Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 11. Image-Guided Radiation Therapy

Loren K. Mell, William Y. Song, Todd Pawlicki, and Arno J. Mundt

Image-guided radiation therapy (IGRT) consists of a panoply of technological applications with the common purpose of maximizing target and normal tissue localization for radiotherapy. The exact subset of applications that defines IGRT is somewhat controversial. Proposed definitions of IGRT have ranged from narrow (“external beam radiation therapy with positional verification using imaging prior to each treatment fraction”¹) to broad (“any use of imaging to aid in decisions in the radiotherapy process”²), the former risking the exclusion of techniques as avant garde as adaptive four-dimensional (4D) positron emission tomography (PET), and the latter risking the inclusion of techniques as banal as a staging chest x-ray. The American College of Radiology and American Society of Radiation Oncology practice guideline defines IGRT as “a procedure that refines the delivery of therapeutic radiation by applying image-based target relocalization to allow proper patient repositioning for the purpose of ensuring accurate treatment and minimizing the volume of normal tissue exposed to ionizing radiation,”³ while Greco and Ling⁴defined IGRT more broadly as “the use of imaging for detection and diagnosis, delineation of target and organs at risk (OARs), determining biological attributes, dose distribution design, dose delivery assurance, and deciphering treatment response,” a so-called six-dimensional definition. For the purposes of this chapter, the authors also favor a broader perspective and define IGRT as the use of innovative imaging modalities to augment target and normal tissue localization for radiotherapy planning and delivery. This encompasses a wide range of imaging techniques used for delineation, adjusting for motion or positional uncertainty, and adapting treatment to response. Exploring IGRT in its many facets leaves one simultaneously awed by the pace and extent of technological achievements, yet daunted by the task of critically assessing their tangible benefits to patients.

RATIONALE FOR IMAGE-GUIDED RADIATION THERAPY

Increasing the accuracy and precision of radiotherapy delivery has always been a therapeutic goal. Inaccuracy refers to systematic errors that, on average, bias the treatment delivery with respect to the true target location. Systematic errors can originate, for example, from improper target delineation, poorly representative simulation, dissociation between skin marks and internal anatomy, or predictable organ motions (e.g., periodicity of a lung tumor). Imprecision, on the other hand, refers to stochastic (random) errors that introduce variance in the spatial location of treatment around the true target. Stochastic errors can originate, for example, from inevitable fluctuations in daily setup and from unpredictable target motions (e.g., uterine anteversion or retroversion). Insufficient compensation for these uncertainties leads to target underdosing and overdosing of nearby OARs, whereas overcompensation for uncertainties leads to unnecessary irradiation of normal tissue and constraints in treatment planning. This creates a tradeoff between tumor control probability (TCP) and normal tissue complication probability (NTCP) and emphasizes the role of minimizing uncertainties to enhance the therapeutic ratio of radiation.

Uncertainty in target delineation is a well-documented problem.^5,6 Even among experts, reproducibly defining targets is a challenge, as both intra- and interobserver variation contribute to ambiguity in target localization, and existing guidelines for target delineation are predominantly based on qualitative judgments. Furthermore, while computed tomography (CT) and magnetic resonance imaging (MRI) have become standard for 3D planning, functional imaging techniques—particularly PET—have been increasingly incorporated into treatment planning⁷ to facilitate demarcation of tumor borders and characterize subregions of targets with different physiologic properties. Quantitative imaging can help raise consistency in target delineation, while automated segmentation and deformable image registration software are becoming increasingly available to facilitate and standardize treatment planning.

The use of conformal and hypofractionated radiotherapy techniques, with prolonged treatment times and steeper dose gradients, accentuates the effects of uncertainties related to target localization and the need for IGRT to compensate for them. Toxicity is often an important barrier to treatment intensification, including radiation dose escalation and intensive combined modality therapy. By mitigating toxicity, IGRT may permit implementation of more intensive, but isotoxic, treatment approaches. Furthermore, as therapies continue to improve tumor control, the importance of reducing late and chronic effects of radiotherapy becomes increasingly imperative to maximize patients’ quality of life. Determining the functional relation between IGRT, changes in tumor and OAR dose, and changes in clinical outcomes (e.g., TCP and NTCP models) are of critical importance in evaluating the effectiveness of IGRT techniques compared to standard approaches. There is a rapidly growing need for validated models to estimate the impact of IGRT on cumulative dose distributions and the corresponding effects of cumulative dose on TCP and NTCP.

Conventional radiotherapy techniques are limited due to motion and changes of both tumor and normal tissues occurring between (interfraction) or during (intrafraction) treatment. In many situations, the treatment model based on a static initial simulation is inadequate, necessitating adaptation of the initial plan. In particular, changes that occur in response to therapy could be indicative of a more or less favorable prognosis, in which case modifications to the treatment strategy could be considered. Theoretically, adaptive radiotherapy can take place either between fractions (offline) or while the patient is in the treatment position (online). Innovative strategies to monitor and optimize therapy throughout the treatment course, such as 4D PET-CT, in-room MRI, and fast online adaptive replanning, ideally will advance the quality of radiotherapy for current and future generations.

