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CyberKnife Stereotactic Ablative Radiotherapy for Lung Tumors (589-596)

Stereotactic ablative radiotherapy (SABR) has emerged as a promising treatment for early stage non-small cell lung cancer, particularly for patients unable to tolerate surgical resection. High rates of local tumor control have been demonstrated with acceptable toxicity and the practical advantage of a short course of treatment. The CyberKnife image-guided robotic radiosurgery system has unique technical characteristics that make it well suited for SABR of tumors that move with breathing, including lung tumors. We review the qualities of the CyberKnife platform for lung tumor SABR, and provide a summary of clinical data using this system specifically.

Key words: Lung cancer; Stereotactic ablative radiotherapy (SABR); Stereotactic body radiotherapy (SBRT); Radiosurgery; CyberKnife.
Introduction

Lung cancer is the leading cause of cancer death in the United States and worldwide (1, 2). The 5-year survival rate is quite poor at 16%, as many tumors are discovered in advanced stages. When lung cancer is detected early, however, the outcome is much more favorable, with 5-year survival rates ranging from 43%-77% (3, 4). The current standard of care for medically fit patients with early stage (stage I) non-small-cell lung cancer (NSCLC) is surgical lobectomy (3). Unfortunately, many patients are deemed to be medically inoperable, due to comorbid conditions. For these medically inoperable patients and those patients who are unwilling to undergo surgery, external beam radiotherapy to cumulative doses of 60 Gy or greater delivered in daily fractions over 6 or more weeks has historically been the standard treatment option. However, the efficacy of conventional radiation therapy is poor with high crude local failure rates of 19-70% and a five-year survival rate of only about 15% (5). When compared to observation alone, radiation therapy improves median overall survival from 14 to 21 months (6). More recently, substantial improvements in radiation therapy technology have allowed for dose-intensification, which has led to promising treatment outcomes. Recent reports of stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), for early stage lung cancer have demonstrated outcomes that in some cases rival the historical results of surgery. The CyberKnife robotic radiosurgery system has unique characteristics that make it well suited for SABR of lung tumors. Here we review these technical strengths of the CyberKnife system and clinical results of CyberKnife SABR for early stage lung cancer.

CyberKnife Image-guided Robotic Stereotactic Ablative Radiotherapy System

The CyberKnife system integrates a compact robotically positioned linear accelerator (linac) with image-guided stereotactic localization, eliminating the need for invasive anatomic fixation while maintaining precise and accurate radiation delivery. The CyberKnife was the first commercial platform to deliver modern image-guided radiosurgery (IGRS). Currently, it remains the system with the greatest degree of automated image-guidance. While the system was initially developed to treat brain lesions, it quickly became useful for treating targets beyond the brain including in the spine, thorax, and abdomen. Its unique ability to dynamically track targets that move with breathing is a key feature that differentiates the CyberKnife from other commercially available image-guided platforms, which typically use either respiratory manipulation or respiratory gating in order to manage breathing-induced motion.

The basic components of the CyberKnife system include a robotic linac (compact 6 MV linear accelerator mounted on a robotic manipulator) and image-guidance hardware (a pair of orthogonal x-ray sources and imaging panels) (Figure 1). For lung tumors and other lesions whose position varies appreciably with the respiratory cycle, an additional component of the CyberKnife system called the Synchrony Respiratory Tracking System is used. Synchrony couples internal motion of the target as assessed by the x-ray image-guidance system with the motion of the chest wall as measured using infrared light-emitting diodes as external surface markers and an optical camera that monitors their position. Complex software is required not only to perform inverse treatment planning, but also to compare real-time images with digitally reconstructed radiographs in order to analyze the imaging data and assess the appropriate corrections to apply to the couch and linac positions during treatment to maintain stereotactic accuracy. The key elements of generating ideal treatment plans and safe treatment delivery include: 1. proper fiducial placement; 2. proper patient positioning and stabilization; 3. appropriate target delineation and margin design; 4. producing an optimal dose distribution during treatment planning; 5. vigilant monitoring during treatment delivery.

