of the knownliterature; neither is it a systematic review, but it can beconsidered a snapshot of the literature currently availableon the issue, especially addressing technical points of view.

The HF studies we analyzed used considerably variedtechniques to manage intra-/interfraction motion of theprostate gland and adjacent organs, as well as to deliverradiation doses. Prostate motion has been associated withchanges in rectum and bladder content and, to a lesserextent, respiratory motion (48). Changes in patient posturewere also of importance (eg, relaxation of pelvic muscles).To reduce motion, specific patient positioning, immobili-zation strategies, controlled diet, and rectum/bladder fillinghave been practiced by different groups (49-51).

In the HF studies we analyzed, the most commonly usedpatient position was the supine position. However, theoptimal treatment position for the prostate remainscontroversial and inconclusive because several studies (48)have reported advantages and disadvantages for both supineand prone approaches. An advantage of the prone positionis that the irradiation dose to the rectum is reduced becausethe SVare pulled away from the rectum (52). Moreover, thegeometric relationship between the prostate and the pelvicbony anatomy is more consistent in the prone position andseems to be very important for centers using bony struc-tureebased positioning (53). Conversely, a disadvantage ofthe prone position is greater prostate motion compared withthe supine position (54). Additionally, the supine position ismore comfortable for patients and more convenient fortherapists than the prone position.

Immobilization frames were routinely used to reducethe degree of spatial uncertainty secondary to positioningerror. Pelvic vacuum cushions, thermoplastic sheets, foamagents, and/or leg, knee, ankl,e and foot supports weregenerally used in the reviewed studies. Despite reportsthat a whole-body cushion ensures more reproducibility(49), the usefulness of specific supports must be sub-stantiated. For example, the use of a knee support duringprostate irradiation, which prevents dorsal rectum shiftsand prostate rotation at the apex around the lefterightaxis, decreases the dose delivered to the rectal wall (55). Apositive impact regarding biochemical control and toxic-ities was observed in patients for whom a frame was used(Tables 5 and 6).

Table 3 Summary of treatment characteristics from studies using moderate hypofractionation

Reference Device Technique Energy (MV) Frame Position

Preparation

bowel

Lukka et al 2005 (24) Linac 3D-CRT

3-4 fields

�10 NR Supine NR

Higgins et al 2006 (25) Linac 3D-CRT

3 fields

15 NR NR NR

Hoffman et al 2014 (26) Linac IMRT NR NR NR NR

Yeoh et al 2011 (27) Linac 2D-3D-CRT

4 fields

6-23 NR NR NR

Arcangeli et al 2011, 2012

(28, 29)

Linac 3D-CRT 6

fields

15 Body fix Supine NR

Pollack et al 2013 (30) Linac IMRT 6 Feet fixation Supine Empty rectum

Martin et al 2007 (31) Linac IMRT 7

fields

6 Vacuum cushion

þ knee immobilizer

þ feet fixation

Supine Empty

rectum (milk

of magnesia

the night

before

treatment)

Kupelian et al 2005, 2007

(32, 33)

Linac IMRT 5

fields

10 Minimal

immobilization

Supine NR

Rene et al 2010 (34) Linac 3D-CRT 5

fields

18 Knee immobilizer

þ feet fixation

Supine Empty rectum

Jereczek-Fossa et al

2011 (35)

Linac 3D-CRT 2

dynamic

arc

6 Leg immobilizer Supine Empty rectum

Zilli et al 2011 (36) Linac IMRT 5-11

fields

6 Vacuum body

cushion

Supine Empty rectum

(enema)

Di Staso et al 2010 (37) Linac 3D-CRT 5

fields

6-15 NR NR NR

Patel et al 2013 (38) Linac 3D-CRT 5

fields

18 NR Supine Empty rectum

Fontayne et al 2012 (39) Linac IMRT or

dynamic

arc

NR NR NR NR

Junius et al 2007 (40) Linac IMRT 5

fields

18 Feet fixation Supine Empty rectum

(enema)

Koukourakis et al 2011 (41) Linac 3D-CRT 4

fields

NR NR Supine NR

Leborgne et al 2012 (42) Linac 3D-CRT 4

fields

6-15 Without Supine Empty rectum

(enema)

Lock et al 2011 (43) Linac IMRT 10 Knee immobilizer Supine Empty rectum

(if volume

<100 cm3

re simulation)

Valeriani et al 2011 (44) Linac 3D-CRT 5

fields

15 Feet fixation Supine Empty rectum

(mini enema)

Thomson et al 2012 (45) Linac IMRT 5

fields

8 Without Supine NR

Wu et al 2012 (46) Linac 3D-CRT 4-6

fields or

IMRT

NR Ankle/foot

immobilizer

Supine Empty

Yassa et al 2008 (47) Linac 3D-CRT 4

fields

18 Vacuum body

cushion

Supine Without

Abbreviations: ADC Z apparent diffusion coefficient; IGRT Z image guided radiation therapy; IR Z infrared. Other abbreviations asin Table 1.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics188

Preparation

bladder Imaging Target volume (cm3) Margin (mm) Marker Method (frequency) Correction

Full CT P (<1 mL) 15, 10 post NR EPID (at day

1 & randomly)