IMAGE-GUIDED TARGET AND NORMAL TISSUE DELINEATION

Positron Emission Tomography

PET has revolutionized the staging and treatment of cancer. PET scanning involves the systemic administration of a tracer labeled with a radioactive isotope, which emits positrons as it decays. The tracer accumulates in a region of interest and the emitted positron annihilates with a local negatron, releasing two 511 keV photons that propagate in 180 degrees opposite directions. The scanner is equipped with parallel mounted sensors that can detect and determine the spatial location of these annihilation events and, therefore, the regions of increased radiotracer accumulation. Most modern treatment planning systems offer tools to facilitate image registration and fusion with the planning CT to aid target delineation. Commercial software systems that incorporate deformable image registration can aid delineation by accommodating changes in patient anatomy and positioning between scans and segmenting target volumes based on quantitative methods (Fig. 11.1).^6,8

FIGURE 11.1. Reductions in contour variability are observed with automatic contouring. Physician manual contours shown in blue, automatic contours modified by physicians shown in purple, and manual contours using Simultaneous Truth and Performance Level Estimation algorithm shown in brown.(From Stapleford LJ, Lawson JD, Perkins C, et al. Evaluation of automatic atlas-based lymph node segmentation for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2010;77:959–966, with permission from Elsevier.)

FIGURE 11.2. Fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) scan in a patient with a right middle lobe lung carcinoma. On CT[MB15] (left), the limits of the tumor are obscured by postobstructive pneumonia and atelectasis. On the fused scan (right), the tumor is intensely FDG avid and more easily differentiated. (From Spratt DE, Diaz R, McElmurray J, et al. Impact of FDG PET/CT on delineation of the gross tumor volume for radiation planning in non-small-cell lung cancer. Clin Nucl Med 2010;35:237-243, with permission.)

F18-Fluorodeoxyglucose

The most widely used tracer is F18-fluorodeoxyglucose (¹⁸F-FDG), which is taken into cells by active transport, then phosphorylated by hexokinase, trapping the molecule intracellularly. ¹⁸F decays to ¹⁸O, and the molecule enters the glycolytic pathway, but the metabolism of FDG is slow relative to normal glucose, accounting for the high relative accumulation in metabolically active cells, including inflammatory tissue, neurons, brown fat, bone marrow, gastrointestinal (GI) epithelium, and tumors.⁹ Studies in many different types of cancer have found that FDG-PET improves staging,^{10–11,12,13,14} leading to more appropriate risk-adapted management. Other studies have found that increased FDG uptake within tumors prior to or following treatment confers an adverse prognosis,^15,16,17 indicating subsets of patients suitable for alternative treatment strategies.

Multiple studies have investigated the role of FDG-PET in radiotherapy planning for lung cancer.^18–23 FDG-PET imaging alters treatment volumes in approximately 40% to 60% of non–small cell lung cancer (NSCLC) patients^19,21,23,24; it appears to aid targeting for mesothelioma as well.²⁵ It is valuable both for detection of occult nodal involvement and for distinguishing tumor from atelectasis,^19,26 which can be difficult to detect on CT alone (Fig. 11.2). Vanuytsel et al.²¹ found that FDG PET-CT altered treatment volumes in 45 of 73 (62%) lymph node–positive patients staged by mediastinoscopy; in 16 the volume was enlarged, and in 29 it was contracted. Results of the Radiation Therapy Oncology Group’s (RTOG) study RTOG-0515, a phase II trial with 52 NSCLC patients, were recently reported²²; incorporation of FDG PET-CT led to alterations in nodal volumes in 51% of the 47 evaluable patients and in general led to smaller tumor gross tumor volumes (GTV) and mean lung dose. There is no definite consensus on how PET-guided volumes should be delineated, although PET does appear to improve interobserver target definitions.¹⁸ Yu et al.²⁴ reported that the optimal standardized uptake value (SUV) threshold correlating with pathologic specimens was 31% ± 11%. However, recent studies in both phantoms and patients indicate that gradient-based methods may be a more accurate and consistent technique for target volume contouring.^8,27

Studies of FDG PET in head and neck cancer (HNC) have similarly found that planning volumes are frequently altered after incorporating PET imaging.^23,28–35 In a study of 40 HNC patients, Paulino et al.³⁰ compared IMRT plans based on FDG PET to those based on CT. In 25% of patients, CT-based plans were suboptimal in covering the PET-delineated GTV. In a prospective analysis of 20 patients, Schwartz et al.³² found that IMRT plans could be optimized with FDG PET-CT to improve parotid and laryngeal sparing and allow dose escalation up to 81 Gy. A study from Memorial Sloan-Kettering Cancer Center found significant differences in target volumes drawn with and without PET or MRI guidance, indicating complementary information comes from multiple sources, including CT and physical examination, and is necessary to optimally tailor target delineation for each patient.³³ GTVs delineated by FDG PET appear to be significantly smaller than those delineated on CT alone.^33–35 Some concerns exist regarding the technical aspects of PET-guided radiation therapy (RT) in HNC, including difficulties in establishing optimal image registration³⁶ and large variability in target definition.³⁷ Recent studies indicate that automated techniques to guide delineation in HNC can improve consistency,^6,38,39 however, target delineation is still highly dependent on both segmentation and reconstruction methods, emphasizing the importance of clarifying and standardizing methodologies across institutions.^40,41

FDG PET for target delineation has been extensively studied in both esophageal^{14,42,43–47} and rectal^48,49–52 cancers. Hong et al.⁴⁴ studied 25 esophageal cancer patients undergoing FDG PET-CT for radiotherapy planning; PET influenced target delineation in 21 patients (84%), with changes classified as major in 9 (34%). However, Muijs et al.¹⁴ reviewed 30 studies spanning 1,222 patients and found no conclusive evidence supporting the necessity of PET for radiotherapy planning. It is clear that PET is helpful in determining lymph node status and detecting occult metastases, but whether it is superior to other modalities for GTV delineation remains unclear. If used to delineate GTV, a threshold of 2.5 for either absolute SUV or SUV relative to liver uptake has been proposed.⁴⁷ As for rectal cancer, Braendengen et al.⁴⁸ compared GTV delineation with MRI versus FDG PET-CT in 77 patients; PET-guided volumes were smaller than MRI volumes, but PET-guidance appeared to complement data from MRI and led to alteration of management in 15% of patients. Dynamic FDG PET-CT is also an emerging technique⁵⁰ that could play a role in the future for image-guided target delineation for rectal and other cancers.