Fiducial Placement

Dynamic target tracking is an integral part of treating tumors that move with respiration using the CyberKnife. This process requires the implantation of metallic fiducial markers in or around the tumor for image-guided tracking. Markers may be placed percutaneously through a CT-guided needle, by endovascular delivery, or bronchoscopically (7-10). The fiducial markers are ideally placed such that they are in close proximity to the lesion to be treated, well-separated (by about 1 cm), and non-overlapping on projections from the in-room x-ray imagers. Three markers are sufficient for unique spatial localization, but in practice 4-5 are often placed in case of loss or suboptimal placement of markers. Implantation and tracking of a single marker in the center of the tumor has also been described (11).

The main challenge in the use of fiducial markers is the invasiveness of the implantation approaches. In fact, the main acute toxicity encountered in CyberKnife SABR of lung tumors is implantation-related pneumothorax. The CT-guided percutaneous approach in particular carries the highest risk of pneumothorax, although this is still a risk albeit small using bronchoscopic approaches. Clinical studies of CyberKnife SABR using percutaneous marker placement have reported 19-45% rates of any pneumothorax, and 3-26% rates of those requiring temporary chest tube placement (7, 8, 12-14). These rates are similar to those of CT-guided percutaneous needle biopsies, and are likely related to the general frailty of this patient population with severe comorbidities such as chronic obstructive pulmonary disease making them medically inoperable.


Figure 1: The major hardware components of the CyberKnife image-guided robotic stereotactic ablative radiotherapy system at Stanford University.

By contrast, Erasmus Medical Center investigators found no pneumothorax associated with endovascular (pulmonary arterial) delivery of 87 vascular embolization coils in 23 patients (9), but cardiac arrythmia requiring pacemaker placement was observed in one patient after intravascular coil implantation in a subsequent study by the same group (15). Similarly a small series described no pneumothorax in 8 patients who underwent electromagnetic navigation bronchoscopy for endobronchial implantation of 39 fiducial markers (10). Also, retention of implanted fiducial markers in lung tissue varies by marker type. For example, the Stanford group found that percutaneously implanted platinum endovascular embolization coils were much better retained than standard smooth gold markers, and could successfully be tracked by the CyberKnife after appropriate acceptance testing (8).

Patient Positioning and Stabilization

Unlike traditional rigid skeletal fixation required by some stereotactic platforms, the CyberKnife generally requires stabilization rather than true immobilization for accurate treatment delivery. The priority is generally placed on patient comfort, which reduces the likelihood of sudden random motions, which may be more difficult to compensate. A commonly used device for position stabilization is a custom molded full body-length vacuum bag. For targets in the body, placement of the upper extremities in a position over-head allows for the most advantageous range of beams for treatment planning. While positioning the upper extremities it is preferable to build up an adequate mass of the cushion material that allows the patient to expend no additional effort to maintain the position during treatment delivery. Fatigue and pain will impair position stability and may lead to undesirable treatment interruptions.

Although patients usually are most comfortably positioned supine, prone positioning using a U-shaped cushion to support the face without obstructing breathing may have more advantages for the treatment of tumors located posteriorly or laterally. Because prone positioning may avoid a long path of entrance dose through the lung while treating posterior lesions and some lateral lesions, the dose distribution for such lesions may be optimized by improved beam access (16).


Figure 2: Axial display of a typical lung tumor SABR treatment plan on the CyberKnife. The prescription isodose line (green) conforms to the planning target volume (red), while lower isodose lines avoid normal structures such as the esophagus and spinal canal.

Treatment Planning

The quality of treatment planning relies heavily on the quality of simulation, in which patient positioning and image acquisition are exquisitely important. Computed tomography (CT) and increasingly positron emission tomography (PET) are the typical imaging modalities used for target delineation and treatment planning. These images are acquired with thin cuts (1.25 mm or finer slice spacing) to produce high-resolution digitally reconstructed radiographs (DRRs) for optimal position and motion compensation. Image-guidance is achieved by comparison of these DRRs with the images acquired by the orthogonal in-room imagers during treatment delivery.

The CyberKnife treatment planning system uses inverse planning algorithms, which allow optimization of conformal targeting and normal tissue avoidance (Figure 2). User selected parameters include the number and size of collimators, and exclusion of beams through specified structures.