NR

NR CT P þ bSV 10, 6 post NR NR NR

NR NR P þ SV (56.7) 10-15, 4-8 post NR US or X-ray NR

NR CT P þ bSV 15 NR NR NR

NR CT (5 mm) P þ SV (PTV Z180 � 44)

10, 6 post Without EPID (daily) NR

Full CT (3 mm)

& MRI

P þ SV 7, 3 post NR US (daily) NR

Full (500 mL

of water 1 h

before

treatment)

CT (2 mm) P þ bSV 10, 7 post 3 gold seeds EPID (daily) If markers

shifts �3 mm

NR CT P or P þ SV 5, 4 post, 8 lat Skin markers US (daily) NR

Full CT (5 mm) P 7 NR US (daily) NR

Full (500 mL

water of 1 h

before CT

and treatment)

CT (3 mm) P or P þ SV (<100) 7, 3 post 2 gold seeds US or X-ray or

CBCT (daily)

NR

Empty CT (3 mm)

& MRI

P or P þ SV 10, 6 post Skin markers EPID or IR (daily)

CT (weekly)

If markers

shifts �1 cm

Full (500 mL

of water 2 h

before

treatment)

CT P or P þ SV 8, 6 post NR EPID or CBCT NR

Full CT (5 mm) P 7 NR US (daily) NR

NR CT or CT

& MRI

P or P þ SV 3-10 Skin markers

or seeds

EPID or US (daily) NR

Full (250 mL

of water)

CT with contrast

(3 mm) & MRI

P or P þ SV 10 (P), 5 (SV) NR US (daily) or EPID NR

NR NR P þ SV NR NR NR NR

Full CT (3.2 mm) P þ SV (<70) 11, 8 ant, 5 post 2 gold seeds EPID (twice weekly) NR

Full (350 mL

of water 2 h

before

treatment)

CT (3 mm) P and P þ SV (42.6) 7.5 5 gold seeds EPID (at day 1) US

or EPID (daily)

If shifts �3 mm

(US); if shifts

�1 mm (EPID)

Full (500 mL of

water 30 min

before)

CT (2.5 mm

with contrast

& MRI

(diffusion ADC)

P þ SV 8 (5 if IGRT), 5 post NR EPID or CBCT (daily) NR

Empty CT (5 mm) P or P þ SV 10, 7 post NR CBCT (at days

1 & 3 then weekly)

NR

Full CT P or P þ bSV 10, 5 post 3 gold seeds EPID or X-ray (daily) If shifts �3 mm

Full (500 mL

of water 2 h

before)

CT P or P þ SV 20, 15 post NR US (daily) If shifts �5 mm

Table 3 Summary of treatment characteristics from studies using moderate hypofractionation (continued)

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 189

Table 4 Summary of dosimetric characteristics from studies using moderate hypofractionation

Reference

Total dose

(Gy)

Dose per

fractions

(Gy)

No. of

fractions

Overall

treatment (d) PTV coverage Rectum constraints

Bladder

constrainsts Other constrainsts

Lukka et al

2005 (24)

52.5 2.63 20 26 (5 d/wk) D100% � 95% NR NR NR

Higgins et al

2006 (25)

52.5 2.63 20 26 NR NR NR NR

Hoffman et al

2014 (26)

72 2.4 30 NR D95% � 100% V65 < 20% V65 < 20% NR

Yeoh et al

2011 (27)

55 2.75 20 26 D100% � 95% NR NR NR

Arcangeli 2011,

2012 (28, 29)

62 3.1 20 33 D90% � 100% V54.25 < 30%

V38.75 < 50%

(wall)

V54.25 < 50%

V38.75 < 70%

(wall)

NR

Pollack et al

2013 (30)

70.2 2.7 26 36 D95% � 100% V50 < 17%

V31 < 35%

V50 < 25%

V31 < 50%

NR

Martin et al

2007 (31)

60 3 20 26 (5 d/wk) D100% � 95%

Dmax �105%

Dmin �95%

Dmax <61 Gy

V40 < 70% (wall)

Dmax <61 Gy

V40 < 70%

(wall)

Femoral heads

Dmax <40 Gy

Kupelian et al

2007 (32, 33)

70 2.5 28 38 D100% Z 75.3 Gy

Dmin Z 67.5 Gy

Dmax Z 80.2 Gy

(mean values)

V50 < 30% Dmax

<74 Gy

V55 < 30%

Dmax <74 Gy

NR

Rene et al

2010 (34)

66 3 22 <37 NR NR NR NR

Jereczek-Fossa

et al 2011 (35)

70.2 2.7 26 36 NR V61 < 30%

V35 < 60%

V61 < 50% Femoral heads

V43 � 50%

Zilli et al

2011 (36)

56 4 14 45 (2 d/wk) Dmax �110%

Dmin �95%

Dmax <53.2 Gy

V50.4 < 30%

V28 < 50%

Dmax <53.2 Gy

V50.4 < 30%

V28 < 50%

Femoral heads

V30 < 5%

V20 < 50%

Di Staso et al

2010 (37)

54.3 3.62 15 33 (3 d/wk) D100% � 95% V49 � 17%

V30 � 35%

V49 � 25%

V30 � 50%

NR

Patel et al

2013 (38)