Researchers at Washington University have extensively studied FDG PET for cervical cancer.^53–55 PET-guided targeting for cervical cancer patients with involved para-aortic lymph nodes can facilitate safe dose escalation to 60 Gy along with intensity-modulated radiation therapy (IMRT).⁵³ Serial changes in cervical tumor volume during brachytherapy⁵⁴ and external beam RT⁵⁵ have been documented, but it is unclear yet how treatment should be adapted in the face of poor response. Lin et al.⁵⁶ reported that FDG PET-based brachytherapy planning significantly optimized GTV coverage without increasing bladder or rectal dose. Liang et al.⁵⁷ analyzed 10 patients treated with FDG PET-guided bone marrow–sparing IMRT for pelvic malignancies in a prospective trial. IMRT plans significantly reduced dose to active bone marrow, and this approach was feasible and well tolerated. Related work by Rose et al.⁵⁸has indicated that dose to metabolically active bone marrow subregions identified by FDG PET is a significant predictor of hematologic toxicity.

Studies of FDG PET for radiation planning in other disease sites have found mixed results. It has potential utility in contouring lumpectomy cavities in breast cancer,⁵⁹ involved nodal or involved field radiation therapy for lymphoma^60,61 and GTV for pancreatic cancer,⁶² but less apparent utility in treating sarcoma.⁶³ Application of FDG PET in central nervous system (CNS) tumors is limited by high background uptake of FDG by normal brain cells, whereas its utility in prostate cancer is limited by relatively lower uptake of FDG in tumor cells. Douglas et al.⁶⁴ successfully used FDG PET in 40 patients for dose escalation in malignant glioma, however, no improvement in patient outcomes was observed. As discussed below, other PET tracers have been more extensively studied in these diseases.

FIGURE 11.3. Comparison of magnetic resonance imaging, L-(methyl-11C)methionine positron emission tomography (PET_, and O-(2-[18F]fluoroethyl)-L-tyrosine PET for a patient with grade III astrocytoma. (From Grosu AL, Astner ST, Riedel E, et al. An interindividual comparison of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)- and L-[methyl-11C]methionine (MET)-PET in patients with brain gliomas and metastases. Int J Radiat Oncol Biol Phys 2011;81:1049–1058, with permission from Elsevier.)

Other Positron Emission Tomography Tracers

Although most studies to date have focused on FDG, many other radiotracers have been studied, including ¹⁸F-thymidine (FLT), ¹⁸F-misonidazole (MISO), ¹⁸F-azomycin arabinoside (FAZA), ¹⁸F-fluoroethyl-L-tyrosine (FET), ¹⁸F-choline, ¹¹C-choline, ¹¹C-methionine (MET), ¹¹C-acetate, and ⁶⁰Cu(II)-diacetyl-bis(N⁴-methylosemicarbazone) (⁶⁰Cu-ATSM). ¹⁵O and ¹³N—labeled H₂O, CO₂, O₂, or NH₃—molecules have also been used to measure blood flow, apoptosis, or hypoxia with PET.^65–67 New tracers are continually being developed and tested. For further discussion of novel molecular imaging applications, refer to several reviews.^{65,66–68,69}

Background uptake of MET in neural tissue is low, making it useful for image-guided planning of brain tumors. Grosu et al.⁷⁰ analyzed 39 patients with glioblastoma multiforme (GBM); in 29 patients (74%), MET uptake extended (up to 4.5 cm) beyond the tumor identified by MRI. MET also appears to improve GTV delineation for skull-base meningiomas.⁷¹ A limitation of MET PET, however, is the short half-life of ¹¹C (20 minutes). FET leads to different GTV compared to MRI alone⁷² but appears to be comparable to MET (Fig. 11.3),⁷³ with the advantage of a longer isotope half-life. Milker-Zabel et al.⁷⁴ evaluated ⁶⁸Ga-(0)-D-Phe (1)-Tyr (221)-octreotide (DOTATOC) PET in 26 meningiomas patients. This technique takes advantage of high expression of the somatostatin type 2 receptor, which binds DOTATOC. In 19 patients, DOTATOC PET significantly influenced target design. Gehler et al.⁷⁵ found similar results, with DOTATOC PET-CT significantly influencing target volumes in 17 of 26 patients.

