Current role of image-guided robotic radiosurgery (Cyberknife ) for prostate cancer treatment

Current role of image-guided robotic radiosurgery (Cyberknife ) for prostate cancer treatment Thomas Seisen, Sarah J. Drouin, Véronique Phé, Jérome Parra, Pierre Mozer, Marc-Olivier Bitker, Olivier Cussenot and Morgan Rouprêt Academic Department of Urology of la Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France and Institut Universitaire de Cancerologie GRC 5 Oncotype Euro, Pitié Hospital, Paris, France Objectives To describe the most recent data from phase I and II clinical trials of stereotactic body radiation therapy (SBRT) using image-guided robotic radiosurgery, specifically the Cyberknife (Accuracy Incorporated, Sunnyvale, CA, USA). To better determine thecurrent role of this type of radiosurgery in prostate cancer (PCa) management. Materials and Methods Current clinical trials and relevant retrospective studies were identified from the literature, clinical trial databases, websites and conference abstracts. The indications, technical aspects, efficacy and toxicity of SBRT using the Cyberknife system were summarized. Results The Cyberknife system is an experimental treatment mostly used for localized PCa in stage ct1/t2a b N0 M0 with a Gleason score 7 and PSA level 20 ng/ml. Hypofractionated radiation therapy was delivered in five fractions of 7 7.25 Gy for a total dose of 35 36.25 Gy. After treatment, the median PSA levelfell from 4.9 8.3 ng/ml to 0.1 1.6 ng/ml at a median follow-up of 4 60 months. The biochemical progression-free survival rates ranged from 78.3 to 100%. Acute and late toxicities were mostly grade 1/2 rectal or urinary complications. Few grade 3 and no grade 4 toxicities occurred during follow-up; however, erectile dysfunction and testes toxicity were also reported. Conclusions The use of the Cyberknife system is limited mainly by its pretreatment and maintenance costs. Despite encouraging preliminary results, longer-term follow-up and randomized controlled phase III clinical trials are necessary before the Cyberknife system becomes a standard treatment method. Keywords Cyberknife, stereotactic body radiation therapy, hypofractionated radiation therapy, prostate cancer Introduction Medicinecontinues to progress through evolutionary change, as reflected in the modern era of robot-assisted surgery, and the terms robot and surgery are becoming more commonplace and interchangeable. Such terms generate visions and perceptions, particularly for patients, of some form of operation (under anaesthesia) that uses state of the art technology to remove or reconstruct tissue with the aim of improving the outcomes and minimizing complications and morbidity. The concepts of therapeutic and technological advancement are common in the management of patients with prostate cancer (PCa) and theattractive notion of robotic surgical intervention has now also extended to non-surgical treatment methods, including radiotherapy (RT)-based treatments for PCa. In an effort to improve precision with regard to the target field, to decrease toxicity related to adjacent structure irradiation and to increase the dose administered to achieve potentially better cancer outcomes, radiobiologists have developed techniques to deliver hypofractionated image-guided RT, e.g intensity-modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). In the literature SBRT is referred to as radiosurgery but it still represents the delivery of RT, albeit high-dose hypofractionated image-guided RT, and does not involve procedures that the public or clinicians would regard as surgical. Cyberknife (Accuracy Incorporated, Sunnyvale, 2013 BJU International 111, 761 766 doi:10.1111/bju.12000 761

Seisen et al. CA, USA) SBRT is a specific form that has features well suited to the SBRT of PCa, as it includes non-coplanar beamsfromalinearacceleratorandtheabilitytotrack real-time prostate motion whilst delivering highly conformal hypofractionated doses [1 3]. The Cyberknife system uses fiducial markers, placed in the prostate, to verify organ position in real time which allows the correction of position during treatment. The procedure usesa robotic arm, leading some to term it robotic radiosurgery. To date, Cyberknife hasbeenusedtotreat tumours of the lung, liver, pancreas, spine, kidney head and neck, vaginal cuff and prostate. In the present review, we describe the current indications, technique, results and limitations of Cyberknife SBRT in the treatment