66 3 22 30 D100% � 95% NR NR NR

Fontayne et al

2012 (39)

56 3.5 16 25 D100% � 95%

Dmin �90%

Dmax �107%

Dmax �53.2 Gy

V50.4 < 30%

Dmax �54.6 Gy

V42 < 50%

Femoral heads

Dmax �28 Gy

Junius et al

2007 (40)

66 2.64 25 33 D99% � 90%

D95% � 95%

D50% � 100%

Dmax �66.5 Gy

V45 < 50%

V38 < 70%

Dmax �66.5

(wall)

NR

Koukourakis

et al

2011 (41)

51 3.64 15 19 NR NR NR NR

Leborgne et al

2012 (42)

60-63 3-3.15 20 33 (4 d/2 wk) NR V61 < 15%

V56.5 < 25%

V48.5 < 40%

NR NR

Lock et al

2011(43)

63.2 3.16 20 26 (5 d/wk) D95% Z 100%

Dmin �95%

Dmax �107%

V61 < 15%

V57 < 25%

V53 < 35%

V49 < 50%

V65 < 15%

V61 < 25%

V57 < 35%

V52 < 50%

Penile bulb

V42.9 � 100%

Femoral heads

V37 � 80%

Valeriani et al

2011 (44)

54.75 3.65 15 33 (3 d/wk) D100% � 95% V45 < 35%

V52 < 25%

V40 < 50% NR

Thomson et al

2012 (45)

57-60 3 19 - 20 25 & 26

(5 d/wk)

D100% � 95% Dmax <47.5 Gy

V45 < 50%

Dmax <47.5 Gy Femoral heads

Dmax �30 Gy

Wu et al

2012 (46)

55 3.44 16 25 (4 d/wk) D100% � 98%

D2% �107%

V55 < 15%

V51 < 25%

V45 < 35%

V37 < 50%

V55 < 15%

V51 < 25%

V45 < 35%

V37 < 50%

Femoral heads

Dmax �33 Gy

Yassa et al

2008 (47)

57 3 19 25 D100% � 95% NR NR NR

Abbreviations as in Table 2.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics190

Displacements of the prostate relative to the radiationbeams occur not only as a result of patient positioning butalso owing to different filling levels and pressures from thebladder and rectum. Graf et al (56) reported reduced

prostate motion when patients were appropriately instruc-ted regarding constant bladder and rectum filling. In mostof the selected HF studies, the bladder volume was keptconstant by having the patient empty the bladder and drink

Table 5 Biochemical relapse-free survival (bRFS) from studies at a median follow-up of 4.8 years

Parameter

Low risk Intermediate risk High risk

Mean (%) Median (%) SD (%) Mean (%) Median (%) SD (%) Mean (%) Median (%) SD (%)

FRAME Y 92.8 94.5 6.5 88.2 86 8.3 83.3 81.8 11.6FRAME N 69.6 69.6 27.5 d d d d d dRectum PREP Y 93.0 93.5 6.4 90.7 91 8.1 80.3 77.6 10.3Rectum PREP N d d d 79.0* d d d d dBladder PREP Y 89.7 93.5 14.0 87.8 88.0 9.5 81.2 77.5 12.4Bladder PREP N 94.4 94.0 5.3 93.9 94.8 7.2 90.4 92.0 10.5MRI Y 94.2 96.4 7.2 93.6 95.0 8.5 88.7 89.0 10.5MRI N 86.8 91.5 15.2 84.0 85.0 13.1 71.7 72.0 25.1Only P Y 95.4 97.9 4.8 99.3 100.0 1.2 100* d dOnly P N 86.1 91.3 16.0 83.7 84.0 12.7 75.6 77.5 22.2MARG �5 mm Y 85.7 91.2 15.1 83.5 84.0 12.4 71.7 74.8 21.6MARG �5 mm N 95.9 97.9 4.9 95.9 100.0 6.4 92.1 98.0 9.9MARKERS Y 95.1 95.0 4.5 91.4 91.0 8.2 84.9 83.0 11.6MARKERS N 87.0* d d d d d d d dIMG3D Y 81.7 95.0 27.5 89.0 89.0 15.6 d d dIMG3D N 93.4 94.0 6.0 90.2 90.3 8.4 84.9 83.0 11.6IMGDAY Y 94.1 95.0 5.9 92.1 94.0 7.8 85.9 84.5 11.4IMGDAY N 75.6 87.6 22.1 78.0* d d d d dTRACK Y 95.8 97.7 5.2 95.1 100.0 6.8 92.1 98.0 9.9TRACK N 87.9 91.7 14.3 85.6 88.0 13.3 71.7 74.8 21.6

Mean, median, and standard deviation (SD) values of percentage incidence in which an immobilization frame was used (FRAME Y) or not (FRAME

N), a bladder or rectum preparation was (PREP Y) or was not (PREP N) performed, contouring was (MRI Y) or was not (MRI N) performed on magnetic

resonance images, only the prostate was treated (only P Y) or the seminal vesicles were also treated (only P N), a margin of �5 mm was (MARG �5 mm

Y) or was not (MARG �5 mm N) applied to the clinical target volume, markers were used (MARKERS Y) or not (MARKERS N), imaging methods to

verify treatment were (IMG 3DY) or were not (IMG 3D N) 3-dimensional, imaging for treatment verification was (IMGDAY Y) or was not (IMGDAY N)

performed daily, methods for tracking the tumor were (TRACK Y) or were not (TRACK N) used.