Several investigators have explored PET-guided RT using MISO^76,77 and FAZA.⁷⁸ The Trans-Tasman Radiation Oncology Group correlated hypoxia identified on MISO PET with outcomes in 45 stage III or IV HNC patients undergoing chemoradiotherapy, with or without the hypoxic cytotoxin tirapazamine.⁷⁷ Baseline hypoxia and residual hypoxia (detected on MISO PET scans at week 4 or 5 of treatment) were correlated with higher rates of locoregional failure. Four of six patients with residual hypoxia recurred locally compared to 4 of 23 patients without residual hypoxia. ⁶⁰Cu-ATSM has attracted attention for hypoxia imaging due to its potential biokinetic advantages and better resolution. ⁶⁰Cu-ATSM PET-guided hypoxia imaging has been investigated in HNC and cervical cancer.^79,80 In a pilot study in 14 cervical cancer patients, ⁶⁰Cu-ATSM appeared to provide good prognostic discrimination; 5 of 5 patients with hypoxic tumors developed recurrence versus 3 of 9 with normoxic tumors.⁸⁰

Both ¹¹C-choline and ¹⁸F-choline have been studied in prostate cancer^81,82; however, the utility of this approach in routine settings is unclear. SUV at 60% of the maximum value appears to correlate well with histopathologic specimens as a threshold for contouring dominant intraprostatic lesions.⁸¹ FLT PET has shown utility in some settings, such as esophageal cancer, where its positive predictive value for involved nodes may be higher than for FDG PET.⁵¹ In a study of five NSCLC patients undergoing serial baseline and on-treatment FLT PET, reductions in FLT uptake within both tumor and bone marrow were observed.⁸³ However, its value for tumor and nodal delineation in rectal cancer and HNC appears more limited.^84,85

In summary, a wide body of literature supports the utility of PET for image-guided treatment planning. Further research efforts are needed to standardize approaches and determine the impact of PET-guided planning on patient outcomes.

Magnetic Resonance Imaging

The utility of MRI in RT planning, particularly for CNS, HNC, and pelvic malignancies, is well known.^86–94 In addition, MR simulators and MRI-only planning approaches are becoming more widely available (Fig. 11.4).⁹⁵Increasingly, quantitative MRI techniques have been used to improve RT planning. For example, functional MRI (fMRI) has been used to reduce radiation dose to normal functioning brain during planning for CNS tumors.^96–100Aoyama et al.⁹⁹ evaluated the use of magnetoencephalography and anisotropic diffusion weighted MRI to plan 20 patients, 15 of whom had arteriovenous malformation (AVM). In 15 patients, targets were modified with significant reduction in the volume of sensitive regions receiving more than 15 Gy. Fast imaging employing steady-state acquisition can facilitate visualization of the trigeminal nerve during radiosurgery planning.^101,102 The ¹H MR spectroscopy (MRS) has also been used to guide planning in gliomas.^103,104 Underdosing of ¹H MRS-delineated metabolically active areas has been associated with worse outcomes in GBM.¹⁰⁴

In patients with prostate cancer, van Lin et al.¹⁰⁵ have reported the feasibility of escalating doses to 90 Gy to dominant intraprostatic lesions identified by ¹H MRS. MR lymphography with intravenous ferumoxtran-10 has also been used to identify pathologic nodal involvement in prostate cancer (Fig. 11.5).^106,107 In a study of 47 patients treated with salvage RT for rising postprostatectomy prostate-specific antigen (PSA), 79% were found to have at least one aberrant positive lymph node, including 10 of 18 (61%) with a PSA less than 1.0 ng/mL. MR lymphography may therefore be useful in helping to define nodal boost volumes in prostate cancer.

FIGURE 11.4. Integration of magnetic resonance (MR) imaging and radiotherapy, with trolley solution and specialized docking device for smooth transfer between MR and linear accelerator. (From Karlsson M, Karlsson MG, Nyholm T, et al. Dedicated magnetic resonance imaging in the radiotherapy clinic. Int J Radiat Oncol Biol Phys 2009;74:644–651, with permission from Elsevier.)

FIGURE 11.5. Fusion of magnetic resonance (MR) lymphography (upper right and left and lower left) and computed tomography (CT) (lower right). With the help of MR lymphography, the node identified on CT is identified as pathologic. (From Meijer HJ, van Lin EN, Debats OA, et al. High occurrence of aberrant lymph node spread on magnetic resonance lymphography in prostate cancer patients with a biochemical recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2012;82(4):1405–1410; with permission from Elsevier.)

FIGURE 11.6. Axial iterative decomposition of water and fat with echo asymmetry and least-squares estimation magnetic resonance imaging scans of the pelvis in a gynecologic cancer patient undergoing chemoradiotherapy. Scans were acquired at baseline (left), midtreatment (middle), and posttreatment (right) and show a steady increase in fraction of fat relative to water within the pelvic bones, indicated by conversion to progressively higher signal.

Dynamic contrast-enhanced (DCE) MRI has been investigated for RT planning in a variety of tumors including HNC, lung, rectal, and cervical cancers.^{108–110,111} Mayr et al.¹¹¹ studied 102 cervical cancer patients treated with DCE MRI. Patients with a low total volume of tumor voxels with low DCE signal had significantly worse tumor control and disease-specific survival. Liang et al.¹¹² used an MRI technique called iterative decomposition of water and fat with echo asymmetry and least-squares estimation to study fractional changes in fat content of pelvic bone marrow during pelvic chemoradiotherapy (Fig. 11.6). Conversion of bone marrow from low fat, high cellularity to high fat, low cellularity during RT is readily observed, enabling noninvasive quantitative methods to analyze the impact of local changes in radiation dose.

In summary, novel and quantitative or functional MRI techniques have been increasingly implemented for RT planning. Ongoing research is seeking to define the clinical benefits of MRI-based IGRT techniques.