of PCa and discuss the merits and implications of such terms as robot, knife and radiosurgery when referring to non-surgical procedures. Studies of Cyberknife in PCA Currently, SBRT using Cyberknife is still regarded as an experimental treatment for PCa andthere areno international guideline recommendations on its use. Most published studies report prospective phase I or II clinical trial data, including patients with low- or intermediate-risk PCa (e.g. ct1/t2a b N0 M0 with a Gleason score 7 and PSA level 20 ng/ml). To date, 12 phase I or II prospective clinical trials and a few retrospective studies have been reported in the literature for Cyberknife as treatment for PCa [1 13]. Table 1 [1 13]shows the patient populations, PCa risk groups, SBRT protocols and trial designs for these studies. Cyberknife has also been used for the management of locally recurrent, lymph-node-positive or systemic metastatic PCa. One prospective clinical trial, whichincluded 34 patients, evaluatedthe Cyberknife system as a treatment for local lymph node recurrence (obturator or external iliac) or metastases to retroperitoneal lymph nodes or bone after external beam radiation therapy or radical prostatectomy [14]. Technical Aspects of Cyberknife Cyberknife is a treatment device used to deliverhigh-dose hypofractionated SBRT and, owing to the use of a robotic arm in combination with intrafractional prostate motion tracking, it hassuperior target accuracycompared with external beam radiation therapy (<5 mm). Cyberknife has been used for almost 20 years to treat different types of tumour but the first feasibility study on its use for PCa was published in 2003 by King et al. [15]. The system has undergone several technological advances and the latest model was released in 2010 (the Cyberknife VSI System) [16]. There are two principal phases of a Cyberknife SBRT protocol: treatment planning and treatment delivery. Treatment Planning Approximately 10 days before treatment, three to four gold fiducial markers (GFMs) are implanted in the prostate using TRUS for image-guided positioning and motion tracking. GFMs must be implanted at the apex, intermediate lateral zone and base of the prostate. Sometimes fused to MRI, treatment planning with CT is performed at a slice thickness of 1.25 mm 1week after GFM placement to differentiate the prostate and proximal seminal vesicles from surrounding tissues. The prostate Table 1 Population characteristics and protocol for the management of localized PCa using Cyberknife. Analysis type LE N Risk group Median (range) initial PSA, ng/ml Protocol Choi et al., 2007 [1] Prospective, P2 2b 44 Low, Intermediate, High 32 Gy (4 8Gy) 36 Gy (4 9Gy) Fuller et al., 2008 [2] Prospective, P2 2b 10 Low, Intermediate 6.9 (1.3 11.45) 38 Gy (4 9Gy) King et al., 2009 [3] Prospective, P2 2b 41 Low 5.6 (0.7 10) 36.25 Gy (5 7.25 Gy) Friedland et al. 2009 [4] Prospective, P2 2b 112 Low, Intermediate 5.2 (1.1 17.2) 35 Gy (5 7Gy) Meier et al. 2009 [5] Prospective, P1 2b 29 Low, Intermediate <20 36.25 Gy (5 7.25 Gy) Aluwini et al. 2010 [6] Prospective, P1 2b 10 Low, Intermediate 8.3 (1.3 13.6) 38 Gy (4 9.5 Gy) Katz et al. 2010 [7] Prospective, P2 2b 304 Low, Intermediate, High 5.8 (0.7 27.3) 35 Gy (5 7Gy) 36.25 Gy (5 7.25 Gy) Bolzicco et al. 2010 [8] Prospective, P2 2b 45 Low, Intermediate 8.07 (2 20) 35 Gy (5 7Gy) Mc Bride et al. 2011 [9] Prospective, P1 2b 45 Low 4.9 (1.4 9.4) 36.25 Gy (5 7.25 Gy) 37.5 Gy (5 7.5 Gy) Freeman et al. 2011 [10] Prospective, P2 2b 41 Low 5.4 (3 7.8) 36.25 Gy (5 7.25 Gy) Katz et al. 2011 [11] Prospective, P2 1b 82 Low, Intermediate 5.35 (0.9 13.2) 35 Gy (5 7Gy) 36.25 Gy (5 7.25 Gy) Kang et al. 2011 [12] Retrospective 3 44 Low, Intermediate, High 32 GY (4 8Gy) 34 Gy (4 8.5 Gy) 36 Gy (4 9Gy) King et al. 2012 [13] Prospective, P2 2b 67 Low <10 36.25 Gy (5 7.25 Gy) 762 2013 BJU International