* Only 1 value.

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 191

a known amount of water before the simulation and treat-ment. Different strategies were adopted for the rectum, forwhich filling is more difficult to control. Frequently, a rectalenema was performed in patients treated with either theMHF or EHF regimes. In fact, several studies showed adecrease in the interfraction prostate displacement with aconsequent reduction in the target margin when an enemawas used (57, 58). None of the drugs or compoundsdelivered in the analyzed articles was shown to be useful inpreventing or mitigating acute damage to healthy tissues.Only 1 study reported the use of a rectal balloon, whichpositively influences intrafraction prostate stability. The useof tissue spacers in the region between the prostate and theanterior rectal wall has never been referenced. A reducedvariability in the data regarding bladder toxicity, especiallylate toxicity, was observed in patients who received prep-aration (Table 6). This indicates a more accurate predictionof the expected toxicity when assessed for a loweranatomical interpatient variability.

Most of the analyzed studies reported the use ofCTeMRI image fusion for more precise target volumeidentification in prostate cancer patients. Hentschel et al (59)reported that CT scans overestimate prostate volume by 35%compared with MRI. In particular, they found that the meanarea defined by CT imaging was larger than the area definedby MRI, mainly at the base and the apex of the prostate.

However, in the segmentation process, it is necessary to takeinto account the prostate swelling that occurs during treat-ment (60). In a recent study performed by Gunnlaugssonet al (61), the adoption of an EHF regimen showed a sig-nificant increase in prostate shape and size of 14% at themiddle of treatment (Equivalent dose in 2 Gy fractions Z33 Gy) and 9% at the end of treatment (Equivalent dose in 2Gy fractions Z 67 Gy). This trend differs from the con-ventional fractionation trend (62). Our data showed a posi-tive impact on biochemical control and GU toxicity whenMRI imaging was used for contouring (Tables 5 and 6). Thismost likely occurs because the contoured prostate volume issmallest and the boundary between organs and prostate ismore visible, allowing a high dose reduction at the interfacebetween the OAR and PTV. This effect is less evident for GItoxicity. A possible explanation of this trend may be that theadoption of MRI mostly occurred in EHF studies (9 of 15,60%), which can introduce a similar bias.

Analysis of the size of the volume irradiated (prostate orprostate plus SV) highlighted differences in bRFS and GUand GI toxicity incidences (Tables 5 and 6). It is worthnoting that studies including SV in the target volume re-ported a larger spread of the data for toxicity, most likelybecause for SV there is a huge variability in contouredtarget volume detection among patients. The inclusion ofSV in the target volume involves a higher rectal and bladder

Table 6 Acute and late grade �2 (�G2) genitourinary (GU) and gastrointestinal (GI) toxicity

Parameter

�G2 GU toxicity �G2 GI toxicity

Mean (%) Median (%) SD (%) Mean (%) Median (%) SD (%)

Acute FRAME Y 21.4 19.0 14.7 13.7 12.0 11.6Acute FRAME N 4.3* d d 4.0* d dLate FRAME Y 15.0 11.5 13.7 11.5 7.5 10.6Late FRAME N 2.5 2.5 3.5 2.5 2.5 3.5Acute PREP Y 19.7 13.9 14.5 11.7 12.0 9.0Acute PREP N 18.9 16.3 14.7 36.0* d dLate PREP Y 13.9 7.0 14.7 11.9 5.0 11.9Late PREP N 9.7 8.5 6.6 2.5* d dAcute MRI Y 21.4 22.0 13.4 10.3 10.4 5.5Acute MRI N 19.8 13.8 16.2 13.0 9.0 12.7Late MRI Y 15.9 11.5 13.2 8.1 5.0 8.3Late MRI N 10.3 5.2 11.1 10.1 4.3 11.6Acute only P Y 15.8 13.0 13.8 7.6 6.0 6.0Acute only P N 24.7 25.5 15.7 17.6 12.3 11.5Late only P Y 12.1 11.0 11.7 10.2 6.0 11.0Late only P N 14.3 12.0 13.4 10.2 5.0 10.6Acute MARG �5 mm Y 22.3 22.0 16.5 15.7 12.2 12.2Acute MARG �5 mm N 17.9 13.6 13.1 7.7 7.0 5.7Late MARG �5 mm Y 13.6 9.5 13.3 11.2 5.0 10.8Late MARG �5 mm N 11.1 9.0 9.3 6.4 2.3 8.5Acute MARKERS Y 20.9 19.0 14.6 10.5 9.0 8.7Acute MARKERS N 47.0* d d 35.0* d dLate MARKERS Y 11.5 8.5 9.6 8.9 4.8 10.5Late MARKERS N 16.0* d d 17* d dAcute IMG3D Y 20.5 18.0 13.8 11.7 11.7 5.5Acute IMG3D N 19.2 13.6 16.0 12.5 8.0 11.9Late IMG3D Y 12.5 14.9 9.2 14.5 14.2 14.5Late IMG3D N 12.6 7.8 12.5 8.2 4.8 9.4Acute IMGDAY Y 21.8 19.0 14.8 12.3 9.7 10.7Acute IMGDAY N 10.2 4.3 13.8 9.7 4.1 9.8Late IMGDAY Y 13.7 9.5 12.4 9.6 4.5 10.4Late IMGDAY N 8.4 5.0 8.7 7.9 5.0 9.7Acute TRACK Y 20.7 16.3 16.1 5.1 5.0 2.8Acute TRACK N 19.5 16.5 15.1 14.5 12.0 10.9Late TRACK Y 11.2 8.5 9.9 4.1 2.0 5.3Late TRACK N 12.5 9.0 12.6 10.5 5.0 10.8