The CyberKnife is designed to compensate for breathing-induced target motion by dynamic tracking, as discussed in detail below. While a tumor tracking plan can be created from a static (breath-hold) CT scan, 4-D CT simulation which provides data on all phases of the respiratory cycle can be used to calculate dynamic dose distributions by deformably propagating the doses to the reference phase from all the phases of the 4-D CT data set.

Conventional dose calculation algorithms are considered poor for modeling dose build-up and penumbra from lateral electron scatter when radiation beams traverse interfaces between materials of substantially different density. While the standard dose calculation algorithm in the CyberKnife treatment planning system uses a pencil beam (electronic path length, EPL) model that produces accurate dose distributions for targets in regions of homogeneous density such as the brain, significant inaccuracies arise using this method in regions of heterogeneous density as in and around the lungs. A more accurate dose calculation method, Monte Carlo (MC) calculation, has been incorporated as an option for CyberKnife dose calculation. MC models the interactions generated by individual photons to produce accurate dose distributions when simulating many events. Discrepancies in calculated dose as much as 40% (averaging about 8-20%) have been demonstrated between the EPL and MC algorithms depending on the size and location of the specific target, with the largest discrepancies for small tumors surrounded by air-filled lung parenchyma (17-19). Although the EPL calculation consistently overestimates the tumor coverage, the degree of error is not predictable without doing an actual comparative calculation. Thus MC calculation should be used for all cases of thoracic tumors.

Treatment Delivery

The key to dynamic tracking of the CyberKnife is the correlation of two separate imaging systems: 1. the intermittent x-ray localization of the internal fiducial markers; 2. the continuous signal of the external markers by optical tracking (20, 21). The first imaging system comprises a pair of x-ray imagers that acquire intermittent static orthogonal images of the fiducial markers. By automatically extracting the projections of the markers from the images, the image analysis software determines the 3-dimensional coordinates of each of the markers and their center of mass and compares their position relative to the DRRs. The second imaging system is an optical camera that continuously monitors the position of 3 infrared light emitting diodes that are placed on the external surface of the patient’s chest at the beginning of the treatment session, and move as the patient breathes. The trajectories of the external markers follow the breathing cycle, including variations in the breathing pattern.

A series of 10-15 x-ray image pairs is acquired prior to the start of treatment in order to build a correlation model between the internal marker coordinates and various portions of the breathing cycle as determined by the signal from the optical camera. The correlation model generates a continuously calculated position of the center of mass of the internal markers based on the external marker coordinates, and the robotic delivery system is directed to track this position dynamically during each beam delivery. As the model is periodically updated throughout the treatment, changes in patients’ breathing patterns can be accounted for over the course of each treatment session. The clinical accuracy of the Synchrony system was assessed retrospectively in 44 patients, finding a maximum correlation model error of 2.5 mm (standard deviation) (22).

The XSight Lung Respiratory Tracking System is available as an option for dynamic tracking without the use of implanted fiducials. Tumor localization is accomplished using automated real-time image segmentation of the in-room x-ray images based on the contrast of the tumor itself. Thus the system is best used for lesions with sufficient contrast in density from the surrounding anatomy to be clearly visualized on both of the in-room x-ray imagers, i.e., those located in the lung periphery at least 1.5 cm in size, and that do not overlap other dense anatomical structures, such as the spine, diaphragm, and heart in the projection views. As such, XSight Lung may be useful for a small minority of lung tumors currently. Furthermore its accuracy remains to be rigorously validated clinically, and presently all of the publications on this subject pertain to measurement of its performance in artificial settings, although early clinical reports of favorable tumor control when using this method provide indirect evidence of its accuracy (11).

A typical SABR plan is delivered in 60-90 minutes owing to the sequential delivery of approximately 100-200 non- coplanar beams. Options are available for a higher output linac with a dose rate up to 1000 MU/minute, a treatment couch capable of full 6 degree of freedom robotic positioning, and a variable aperture collimator which together can reduce treatment times by as much as 20-30%, making the treatment times comparable to those of other linac-based SABR treatment systems.

While the most unique strength of the CyberKnife system is its automation, this in no way diminishes the importance a highly skilled and attentive treatment team. Because errors in automated image analysis, such as fiducial extraction, can occur, manual inspection of the images displayed during the treatment is crucial in order to confirm treatment is delivered appropriately. Ultimately the treating physicians and therapy staff, rather than the technology itself, are the most important determinants of quality treatment and technical accuracy.