Image-guided robotic radiosurgery for prostate cancer gland, seminal vesicles, rectum, bladder, penile bulb and femoral heads can be contoured. The planning target volume depends on the PCa risk category but often consists of a 5-mm expansion zone anteriorly/laterally, reduced to 3 mm posteriorly. When coregistering and for MRI it is alsopossible to segment neurovascular bundles in some cases. Treatment Delivery The Cyberknife system is composed of a 6 MV linear accelerator mounted on a robotic arm, with two orthogonal X-ray imagers to track GFM and perform real-time corrections for target repositioning during the treatment. Re-imaging every 40 s ensures adequate and precise tracking to deliver hypofractionated RT [17]. Cyberknife produces hypofractionated RT with treatment plan conformality superior to IMRT [18]. Several treatment schedules have been reported in the literature to treat localized PCa. Kang et al. [12] used four fractions of 8.5 Gy for a total dose of 34 Gy, whereas Aluwini et al. [6] delivered four fractions of 9.5 Gy for a total dose of 39 Gy; however, most studies describe a protocol using five fractions of 7 7.25 Gy, amounting to a total dose of 35 36.25 Gy. In two SBRT protocols, androgen deprivation therapy (ADT) was administered in combination with the Cyberknife [7,8]. The principal treatment schedules for the management of localized PCa are listed in Table 1. For the management of local recurrence, lymph-node-positive or metastatic disease, Cyberknife SBRT protocols differ. Patients with local recurrence after external beam radiation therapy or radical prostatectomyreceived 30 Gy in five fractions (55% also received ADT), whereas those with lymph-node-positive disease or metastatic spread received 33 or 36 Gy in three fractions (75% ADT), respectively [14]. Oncological Resultsfor Cyberknife In the available studies, patients with localized PCa had a median initial PSA level ranging from 4.9 to 8.3 ng/ml. The median post-treatment PSA levels fell to between 0.1 and 1.6 ng/ml with median follow-up ranging from 4 to 60 months. There is no evidence that the total dose of SBRT correlates with PSA response [2,3,6]. The comparison of two SBRT protocols revealed no significant correlation between doses of 35 Gy (5 7 Gy) and 36.25 Gy (5 7.25 Gy) and subsequent PCa control (Level of Evidence [LE]:1b) [6]. Overall, 16 38% of patients experience PSA bounce with median values ranging from 0.35 to 0.4 ng/mland a median follow-up between 11.6 and 18 months. Post-PSA bounce, levels decreased progressively to reach the median PSA nadir. Though not mentioned in the majority of studies, the median PSA nadir was often equivalent to the median post-treatment value and also ranged from 0.1 to 1.6 ng/ml. The biochemical progression-free survival (bpfs) rates of patients with localized PCa treated using Cyberknife range from 78.3 to 100%. bpfs was defined as the time from pathological diagnosis to biochemical failure or patient s death. The Phoenix criteria of biochemical failure (PSA nadir + 2 ng/ml) was used. Overall, five studies reported no biochemical failure and a bpfs rate of 100%. Freeman et al. [10] reported a bpfs rate of 92.7% with a median follow-up of 60 months. Among 41 patients with low-risk PCa, only three developed biochemical progression, at 33, 37 and 42 months, respectively. Katz et al. [11] observed a bpfs rate of 97.6% in a population of patients with lowand intermediate-risk PCa. In their population study including a high risk PCa cohort, Kang et al. [12] reported a bpfs rate of 100% with a median follow-up of 40 months. Overall, 11 clinical recurrences have been diagnosed amongst the 874 patients included in the available phase I or II clinical trials evaluating Cyberknife. In 72% of cases, recurrence was local, confirmed pathologicallyby TRUS biopsy and treated with cryotherapy or high-intensity focused ultrasonography as salvage therapy [4]. In 28% of cases, metastatic evaluation revealed secondary bone deposits which were treated by conventional ADT. Cyberknife outcomes in relation to local, lymph node or metastatic recurrent PCa are disappointing. The overall 30-month bpfs rate is 42.6% [14]. The oncological results for the management of localized PCa with Cyberknife are shown in Table 2 [1 13]. Toxicity of Cyberknife Acute and late toxicity were reported with oncological results during phase I or II clinical trials and retrospective studies. Rectal (rt) and urinary toxicities (ut) were scored according to the Radiation Therapy Oncology Group scale. Acute grade 1/2 rtranged from 9 to 80%, compared with 10% for grade 3 [6]. In the majority of studies, rt was proctitis with faecal urgency and diarrhoea. During the evaluation of long-term rectal functional outcomes, late grade 1/2 rt ranged from 0 to 48% with grade 3 rtoccurring in only 1 5% of patients [4,9]. Rectal bleedingwas rarely observed after SBRT using Cyberknife [4]. Some patients experienced late grade 3 proctitis that resolved with argon plasma laser ablation, butno acute or late grade 4 rt was reported. During phase I or II clinical trials, acute grade 1/2 ut ranged from 13.5 to 78%, whereas only 5% reported grade 2013 BJU International 763