Mean, median, and standard deviation (SD) values of percentage incidence in which an immobilization frame was used (FRAME Y) or not (FRAME

N), a bladder or rectum preparation was (PREP Y) or was not (PREP N) performed, contouring was (MRI Y) or was not (MRI N) performed on magnetic

resonance images, only the prostate was treated (only P Y) or the seminal vesicles were also treated (only P N), a margin of �5 mm was (MARG �5 mm

Y) or was not (MARG �5 mm N) applied to the clinical target volume, markers was used (MARKERS Y) or not (MARKERS N), imaging methods to

verify treatment were (IMG 3D Y) or were not (IMG 3D N) three-dimensional, imaging for treatment verification was (IMGDAY Y) or was not

(IMGDAY N) performed daily, methods for tracking the tumor were (TRACK Y) or were not (TRACK N) used.

* Only 1 value.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics192

volume in the high-dose regions, which could justify anincreased incidence above all of acute GU and GI toxicity(Table 6).

The rate of acute/late toxicities was generally lower andthe bRFS higher when margins smaller than 5 mm were used(Tables 5 and 6). However, when a margin<5 mm was used,GI late toxicity data were less sparsely distributed than GIacute toxicity data. This could be because dose-volumeconstraints on the rectum, which were always achieved inthese studies, are modeled on late toxicity data only.

Nevertheless, data of toxicity from different studies haveto be compared with caution because it is well known that

different toxicity scales can assign a slightly different scoreto the same symptom. In Supplementary Table e1 (availableonline) we report toxicity scales and cut-off times used toevaluate acute and late GU and GI toxicities in the analyzedstudies.

The analyzed studies reported a daily or random prostatelocalization timing using several different technologies,including transabdominal US, x-ray portal imaging,and kilovoltage and megavoltage CBCT. With these tech-nologies, patient localization uses bony anatomy, implantedfiducials (seeds or electromagnetic transponders), or soft-tissue images. All EHF studies reported that prostate

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 193

alignment was performed with implanted fiducial markers.Intermodality shifts between the different technologiesseem comparable, as reported by Mayyas et al (63). Amongthe methods, localization using markers results in the leastinteruser disagreement compared with using anatomy orsoft tissues (57, 64). Our analysis revealed the same toxicitytrend when the patient positioning occurred with 3-dimensional (CBCT/US) compared with 2-dimensional(portal) imaging (Tables 5 and 6). The imaging frequencytiming has an impact both on toxicity and biochemicalcontrol (Tables 5 and 6). Different authors have reportedthat the choice of imaging frequency and timing are keycomponents in delivering the desired dose while reducingthe associated overhead, such as imaging dose, preparation,and processing time (65). We agree with the opinion thatimage scheduling according to the characteristics of thetreatment plan can improve the efficiency of intrafractionalmotion management.

Finally, the use of tracking systems seems to have afavorable impact on GU toxicities and bRFS (Tables 5 and6). In fact, the incidence is lower when more-accuratelocalization is performed with tracking.

No adaptive strategy was adopted in the selected studies.Several groups have conducted research in the pelvic regionwith different adaptive approaches (66, 67). One notablemethod that could be applied to HF regimens is the socalled “plan of the day” approach (68). In this strategy, amultiple-plan library was generated before the treatmentcourse from weekly serial 6-8 CT datasets from 4 patients.During each fraction, a daily plan was manually chosenfrom the library according to the patient’s daily anatomy.Chen et al (68) reported an excellent target coverage usinga similar approach, with the dose delivered to the OARsbeing only slightly increased.

Strategies that aim to reduce the impact of organ motionand setup errors, especially on OAR toxicity, wouldenhance the overall gain of an HF treatment. Although areduction in the total number of fractions increases thedetrimental effects of patient setup errors and organ motionon clinical outcomes, it has been reported that the absolutegain in tumor control probability due to HF is significantlyhigher compared with the losses due to geometric un-certainties (69).

Conclusions

Recent clinical data support a low value for a/b ratio aspredicted by radiobiological models; hence, large doses perfraction should result in a higher probability of tumorcontrol together with a reduced probability of complica-tions for healthy tissue. Nevertheless, in the evaluation ofthe cost-effectiveness of the treatment, it is mandatory toalso consider the associated morbidity. In this review, wefocused on the technical parameters and treatment strate-gies adopted in the analyzed HF studies to highlight apossible correlation with clinical outcomes.

