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Keywords:

  • Cyberknife®;
  • stereotactic body radiation therapy;
  • hypofractionated radiation therapy;
  • prostate cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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.

Abbreviations
SBRT

stereotactic body radiation therapy

PCa

prostate cancer

bPFS

biochemical progression-free survival

RT

radiotherapy

IMRT

intensity-modulated radiation therapy

GFM

gold fiducial marker

ADT

androgen deprivation therapy

rT

rectal toxicity

uT

urinary toxicity

LE

level of evidence

ED

erectile dysfunction

SHIM

Sexual Health Inventory for Men

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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, CA, USA) SBRT is a specific form that has features well suited to the SBRT of PCa, as it includes non-coplanar beams from a linear accelerator and the ability to track 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® has been used to treat 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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.

Table 1. Population characteristics and protocol for the management of localized PCa using Cyberknife®
 Analysis typeLENRisk groupMedian (range) initial PSA, ng/mLProtocol
Choi et al., 2007 [1]Prospective, P22b44Low, Intermediate, High

32 Gy (4 × 8 Gy)

36 Gy (4 × 9 Gy)

Fuller et al., 2008 [2]Prospective, P22b10Low, Intermediate6.9 (1.3–11.45)38 Gy (4 × 9 Gy)
King et al., 2009 [3]Prospective, P22b41Low5.6 (0.7–10)36.25 Gy (5 × 7.25 Gy)
Friedland et al. 2009 [4]Prospective, P22b112Low, Intermediate5.2 (1.1–17.2)35 Gy (5 × 7 Gy)
Meier et al. 2009 [5]Prospective, P12b29Low, Intermediate<2036.25 Gy (5 × 7.25 Gy)
Aluwini et al. 2010 [6]Prospective, P12b10Low, Intermediate8.3 (1.3–13.6)38 Gy (4 × 9.5 Gy)
Katz et al. 2010 [7]Prospective, P22b304Low, Intermediate, High5.8 (0.7–27.3)

35 Gy (5 × 7 Gy)

36.25 Gy (5 × 7.25 Gy)

Bolzicco et al. 2010 [8]Prospective, P22b45Low, Intermediate8.07 (2–20)35 Gy (5 × 7 Gy)
Mc Bride et al. 2011 [9]Prospective, P12b45Low4.9 (1.4–9.4)

36.25 Gy (5 × 7.25 Gy)

37.5 Gy (5 × 7.5 Gy)

Freeman et al. 2011 [10]Prospective, P22b41Low5.4 (3–7.8)36.25 Gy (5 × 7.25 Gy)
Katz et al. 2011 [11]Prospective, P21b82Low, Intermediate5.35 (0.9–13.2)

35 Gy (5 × 7 Gy)

36.25 Gy (5 × 7.25 Gy)

Kang et al. 2011 [12]Retrospective344Low, Intermediate, High

32 GY (4 × 8 Gy)

34 Gy (4 × 8.5 Gy)

36 Gy (4 × 9 Gy)

King et al. 2012 [13]Prospective, P22b67Low<1036.25 Gy (5 × 7.25 Gy)

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®

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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 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®

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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 low- and 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].

Table 2. Oncological results for localized PCa management using Cyberknife®
 Median (range) follow-up, monthsMedian PSA, ng/mLMedian PSA nadir, ng/mL% of patients with benign PSA bounce (value)Median time to benign PSA bounce, monthsbPFS rate, %Reccurence
  1. L, local recurrence; M, metastatic recurrence.

Choi et al. 2007 [1]13 (4–46)78.3
Fuller et al. 2008 [2]40.970.97
King et al. 2009 [3]33 (6–45)0.40.3229 (0.4 ng/mL)181000
Friedland et al. 2009 [4]240.60.597.42L, 1M
Meier et al. 2009 [5]180.40.35381000
Aluwini et al. 2010 [6]5.11.61.601000
Katz et al. 2010 [7]30 (26–37)0.30.316 (0.35 ng/mL)1898.71L
Bolzicco et al. 2010 [8]20 (6–42)0.41000
Mc Bride et al. 2011 [9]44.5 (0–62)0.20.220 (0.4 ng/mL)11.6 (7.2–18.2)97.70
Freeman et al. 2011 [10]600.350.392.73L
Katz et al. 2011 [11]51 (45–58)0.10.197.62M
Kang et al. 2011 [12]40 (12–78)1000
King et al. 2012 [13]32.40.5942L

Toxicity of Cyberknife®

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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 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].

Table 3. Toxicity of the localized PCa management using Cyberknife®
 Acute toxicitiesLate toxicities
rTuTSexual toxicityrTuTSexual toxicity
Choi et al. 2007 [1]32% G1/239% G1/20%0%
Fuller et al. 2008 [2]60% G1/260% G1/2
King et al. 2009 [3]48% G1/2 + 5%G358% G1/2 + 16% G348% G1/265% G1/2 + 5% G3
Friedland et al. 2009 [4]Rectal urgencyDysuriaED1% G30%18% ED
Meier et al. 2009 [5]
Aluwini et al. 2010 [6]20% G1/2 + 10% G350% G1
Katz et al. 2010 [7]80% G1/276% G1/29% G1/29% G1/2, + 0.5% G313% ED
Bolzicco et al. 2010 [8]48.8% G1/246.6% G1/22.2% G28.8% G1/2 + 2.2% G3
Mc Bride et al. 2011 [9]38% G1/278% G1/20%14% G1/2 + 5% G334% G1/2ED
Freeman et al. 2011 [10]G1/2G1/215.5% G1/232% G1/2 + 2.5% G3
Katz et al. 2011 [11]11%12% G1/2ED
Kang et al. 2011 [12]9% G213.5% G211.4% G27% G2
King et al. 2012 [13]16% G1/228% G1/2+ 3.5% G3

Limitations of Cyberknife®

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References

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 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.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies of Cyberknife® in PCA
  5. Technical Aspects of Cyberknife®
  6. Oncological Resultsfor Cyberknife®
  7. Toxicity of Cyberknife®
  8. Limitations of Cyberknife®
  9. Conflict of Interest
  10. References
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