Seisen et al. Table 2 Oncological results for localized PCa management using Cyberknife. Median (range) follow-up, months Median PSA, ng/ml Median PSA nadir, ng/ml % of patients with benign PSA bounce (value) Median time to benign PSA bounce, months bpfs rate, % Reccurence Choi et al. 2007 [1] 13 (4 46) 78.3 Fuller et al. 2008 [2] 4 0.97 0.97 King et al. 2009 [3] 33 (6 45) 0.4 0.32 29 (0.4 ng/ml) 18 100 0 Friedland et al. 2009 [4] 24 0.6 0.5 97.4 2L, 1M Meier et al. 2009 [5] 18 0.4 0.35 38 100 0 Aluwini et al. 2010 [6] 5.1 1.6 1.6 0 100 0 Katz et al. 2010 [7] 30 (26 37) 0.3 0.3 16 (0.35 ng/ml) 18 98.7 1L Bolzicco et al. 2010 [8] 20 (6 42) 0.4 100 0 Mc Bride et al. 2011 [9] 44.5 (0 62) 0.2 0.2 20 (0.4 ng/ml) 11.6 (7.2 18.2) 97.7 0 Freeman et al. 2011 [10] 60 0.35 0.3 92.7 3L Katz et al. 2011 [11] 51 (45 58) 0.1 0.1 97.6 2M Kang et al. 2011 [12] 40 (12 78) 100 0 King et al. 2012 [13] 32.4 0.5 94 2L L, local recurrence; M, metastatic recurrence. 3 ut in one study [3] (LE:2b). In a retrospective study, Towsend et al. [19] observed 64% of acute grade 1/2 ut including symptoms of frequency/nocturia and dysuria because of epididymitis from fiducial placement (LE:3). Acute grade 3 ut was reported by 8% of patients and included symptoms such as frequency/nocturia and dysuria. Late grade 1/2 ut ranged from 0 to 65%. Late grade 3 ut was observed in four studies with a rate ranging from 0.5 to 5%. The main complication was urinary obstruction requiring TURP [9] (LE:2b); however, no acute or late grade 4 ut was reported. Erectile dysfunction (ED) was the main acute or late sexual toxicity during phase I or II clinical trials. ED analyses were performed using the Sexual Health Inventory for Men (SHIM). Concerning acute ED, the mean SHIM score seemed to decrease during treatment but returned to baseline within 1 month [4]. There was no significant decrease in SHIM score at 3 months [9]. Late ED ranges from 13 to 18%. Katz et al. [7] reported 87% of patients maintained potency with or without ED medication at 18 months follow-up. Friedland et al. [4] reported apotency rate of ~82%at 3 years. Wiegener et al. [20] specifically evaluated ED after SBRT using the Cyberknife system. The mean Expanded Prostate Cancer Index Composite sexual domain summary score, sexual function score and sexual bother score decreasedby 45, 49 and 25%, respectively (at 50 months follow-up). The baseline ED rate was 38% and increased significantly to 71% after treatment. ED medication was usedby 3% of patients at baseline and this increased to 25% after SBRT treatment. In patients <70 years, 60% maintained satisfactory erectile function after treatment compared with only 12% of patients >70 years. Penile bulb dose was not associated with ED. Owing to the use of non-coplanar beams, testes toxicity can ariseafter treatment with the Cyberknife system, as noted by King et al. [21]. Potentially excessive testicular radiation exposure might be responsible for hypogonadism and might also confound PSA results; however, 80% of patients maintained at least 80% of their pretreatment testosterone levels. Among these, 97 and 90% retained absolute testosterone levels >100 ng/dl and 200 ng/dl, respectively. Despite this, Fuller et al. [22] recommended that all transtesticular beam pathways be blocked because, like King et al. [21], they found that it caused no significant degradation in target volume coverage or other dosimetry statistics. As mentioned, Fossa et al. [14] reported poor oncological outcomes (an overall 30-month bpfs rate of 42.6%) after using Cyberknife to treat recurrent (local, lymph node or metastatic) PCa. The authors also reported a 15% rate of acute and late grade 1/2 ut and 6% grade 3 toxicity. Acute and late grade 1/2 rt occurred in 6% of patients. Data are summarized in Table 3 [1 13]. Limitations of Cyberknife Despite cost-savingsforseveral applications, the real cost of the Cyberknife system for the management of PCa remains unknown. The price of equipment alone seems to be $4 5 million. This pretreatment cost might be offset by the fact that far fewer fractions are delivered with Cyberknife compared with IMRT or other forms of conventional radiation therapy; however, robotic system maintenance appears to be far more expensive, and other treatment methods currently used forlow-risk PCa might be as effective but cheaper. Parthan et al. [23] presented an abstract about the cost of Cyberknife at the 2011 ASCO congress. Compared with SBRT and IMRT, surgery was the least expensive treatment option. The cost-effectiveness of Cyberknife is yet to be assessed and compared with 764 2013 BJU International