Clinical Results of CyberKnife SABR for Lung Cancer

A large, rapidly growing literature has emerged in recent years documenting the high promise of SABR for early lung cancer using a wide range of treatment platforms. Notable for being a prospective cooperative group trial in a uniform population of medically inoperable patients with peripherally located early lung cancer, the RTOG 0236 study demonstrated 98% local control (within the primary tumor) and 87% local-regional control (within the ipsilateral lobe, hilum, and mediastinum) at 3 years with an intensive regimen of 60 Gy in 3 fractions (23). Of note for comparison purposes, surgical series tend to define local relapse as within the ipsilateral lung or the regional nodes, more commonly referred to in the radiation oncology literature as local-regional relapse.

With respect to SABR using the CyberKnife specifically, to date there have been 21 peer-reviewed English language publications reporting clinical outcomes of lung tumor SABR with this platform, including updates of previously reported series (11-15, 24-39). The large majority of these comprise the experiences of five major centers: Stanford University, Erasmus Medical Center in Rotterdam, University of Pittsburgh, Georgetown University, and the CyberKnife Center of Miami.

In 2003 the first published report of lung tumor SABR using the CyberKnife was of the preliminary results and feasibility analysis of a prospective phase I dose escalation trial conducted by Stanford University and Cleveland Clinic that was in fact the first published North American clinical trial of SABR for lung cancer (24). 23 patients with primary NSCLC (15 patients) or single lung metastases (8 patients) were treated in a single fraction of 15 Gy (the starting dose level of the Phase I trial). In the early period of this study, motion management was achieved by respiratory breath-hold technique or an early version of respiratory-tracking techniques that required very long treatment times. The updated results of the completed phase I study at Stanford University included 32 patients (20 NSCLC, 12 metastases) treated with 15 Gy, 20 Gy, 25 Gy, or 30 Gy in a single fraction (12). There were 3 possible treatment related deaths, all in patients who had received prior or subsequent chemotherapy and 2 of 3 in patients who had received prior thoracic radiotherapy. Pulmonary toxicity was encountered at doses 25 Gy or higher, mainly in patients with central tumors or PTV greater than 50 mL (cm3), leading to the conclusion that 25 Gy single fraction SABR for small lung tumors is safe in properly selected patients. No significant changes in pulmonary function testing (PFT) were found in 17 patients who had pre- and post-treatment PFT. With respect to tumor control, local control appeared to be better with higher doses (91% at 1 year for doses &#8805;25 Gy) and primary lung cancer histology (as opposed to metastases). However, subsequent analysis of outcomes in this series found the main predictor of local control with single fraction SABR to be tumor volume, with excellent local control of tumors smaller than 12 mL but inadequate control of larger tumors in the dose range tested: the Kaplan-Meier estimate of local control at 11 months was 100% for tumors <6 mL, 93% for tumors 6-12 mL, and 47% for tumors >12 mL (36). A preliminary analysis of a tumor volume adapted dosing strategy in which a single fraction of 25 Gy was used for tumors <10 mL and more dose intensive regimens for larger tumors found only a single local failure in 50 patients at a median follow-up of 11 months (40). Figure 3 shows an example of treatment response following CyberKnife SABR of a peripheral lung tumor.



Figure 3: Peripherally located stage I NSCLC in a medically inoperable patient, treated with CyberKnife SABR to a dose of 50 Gy in four fractions. There was a complete response with only minimal fibrosis surrounding the implanted markers (arrow), and no evidence of disease 26 months after treatment.