Single Photon Emission Computed Tomography

Single photon emission computed tomography (SPECT) is a relatively inexpensive functional imaging technique, with a wide range of potential tracers. Although PET is generally more quantitatively accurate than SPECT in determining in vivo radioactivity distribution,⁶⁹ SPECT tracers often have a longer half-lives and release less energy, leading to favorable dosimetry and utility for studying slower biological processes.⁶⁹ Nonetheless, SPECT appears to have more limited utilization than PET in RT planning.⁷

Several studies of ¹¹¹In-capromab pendetide radioimmunoscintigraphy (RIS) have found it useful in planning both external beam RT^{113,114–115} and brachytherapy^116,117 for prostate cancer. Jani et al.¹¹⁴ reported that RIS influenced RT volumes and decision making in a significant proportion of patients undergoing postprostatectomy salvage RT. Of 54 evaluable patients, 18.5% had treatment plans altered by RIS, including 4 who were not offered RT based on the RIS findings. In a multivariate analysis of 107 patients (53 planned with RIS), RIS was associated with an improved 3-year biochemical failure-free survival (bFFS).¹¹⁵ A similar analysis of 82 patients undergoing RIS for salvage therapy, however, did not reveal a clear benefit of RIS.¹¹⁸ Ellis et al.¹¹⁶ treated 80 low-intermediate risk prostate cancer patients with RIS-assisted brachytherapy. Regions of the prostate showing increased RIS uptake were prescribed 150% of the standard dose. The overall 4-year biochemical failure-free survival was 97.4%.

Other applications of SPECT-guided treatment planning have been studied, including ¹²³IMT (¹²³I-alpha-methyl-L-tyrosine) SPECT for gliomas^119–121 and meta-¹²³iodo-benzylguanidine scans for neuroblastoma.¹²² Krengli et al.¹²¹ studied 21 patients with high-grade gliomas using fused ^99mTc-MIBI SPECT and MRI. Similar to findings of Grosu et al.,¹¹⁹ target volumes were significantly augmented by SPECT, with an average increase of 33% over MRI alone, particularly in resected cases.

SPECT has also been used to guide normal tissue avoidance. In patients with NSCLC, Christian et al.¹²³ used ^99mTc SPECT to identify functional lung to avoid using inverse RT planning, and showed the V20 of functioning lung could be reduced without compromising target coverage. Roeske et al.¹²⁴ used ^99mTc SPECT to identify active bone marrow subregions to reduce hematologic toxicity in patients receiving pelvic chemoradiotherapy.

IN-ROOM IMAGE-GUIDED RADIOTHERAPY TECHNIQUES

Numerous studies have found that motion and setup errors for various disease sites can be quite substantial,¹²⁵ leading to inaccurate or suboptimal treatment plans and potentially poorer tumor control.^{126–129,130} For example, in a study of 127 prostate cancer patients treated without daily prostate localization, de Crevoisier et al.¹³⁰ found that significant rectal distension resulting in anterior displacement of the prostate at simulation was an independent risk factor for biochemical failure. Strategies to address motion have included wide margins, elaborate immobilization techniques, resimulation and replanning, and portal radiography. IGRT approaches take advantage of more frequent and sophisticated imaging to setup the patient and localize the target with greater accuracy, ostensibly improving treatment delivery and allowing reduction of margins.

This section will describe various IGRT technologies developed to address both interfraction and intrafraction motion. Particular attention is devoted to clinical applications of in-room IGRT technologies and data supporting their use. Although some of these technologies have been available for many years, others have only recently been introduced, yet appear to have been adopted rapidly by clinicians.¹³¹ Many others are still under development and have not yet been implemented clinically.

Ultrasound

Ultrasound (US) is one of the most common IGRT approaches in practice, particularly for prostate cancer.¹³¹ It involves emission of high-frequency sound waves to produce images of internal anatomy, consisting of a transducer encased in a probe applied to the skin surface, reflecting sound waves back as echoes when a change in impedance is encountered due to density differences between tissues. The time an echo takes to return is used to calculate the depth of the tissue interface. Image information is obtained along the beamline of the probe, with a complete image created by sweeping across the region of interest. Although three operational modes are available, B (brightness) mode is the primary one used. Readers interested in a more complete description are referred elsewhere.¹³²

Several US products are currently available. All have a system to map the image coordinate system to both the linear accelerator (LINAC) coordinate system and the simulation images. This can be achieved either by tracking the position of a stereotactic arm or using an infrared imaging system to detect the probe position. The target location can be determined in the room prior to treatment, with the necessary shifts conducted to bring the anatomy into position. A widely used US system is the B-mode acquisition and targeting (BAT) transabdominal system (NOMOS, North American Scientific, Chatsworth, CA). The probe is registered to a stereotactic arm on the LINAC gantry, allowing its position to be tracked. Prior to treatment, transverse and sagittal images are generated and the target and normal tissue contours from the planning CT scan are overlaid on the US images. If the target is displaced, the CT structures are maneuvered on a touch screen and the necessary 3D couch shifts are calculated. Another system is SonArray (Varian Medical Systems, Palo Alto, CA), which combines US localization with an optical guidance system to track the position of the probe in the treatment room.^133,134 A similar system is available from BrainLab (Heimstetten, Germany). The I-Beam system (Computerized Medical Systems Inc, St. Louis, MO) uses a machine vision pattern recognition technique to calibrate the probe relative to the gantry. Clarity (Elekta, Stockholm, Sweden) incorporates structure-based tissue matching and segmentation tools to facilitate contouring.