The heterogeneity of parameters in the studies makesthis task difficult to achieve, although some interestingtrends have been observed. Ongoing trials, focusing moreon clinical data than on techniques, will most likely providean objective basis for a rational selection of optimumtreatment strategies, clarifying the role of the differentparameters and highlighting more-clear correlations amongoutcome, morbidity, and technical factors.

References

1. Miralbell R, Roberts SA, Zubizarreta E, et al. Dose-fractionation

sensitivity of prostate cancer deduced from radiotherapy outcomes of

5,969 patients in seven international institutional datasets: a/b Z 1.4

(0.9-2.2). Gy. Int J Radiat Oncol Biol Phys 2012;82:17-24.

2. Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors

really low? Int J Radiat Oncol Biol Phys 2001;50:1021-1031.

3. Brenner MJ, Kaplan ID. Is there any benefit from hypofractionation in

external-beam irradiation for prostate cancer? JClinOncol 2014;32:1-2.

4. Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS

and SBRT: Are more than the 5 Rs involved? Int J Radiat Oncol Biol

Phys 2014;88:254-262.

5. Tree AC, Khoo VS, van As NJ, et al. Is biochemical relapse-free

survival after profoundly hypofractionated radiotherapy consistent

with current radiobiological models? Clin Oncol 2014;26:216-229.

6. Rosenschold PM, Desai NB, Oh JH, et al. Modeling positioning

uncertainties of prostate cancer external beam radiation therapy using

pre-treatment data. Radiother Oncol 2014;110:251-255.

7. Craig T, Moiseenko V, Battista J, et al. The impact of geometric

uncertainty on hypofractionated external beam radiation therapy of

prostate cancer. Int J Radiat Oncol Biol Phys 2003;57:833-842.

8. Schiller K, Petrucci A, Geinitz H, et al. Impact of different setup

approaches in image-guided radiotherapy as primary treatment for

prostate cancer: A study of 2940 setup deviations in 980 MVCTs.

Strahlenther Onkol 2014;190:722-726.

9. Madsen BL, Hsi RA, Pham HT, et al. Stereotactic hypofractionated

accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five

fractions for localized disease: First clinical trial results. Int J Radiat

Oncol Biol Phys 2007;67:1099-1105.

10. Boike TP, Lotan Y, Cho LC, et al. Phase I dose-escalation study of

stereotactic body radiation therapy for low- and intermediate-risk

prostate cancer. J Clin Oncol 2011;29:2020-2026.

11. Kim DWN, Cho LC, Straka C, et al. Predictors of rectal tolerance

observed in a dose-escalated phase 1-2 trial of stereotactic body ra-

diation therapy for prostate cancer. Int J Radiat Oncol Biol Phys

2014;89:509-517.

12. Loblaw A, Cheung P, D’Alimonte L, et al. Prostate stereotactic

ablative body radiotherapy using a standard linear accelerator:

Toxicity, biochemical, and pathological outcomes. Radiother Oncol

2013;107:153-158.

13. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk

prostate cancer: Five-year outcomes. Radiat Oncol 2011;6:3.

14. King CR, Brooks JD, Gill H, et al. Long-term outcomes from a

prospective trial of stereotactic body radiotherapy for low risk

prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:877-882.

15. King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy

for localized prostate cancer: Pooled analysis from a multi-

institutional consortium of prospective phase II trials. Radiother

Oncol 2013;109:217-221.

16. Jabbari S, Weinberg VK, Kaprealian T, et al. Stereotactic body

radiotherapy as monotherapy or post-external beam radiotherapy

boost for prostate cancer: Technique, early toxicity, and PSA

response. Int J Radiat Oncol Biol Phys 2012;82:228-234.

17. Kang JK, Cho CK, Choi CW, et al. Image-guided stereotactic body

radiation therapy for localized prostate cancer. Tumori 2011;97:43-48.

Clemente et al. International Journal of Radiation Oncology � Biology � Physics194

18. McBride SM, Wong DS, Dombrowski JJ, et al. Hypofractionated

stereotactic body radiotherapy in low-risk prostate adenocarcinoma:

Preliminary results of a multi-institutional phase 1 feasibility trial.

Cancer 2012;118:3681-3690.

19. Tang CI, Loblaw DA, Cheung P, et al. Phase I/II study of a five-

fraction hypofractionated accelerated radiotherapy treatment for

low-risk localised prostate cancer: Early results of pHART3. Clin

Oncol (R Coll Radiol) 2008;20:729-737.

20. Lee YH, Son SH, Yoon SC, et al. Stereotactic body radiotherapy for

prostate cancer: A preliminary report. Asia Pac J Clin Oncol 2014;

10:46-53.

21. Katz AJ, Santoro M, Ashley R, et al. Stereotactic body radiotherapy

as boost for organ-confined prostate cancer. Technol Cancer Res

Treat 2010;9:575-582.

22. Katz A, Kang J. Stereotactic body radiotherapy with or without

external beam radiation as treatment for organ confined high-risk

prostate carcinoma: A six year study. Radiat Oncol 2014;9:1.

23. Chen LN, Suy S, Uhm S, et al. Stereotactic body radiation therapy

(SBRT) for clinically localized prostate cancer: The Georgetown

University experience. Radiat Oncol 2013;8:58.