Investigators from Erasmus Medical Center reported a retro­spective series of 70 patients with inoperable early stage peripheral NSCLC (39 T1 tumors; 31 T2 tumors) treated with either 45 Gy or 60 Gy in 3 fractions (1 treated to 36 Gy) (15). The median follow-up was 15 months. There was a trend toward improved local control with higher radiation dose, with 2-year actuarial local control of 96% in those treated with 60 Gy versus 78% in those treated with 45 Gy (p = 0.197). The 4 local recurrences were in patients with T2 tumors. Actuarial overall survival was 83% and 62% at 1 year and 2 years, respectively, with 19 deaths during follow-up (6 from lung cancer, 13 from intercurrent illness), yielding cause-specific survival rates of 94% and 86% at 1 and 2 years, respectively. Late toxicities included grade 3 pneumonitis in 3 patients, and grade 3 thoracic pain in 4 patients with lesions near the chest wall. An analysis by the same institution of a subgroup of 38 octagenarians with stage I NSCLC found 100% 2-year local control and 1- and 2-year overall survival of 65% and 44%, respectively, which are favorable results in this especially frail patient population (39). In addition, a quality of life analysis of 39 patients on a prospective phase II trial of 48-60 Gy in 3-6 fractions found maintenance of quality of life and significant improvement in emotional functioning after SABR along with 97% local control and 62% overall survival at 2 years and no severe (> grade 3) treatment related toxicity (38).

The University of Pittsburgh group reported their retrospective experience treating 100 patients, 46 with primary NSCLC, 35 with locally recurrent tumors after prior therapy, and 19 with pulmonary metastasis (14). The majority (72 patients) were treated with 20 Gy in a single fraction, while 28 received 60 Gy in 3 fractions. With a median follow-up of 20 months, median time to local progression was 22 months and median overall survival was 24 months. There was a statistically significantly longer time to local progression with the higher dose.

Georgetown University investigators reported a series 20 medically inoperable patients with small peripheral stage I NSCLC treated with CyberKnife SABR to an average dose of 53 Gy (range 42-60 Gy) in 3 fractions over a 3-11 day period (37). The mean tumor volume in this series was 10 mL (range 4-24 mL). With a median follow-up of 43 months, the 2-year actuarial survival was 90% and local control was 95%. No regional and 3 distant recurrences were observed. Chest wall discomfort occurred in 8 of 12 patients with tumors near the pleura and 1 case of subacute grade 3 pneumonitis was encountered in a patient who had received radiation concurrently with gefitinib (13).

The CyberKnife Center of Miami group reported a retrospective series of 31 patients with Stage IA or IB NSCLC with tumors ranging in volume from 0.6 mL to 71 mL treated to doses of 60-67.5 Gy in 3-5 fractions (11). After a median follow-up time of 27.5 months, actuarial local control rates of 93.2% and 85.8% were observed at 1 and 4.5 years, respectively, and overall survival was 93.6% and 83.5% at 1 and 4.5 years, respectively. There were no observed grade 3 or higher toxicities.

In summary, the clinical outcomes of CyberKnife SABR of pulmonary tumors are very consistent with the promising results reported in the broader literature of SABR for lung tumors.

Conclusions

SABR has been shown to be effective and feasible for the treatment of medically inoperable early stage NSCLC, and the CyberKnife system employs novel solutions to some of the technical challenges involved in these complex treatments. Treatments of high biologically effective doses (e.g., 60 Gy in 3 fractions) have yielded excellent local control results, particularly for smaller, peripheral tumors. Additional studies are needed to optimize the dose for large and centrally located tumors. Given the favorable results that are competitive with results historically observed after surgery for these tumors, ongoing trials aim to study this treatment modality in operable patients, including multi-center cooperative group trials being conducted by the Radiation Therapy Oncology Group (RTOG) and the Japan Clinical Oncology Group (JCOG). In addition to these, the international Lung Cancer STARS (Stereotactic Radiotherapy vs. Surgery) trial, coordinated by the M.D. Anderson Cancer Center and sponsored by Accuray, Inc., will study in a randomized fashion the comparative effectiveness of fractionated SABR (nominally 60 Gy in 3 fractions for peripheral lesions, and 60 Gy in 4 fractions for central lesions) using the CyberKnife system specifically versus surgical lobectomy for stage I NSCLC (41).

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TCRT December 2010

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Volume 9
No. 6 (539-656)
December 2010
ISSN 1533-0338

DOI: 10.7785/tcrt.2012.500168

Iris C. Gibbs, M.D.
Billy W. Loo, Jr., M.D., Ph.D.

Department of Radiation Oncology Stanford University and Cancer Center 875 Blake Wilbur Drive; MC 5847 Stanford, CA 94305-5847

iris.gibbs@stanford.edu



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