At experienced centers, the additional time required to implement US-based IGRT is reported to be 5 minutes or less.^135,136 Additional time may be necessary, however, when the technology is first adopted or if moves need to be checked online by a physician. Increased skin-to-prostate distances, increased thickness of tissue anterior to the bladder, and less prostate gland present superior to the symphysis can reduce image quality.¹³⁷ However, reproducibility and image quality are generally reported to be high for prostate localization.^137–139 Probe-induced prostate motion is also a consideration, as displacements up to 1 cm have been observed,¹⁴⁰ although generally the magnitude of displacements is 3 mm or less.^{133,135,138,140,141}

Numerous investigators have compared US systems versus conventional setup techniques (i.e., external skin markers) for prostate localization.^{133–135,136,137,138,139,140,141–144,145} In a review of nine series, Kuban et al.¹⁴⁵ reported that shifts from the initial setup were greatest in the anterior-posterior (AP) direction, with standard deviations in the AP, superior-inferior (SI), and right-left (RL) directions ranged from 2.7 to 6.4 mm, 2.8 to 7.3 mm, and 2.1 to 4.6 mm, respectively, with maximum values of 29.8, 30.3, and 34.9 mm, respectively. Several investigators have evaluated shifts in prostate patients undergoing daily portal imaging,^138,140 removing the impact of patient setup uncertainty. In a study of 35 patients using BAT, Little et al.¹⁴⁰ reported mean shifts of –1.3, –1.6, and –0.89 mm in the AP, SI, and RL directions, respectively. Trichter and Ennis¹³⁸ reported that the margins necessary to encompass the prostate at the 95% confidence level using daily portal imaging alone (without US) were 9.2, 14.6, and 10.2 mm in the RL, SI, and AP directions, primarily due to organ motion rather than setup error.

Although US-based localization accounts for interfraction organ motion, it does not address intrafraction motion. However, the magnitude of such motion in patients with prostate cancer appears to be small. In a study of 20 patients undergoing pre- and posttherapy US, Huang et al.¹⁴⁶ noted mean shifts of 0.2 ± 1.3 mm, 0.1 ± 1 mm, and 0.01 ± 0.4 mm, in the AP, SI, and RL directions, respectively. Trichter and Ennis¹³⁸ similarly noted small mean intrafraction shifts using pre- and posttherapy US; however, large maximum shifts of 8.1, 20.4, and 8.3 mm in the AP, SI, and RL directions, respectively, were noted.

Several authors have compared prostate localization with CT^{136,145,147,148} and implanted fiducial markers (144,149,150). Lattanzi et al.¹³⁶ found average disagreements between the modalities were small: –0.09 mm (AP), –0.03 mm (SI), and –0.16 mm (RL). O’Daniel et al.¹⁴⁸ compared four target alignment techniques: skin marks, bony registration, US, and in-room CT. Direct alignment with US and CT provided better target coverage compared to the other methods. Scarbrough et al.¹⁵⁰ compared US with fiducial markers in 40 patients and found that US was associated with significantly greater systematic and random errors than fiducials. Similarly, Gayou and Miften¹⁵¹ found that US was associated with a higher percentage of shifts greater than 5 mm compared to cone beam CT (CBCT).

Limited data exist regarding the impact of US IGRT on patient outcomes. Indirect support is garnered, however, from the excellent outcome of prostate cancer patients treated using daily US guidance.^{152,153–154} Kupelian et al.¹⁵²reported on 100 patients undergoing short-course IMRT, using daily BAT. Margins around the target were 4 mm posteriorly, 8 mm laterally, and 5 mm in other directions. With a median follow-up of 66 months, the 5-year bFFS was 85%, with 5% of patients developing grade 2 or 3 rectal sequelae. Similarly, Zerini et al.¹⁵³ treated 25 low- to intermediate-risk patients to 70 Gy in 30 fractions with daily BAT. With a mean follow-up of 45 months, one patient had biochemical relapse and no patients developed grade 3 or higher late rectal toxicity.

Jani et al.¹⁵⁵ evaluated acute toxicity in patients treated with (n = 50) versus without (n = 49) daily BAT, reporting that patients treated using BAT experienced less rectal toxicity. They also separately analyzed late sequelae in patients treated with and without BAT.¹⁵⁶ Although less toxicity was observed in patients treated with BAT, there was no significant correlation between BAT usage and toxicity on multivariate analysis. Bohrer et al.¹⁵⁷ also reported that patients treated using BAT had less rectal toxicity compared to patients treated prior to BAT implementation. However, no differences in bladder toxicity or PSA control were seen between the two groups. US may also be useful in the postprostatectomy setting.^158,159 Chinnaiyan et al.¹⁵⁹ evaluated SonArray in six post-prostatectomy patients. The average shifts from the initial setup were 5 ± 4 mm, 3 ± 4 mm, and 3 ± 3 mm, in the AP, SI, and RL directions, respectively.