24. Lukka H, Hayter C, Julian JA, et al. Randomized trial comparing two

fractionation schedules for patients with localized prostate cancer. J

Clin Oncol 2005;23:6132-6138.

25. Higgins GS, McLaren DB, Kerr GR, et al. Outcome analysis of 300

prostate cancer patients treated with neoadjuvant androgen depriva-

tion and hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys

2006;65:982-989.

26. Hoffman KE, Voong KR, Pugh TJ, et al. Risk of late toxicity in men

receiving dose-escalated hypofractionated intensity modulated pros-

tate radiation therapy: Results from a randomized trial. Int J Radiat

Oncol Biol Phys 2014;88:1074-1084.

27. Yeoh EE, Botten RJ, Butters J, et al. Hypofractionated versus

conventionally fractionated radiotherapy for prostate carcinoma:

Final results of phase III randomized trial. Int J Radiat Oncol Biol

Phys 2011;81:1271-1278.

28. Arcangeli G, Fowler J, Gomellini S, et al. Acute and late toxicity in a

randomized trial of conventional versus hypofractionated three-

dimensional conformal radiotherapy for prostate cancer. Int J Radiat

Oncol Biol Phys 2011;79:1013-1021.

29. Arcangeli S, Strigari L, Gomellini S, et al. Update results and pattern

of failure in a randomized hypofractionation trial for high risk

prostate cancer. Int J Radiat Oncol Biol Phys 2012;84:1172-1178.

30. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of

hypofractionated external-beam radiotherapy for prostate cancer.

J Clin Oncol 2013;31:3860-3868.

31. Martin JM, Rosewall T, Bayley A, et al. Phase II trial of hypo-

fractionated image-guided intensity-modulated radiotherapy for

localized prostate adenocarcinoma. Int J Radiat Oncol Biol Phys

2007;69:1084-1089.

32. Kupelian PA, Thakkar VV, Khuntia D, et al. Hypofractionated

intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for

localized prostate cancer: Long-term outcomes. Int J Radiat Oncol

Biol Phys 2005;63:1463-1468.

33. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated

intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for

localized prostate cancer: Cleveland Clinic experience. Int J Radiat

Oncol Biol Phys 2007;68:1424-1430.

34. Rene N, Faria S, Cury F, et al. Hypofractionated radiotherapy for

favorable risk prostate cancer. Int J Radiat Oncol Biol Phys 2010;77:

805-810.

35. Jereczek-Fossa BA, Zerini D, Fodor C, et al. Acute toxicity of image-

guided hypofractionated radiotherapy for prostate cancer: Non-

randomized comparison with conventional fractionation. Urol Oncol

2011;29:523-532.

36. Zilli T, Jorcano S, Rouzaud M, et al. Twice-weekly hypofractionated

intensity-modulated radiotherapy for localized prostate cancer with

low-risk nodal involvement: Toxicity and outcome from a dose

escalation pilot study. Int J Radiat Oncol Biol Phys 2011;81:382-389.

37. Di Staso M, Bonfili P, Gravina GL, et al. Late morbidity and onco-

logical outcome after radical hypofractionated radiotherapy in men

with prostate cancer. BJU Int 2010;106:1458-1462.

38. PatelN, Faria S,CuryF, et al. Hypofractionated radiation therapy (66Gy

in 22 fractions at 3 Gy per fraction) for favorable-risk prostate cancer:

Long-term outcomes. Int J Radiat Oncol Biol Phys 2013;86:534-539.

39. Fonteyne V, Soete G, Arcangeli S, et al. Hypofractionated high-

dose radiation therapy for prostate cancer: Long-term results of a

multi-institutional phase II trial. Int J Radiat Oncol Biol Phys 2012;

84:483-490.

40. Junius S, Haustermans K, Bussels B, et al. Hypofractionated intensity

modulated irradiation for localized prostate cancer, results from a

phase I/II feasibility study. Radiat Oncol 2007;2:29.

41. Koukourakis MI, Kyrgias G, Papadopoulou A, et al. Treatment of

low-risk prostate cancer with radical hypofractionated accelerated

radiotherapy with cytoprotection (HypoARC): An interim analysis of

toxicity and efficacy. Anticancer Res 2011;31:1745-1751.

42. Leborgne F, Fowler J, Leborgne JH, et al. Later outcomes and

alpha/beta estimate from hypofractionated conformal three-

dimensional radiotherapy versus standard fractionation for local-

ized prostate cancer. Int J Radiat Oncol Biol Phys 2012;82:

1200-1207.

43. Lock M, Best L, Wong E, et al. A phase II trial of arc-based hypo-

fractionated intensity-modulated radiotherapy in localized prostate

cancer. Int J Radiat Oncol Biol Phys 2011;80:1306-1315.

44. Valeriani M, Monaco F, Osti MF, et al. Hypofractionated radio-

therapy with or without IGRT in prostate cancer: Preliminary report

of acute toxicity. Anticancer Res 2011;31:3555-3558.

45. Thomson D, Merrick S, Swindell R, et al. Dose-escalated hypo-

fractionated intensity-modulated radiotherapy in highrisk carcinoma

of the prostate: Outcome and late toxicity. Prostate Cancer 2012;

2012:450246.