Image-guided robotic radiosurgery for prostate cancer Table 3 Toxicity of the localized PCa management using Cyberknife. Acute toxicities Late toxicities rt ut Sexual toxicity rt ut Sexual toxicity Choi et al. 2007 [1] 32% G1/2 39% G1/2 0% 0% Fuller et al. 2008 [2] 60% G1/2 60% G1/2 King et al. 2009 [3] 48% G1/2 + 5%G3 58% G1/2 + 16% G3 48% G1/2 65% G1/2 + 5% G3 Friedland et al. 2009 [4] Rectal urgency Dysuria ED 1% G3 0% 18% ED Meier et al. 2009 [5] Aluwini et al. 2010 [6] 20% G1/2 + 10% G3 50% G1 Katz et al. 2010 [7] 80% G1/2 76% G1/2 9% G1/2 9% G1/2, + 0.5% G3 13% ED Bolzicco et al. 2010 [8] 48.8% G1/2 46.6% G1/2 2.2% G2 8.8% G1/2 + 2.2% G3 Mc Bride et al. 2011 [9] 38% G1/2 78% G1/2 0% 14% G1/2 + 5% G3 34% G1/2 ED Freeman et al. 2011 [10] G1/2 G1/2 15.5% G1/2 32% G1/2 + 2.5% G3 Katz et al. 2011 [11] 11% 12% G1/2 ED Kang et al. 2011 [12] 9% G2 13.5% G2 11.4% G2 7% G2 King et al. 2012 [13] 16% G1/2 28% G1/2+ 3.5% G3 surgery or external beam radiation therapyin experimental studies using quality-adjusted life years as a measure of value. Accuracy Incorporated produced a press release in 2007 declaring that >1000 men have been successfully and safely treated for PCa with the Cyberknife system, but no scientific evidence wasproduced to support such a presumption. Indeed, when a robotic device is newly released, its safety and effectiveness must be shown through the use of clinical trials [24]. Despite many phase I or II clinical trials, Cyberknife should also be tested in randomized controlled phase III trials to prove its superior efficacy and to recommend its use. Longer-term follow-up is also necessary to evaluate the best robotic SBRT. The evidencebaseis therefore not available to show whether the Cyberknife system is at least as effective and safe as other forms of radiation therapy for the treatment of localized PCa. According to phase I and II clinical trials results, Cyberknife appears to be more effective than other PCa treatments for the management ofpatients with low- or intermediate-risk PCa than for high-risk or recurrent disease, but such patients might alsobenefit from active surveillance with muchless toxicity. New expensive treatment methods and/or devices for the management of PCa seem to enter the market every day. Despite the importance of introducing new technologyto medicine, only technological advances thatimprove treatment results should be considered and used in daily practice [25]. In conclusion, the use of the Cyberknife system for the treatment of PCa is currently limited by the fact that departments need to demonstratein a business plan that they have a suitable patient workload and mix to justify thepurchase ofa niche machine, especially as phase III data showing a benefit over a conventional linear acceleratorare not available. Despite encouraging preliminary results, longer-term follow-up and randomized controlled phase III clinical trials are necessary before the Cyberknife systemcan become a standard treatment option for PCa. Conflict of Interest None declared. References 1 Choi C, Cho C, Kim G, Park K, Jo M, Lee C. Stereotactic radiation therapy of localized prostate cancer using cyberknife. Int J Radiat Oncol Biol Phys 2007; 69: S375 2 Fuller DB, Naithoh J, Lee C, Hardy S, Jin H. Virtual HDR SM Cyberknife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations. Int J Radiat Oncol Biol Phys 2008; 70: 1588 97 3 King CR, Brooks JD, Gill H. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J RadiatOncolBiolPhys2009; 73: 1043 8 4 Friedland JL, Freeman DE, Masterson-McGary ME, Spellberg DM. Stereotactic body radiotherapy: an emerging treatment approach for localized prostate cancer. Technol Cancer Res Treat 2009; 8: 387 92 5 Meier R, Cotrutz C. MRI-planned stereotactic body radiotherapy for organ-confined prostate cancer: feasibility and early results. Int J Radiat Oncol Biol Phys 2009; 75: S 2339 6 Aluwini S, Van Rooij P, Hoogeman M et al. Cyberknife stereotactic radiotherapy as monotherapy for low to intermediate stage prostate cancer: early experience, feasibility and tolerance. J Endourol 2010; 24: 865 9 7 Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. 2013 BJU International 765

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