Fewer studies have reported on the utility of US in other tumor sites. US can be useful to confirm bladder volume and position in gynecologic patients undergoing pelvic RT, which is known to be volatile.¹⁶⁰ In intracavitary brachytherapy planning, US is a valuable tool for both detection and prevention of perforations.^161,162 Several investigators have also recently evaluated US-based IGRT to define and verify position of the lumpectomy boost cavity in breast cancer.^163,164 Boda-Heggeman et al.¹⁶⁵ used US guidance for frameless stereotactic radiosurgery (SRS) for liver metastases, using active breathing control to reduce tumor motion. Fuss et al.¹⁶⁶ evaluated US-based IGRT in 62 patients with upper abdominal malignancies, predominantly pancreatic cancer. The mean shifts in the AP, SI, and RL directions were 6 ± 5.31 mm, 6 ± 6.7 mm, and 4.9 ± 4.35 mm, respectively. Meeks et al.¹⁶⁷ performed US-guided extracranial SRS in 16 patients. Single-fraction doses ranging from 12.5 to 24.0 Gy were delivered without significant acute complications. US-guided extracranial SRS appears safe for treatment of GI malignancies as well.^168–170For example, in a series of 10 gallbladder cancer patients treated to a median dose of 59 Gy with daily US localization, all but one experienced grade 2 or less acute toxicity.¹⁶⁸

As newer IGRT approaches are introduced in the clinic, the future role of US remains unclear. Declining utilization was noted in a recent survey.¹³¹ Nonetheless, an advantage of US is that it does not involve additional ionizing radiation, making it likely that it will always play a role in clinical practice.

Video and Surface Imaging

Video-based techniques for patient positioning have been used for over 25 years. Connor et al.¹⁷¹ described a close-circuit television camera and monitor system plus a videodisc recorder, which reduced positional errors to less than 1 mm. The recorder stored a reference image of each treatment setup and was superimposed, in reverse color, on the live camera image. Investigators at the University of Chicago developed an online video “subtraction” setup system, consisting of wall- and ceiling-mounted charge-coupled device cameras linked to a computer equipped with a frame grabber.^172,173 After optimal positioning, a reference image is obtained and, on subsequent days, is subtracted in real time from live video images. Subtraction images are displayed on an in-room monitor and used to interactively realign the patient. Milliken et al.¹⁷² reported high levels of accuracy in both 2D and 3D repositioning using this system. Johnson et al.¹⁷³ performed a clinical study of this system in five HNC patients undergoing twice daily RT. Conventional setup was used in the morning, with the video used simply to record the final patient position. In the afternoon, patients were first aligned with conventional techniques and then live subtraction images were used for setup correction. Although the standard deviation of setup error using room lasers was σ = 3.9 mm, it was reduced by 56% (σ = 1.7 mm) using video setup. The entire process generally required approximately 1 minute.

Several investigators have evaluated video-based setup techniques in breast cancer patients. Baroni et al.¹⁷⁴ developed a video system based on optoelectronics and close-range photogrammetry that captures in real time the position of markers on the patient that are used to monitor and adjust the patient position. Bert et al.¹⁷⁵ investigated a commercial stereovision surface imaging system (AlignRT, Vision RT Ltd, London, UK) for setup of partial-breast irradiation patients, which uses close-range photogrammetry to generate a 3D image of the patient’s surface. The resultant image is compared to an image generated at simulation or of the patient’s external surface generated from a CT dataset. Phantom studies found that the system was capable of identifying translational shifts and rotations of less than 0.1 degree. The AlignRT system is currently being used clinically in the treatment of breast cancer patients undergoing adjuvant whole breast RT (Fig. 11.7).¹⁷⁶

A novel use of the AlignRT system is in the setup and monitoring of patient positioning for those undergoing cranial SRS using minimal immobilization. Cerviño et al.¹⁷⁷ used AlignRT to monitor positioning in patients immobilized with only a head mold that leaves the face exposed. Using anthropomorphic head phantoms and volunteers, the motion inside the head mold was small and could be accurately detected by real-time surface imaging. These investigators recently presented their initial experience using this approach in 23 patients undergoing SRS.¹⁷⁸ The average setup time for both surface imaging and CBCT was 26 minutes, with surface imaging requiring on average 14 minutes. The mean time from initial setup on the table through the last delivery was 40 minutes. Overall, eight patients (35%) required repositioning during treatment. Others have similarly used video surface imaging in patients undergoing cranial radiosurgery.¹⁷⁹

Li et al.¹⁸⁰ and Djajaputra and Li¹⁸¹ developed a real-time video-guided IMRT approach in breast cancer patients using a camera capable of capturing full-frame 3D surface images through a single snapshot. Patient setup parameters are determined semiautomatically, and the IMRT leaf segments are modified in real time. Unlike other video approaches, this system compensates for changes in surface topology by modifying the treatment plan rather than adjusting the patient position. This system is also being applied to patients undergoing fractionated stereotactic RT.¹⁸²

Overall, video and surface imaging approaches are among the least commonly used IGRT technologies in the clinic today, with only 3.2% of responding physicians reporting its use on a recent survey performed in the United States.¹³¹ As new commercial systems and new applications are introduced (e.g., real-time positioning monitoring for frameless radiosurgery), utilization of such technologies may increase in the future.

FIGURE 11.7. AlignRT for breast cancer. A: Alignment of patient surface to planning computed tomography using video cameras. B: Surface monitoring showing the region of interest of the breast in pink and the tolerance level displayed on the left in dark blue.

Planar Imaging

Planar imaging approaches, which include both megavoltage (MV) and kilovoltage (kV), are the most common in-room IGRT approaches used today. In a national survey from 2009, the percentage of respondents using megavolt- and kilovolt-planar systems were 63% and 58%, respectively.¹³¹ These systems were used in nearly all disease sites, particularly CNS tumors and prostate cancer (together with implanted fiducial markers). MV-planar systems were adopted earlier, with the majority of users (53%) having implemented them by 2004. The adoption of kilovolt-planar–based systems occurred later, with the majority of users (54%) having adopted them by 2006.