46. Wu JS, Brasher PM, El-Gayed A, et al. Phase II study of hypo-

fractionated image-guided radiotherapy for localized prostate cancer:

Outcomes of 55 Gy in 16 fractions at 3.4 Gy per fraction. Radiother

Oncol 2012;103:210-216.

47. Yassa M, Fortin B, Fortin MA, et al. Combined hypofractio-

nated radiation and hormone therapy for the treatment of

intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys

2008;71:58-63.

48. Butler WM, Merrick GS, Reed JL, et al. Intrafraction displace-

ment of prone versus supine prostate positioning monitored by

real-time electromagnetic tracking. J Appl Clin Med Phys 2013;

14:198-208.

49. White P,YeeCK, ShanLC, et al. A comparison of two systems of patient

immobilization for prostate radiotherapy. Radiat Oncol 2014;9:29.

50. Valdagni R, Rancati T. Reducing rectal injury during external

beam radiotherapy for prostate cancer. Nat Rev Urol 2013;10:345-357.

51. Bell LJ, Cox J, Eade T, et al. The impact of rectal and bladder

variability on target coverage during post-prostatectomy intensity

modulated radiotherapy. Radiother Oncol 2014;110:245-250.

52. O’Neill L, Armstrong J, Buckney S, et al. A phase II trial for the

optimization of treatment position in the radiation therapy of prostate

cancer. Radiother Oncol 2008;88:61-66.

53. Liu B, Lerma FA, Patel S, et al. Dosimetric effects of the prone and

supine positions on image guided localized prostate cancer radio-

therapy. Radiother Oncol 2008;88:67-76.

54. Bayley AJ, Catton CN, Haycocks T, et al. A randomized trial of supine

vs. prone positioning in patients undergoing escalated dose conformal

radiotherapy for prostate cancer. Radiother Oncol 2004;70:37-44.

55. Steenbakkers RJ, Duppen JC, Betgen A, et al. Impact of knee support

and shape of tabletop on rectum and prostate position. Int J Radiat

Oncol Biol Phys 2004;60:1364-1372.

56. Graf R, Boehmer D, Nadobny J, et al. Appropriate patient in-

structions can reduce prostate motion. Radiat Oncol 2012;7:125.

57. Seo YE, Kim TH, Lee KS, et al. Interfraction prostate movement in

bone alignment after rectal enema for radiotherapy. Korean J Urol

2014;55:23-28.

Volume 91 � Number 1 � 2015 Technical aspects of hypofractionated RT for CaP 195

58. Fiorino C, Di Muzio N, Broggi S, et al. Evidence of limited motion

of the prostate by carefully emptying the rectum as assessed by daily

MVCT image guidance with helical tomotherapy. Int J Radiat Oncol

Biol Phys 2008;71:611-617.

59. Hentschel B, Oehler W, Strauß D, et al. Definition of the CTV

prostate in CT and MRI by using CT-MRI image fusion in IMRT

planning for prostate cancer. Strahlenther Onkol 2011;187:183-190.

60. Jonsson JH, Karlsson MG, Karlsson M, et al. Treatment planning

using MRI data: An analysis of the dose calculation accuracy for

different treatment regions. Radiation Oncol 2010;5:62.

61. Gunnlaugsson A, Kjellen E, Hagberg O, et al. Change in prostate

volume during extreme hypo-fractionation analysed with MRI.

Radiation Oncol 2014;9:22.

62. Sanguineti G, Marcenaro M, Franzone P, et al. Neoadjuvant androgen

deprivation and prostate gland shrinkage during conformal radio-

therapy. Radiother Oncol 2003;66:151-157.

63. Mayyas E, Chetty IJ, Chetvertkov M, et al. Evaluation of multiple

image-based modalities for image-guided radiation therapy (IGRT)

of prostate carcinoma: a prospective study. Med Phys 2013;40:

041707.

64. Johnston ML, Vial P, Wiltshire KL, et al. Daily online bony

correction is required for prostate patients without fiducial markers or

soft-tissue imaging. Clin Oncol (R Coll Radiol) 2011;23:454-459.

65. Zhang P, Hunt M, Happersett L, et al. Incorporation of treatment plan

spatial and temporal dose patterns into a prostate intrafractional

motion management strategy. Med Phys 2012;39:5429-5436.

66. Qi P, Pouliot J, Roach M, et al. Offline multiple adaptive planning

strategy for concurrent irradiation of the prostate and pelvic lymph

nodes. Med Phys 2014;41:021704.

67. Kim J, Kumar S, Liu C, et al. A novel approach for establishing

benchmark CBCT/CT deformable image registrations in prostate

cancer radiotherapy. Phys Med Biol 2013;58:8077-8097.

68. Chen W, Gemmel A, Rietzel E. A patient-specific planning target

volume used in ‘plan of the day’ adaptation for interfractional motion

mitigation. J Radiat Res 2013;54(Suppl. 1):i82-i90.

69. Song WY, Schaly B, Bauman G, et al. Evaluation of image-

guided radiation therapy (IGRT) technologies and their impact

of the outcomes of hypofractionated prostate cancer treatments:

A radiobiologic analysis. Int J Radiat Oncol Biol Phys 2006;64:

289-300.