Electronic Portal Imaging Devices

Electronic portal imaging devices (EPIDs) provide a means of generating an electronic image of a treatment field with the patient on the treatment table. Similar to conventional portal imaging, EPIDs produce images using the therapeutic (MV) beam. However, EPIDs overcome many of the limitations of conventional port films, including delays due to image processing. Moreover, EPID images can be digitally processed for better visualization of the relevant anatomy and stored for offline review. Numerous EPIDs have been introduced including video-based, liquid ion chamber, and solid-state systems. Most commercial systems in use today are based on flat-panel amorphous silicon (aSi) detectors. With this method, a scintillator first converts x-rays to visible light. A photodiode array then converts the light to electrons, which in turn activate pixels in a layer of aSi. The pixels are then read out in successive rows, processed, and displayed on a computer screen for viewing. Clinical studies illustrating the benefits of EPID-based IGRT approaches initially appeared in the early 1990s,^{183–184,185} and since then it has been studied in many disease sites.^186–192 Readers interested in an overview of EPID technologies are referred elsewhere.^193,194

Concerns over increased workload and excess dose have increased interest in on offline EPID approaches. One approach is the so-called shrinking action level strategy.¹⁹⁵ Initially, EPID images are obtained on a given number (N_max) of consecutive days. The 3D setup deviation is calculated offline, and the length of the deviation vector is compared to a predetermined “action level.” If exceeded, a setup correction is performed at the next session. The feasibility of this approach was demonstrated in a multi-institutional prostate cancer trial.¹⁹⁶ Favorable results have also been reported in lung cancer¹⁹⁷ and HNC.¹⁹⁸ An alternative approach is the “no action level” strategy, whereby the mean setup error over a fixed number of fractions is calculated and always corrected for.¹⁹⁹

EPID is useful for prostate localization in conjunction with implanted seed markers.^200,201 Pouliot et al.²⁰² presented an overview of the prostate seed marker protocol developed at University of California–San Francisco (UCSF) using EPID. Prior to simulation, three gold markers were inserted (two laterally on each side of the prostate and one in the apex). A planning CT scan was performed, the location of each marker was contoured, and a digitally reconstructed radiograph (DRR) was generated. Prior to treatment, a lateral EPID image was obtained to assess SI and AP shifts, requiring approximately 0.02 Gy of dose. Comparison of the center of mass of the markers with their expected position on the DRR was used to evaluate the need for repositioning. If shifts were greater than 3 mm, the couch was adjusted. Most investigators report excellent marker visualization,^{200–201,202,203,204} particularly when gold markers are used with a minimum diameter of 0.9 mm.²⁰¹ At least two gold markers are typically visible,²⁰³ and high reproducibility has been reported using this approach.^204,205 Although marker migration is a potential concern, several investigators have reported minimal migration of implanted markers.^{200–201,202,203,204} Kupelian et al.²⁰⁶ evaluated seed marker position throughout the course of treatment in 56 prostate cancer patients. Of 2,037 alignments, the average directional variation of all intermarker distances was –0.31 ± 1.41 mm. Only two markers (1%) showed frequent changes in position, most likely caused by prostate deformation. Of note, others have reported marker movement in patients undergoing hormonal therapy as the prostate involutes.²⁰⁷

Limited data exist for EPID and implanted markers in other tumor sites.²⁰⁸ EPID has been compared with CBCT nongenitourinary (GU) sites, with some studies reporting superior setup accuracy with CBCT.^209–211 Topolnjak et al.²¹⁰ compared the two modalities in 20 breast cancer patients undergoing adjuvant RT, noting that EPID underestimated the bony anatomy setup error by 20% to 50%.

Several investigators have reported outcomes of patients treated with EPID-based IGRT. Nichol et al.²¹² treated 140 stage T1 or T2 prostate cancer patients to 75.6 Gy with daily EPID setup corrections based on bony anatomy. Overall, late grade 2 or higher GI and GU toxicities were noted in 2% and 1% of patients, respectively. Others have reported favorable results using EPID and the shrinking action level approach.²¹³ Ost et al.²¹⁴ compared acute GI and GU toxicity in 196 prostate cancer patients treated with postoperative salvage RT. Overall, patient position was corrected using EPID (prior to 2006, n = 116) or CBCT (after 2006, n = 80). Patients treated with CBCT verification had less grade 1 or 2 GU toxicity compared to those treated using EPID. No differences were seen in GI or high-grade GU toxicity between the two groups.

EPID has long been among the most common in-room IGRT technologies used clinically. In the national IGRT survey,¹³¹ EPID was the most commonly used IGRT technology across nearly all disease sites. With the proliferation of newer technologies, notably CBCT, however, its use may decrease in the future.

CyberKnife

CyberKnife (Accuray Inc, Sunnyvale, CA) consists of a compact X-band 6 MV linear accelerator coupled to a multijointed robotic manipulator with 6 degrees of freedom (Fig. 11.8).²¹⁵ The current generation of CyberKnife technology consists of two precisely calibrated diagnostic x-ray tubes fixed to the ceiling of the treatment vault and two nearly orthogonal aSi flat-panel detectors. After coarse alignment, projected images from the cameras are automatically registered with the DRRs from the planning CT. Changes in target position are relayed to the robotic arm, which adjusts pointing of the treatment beam. During treatment, the robotic arm moves through a sequence of positions (nodes). At each node, a pair of images is obtained, the patient position is determined, and adjustments are made.

CyberKnife was initially based on tracking the skeletal anatomy of the skull and upper spine, limiting treatment to tumors of the brain, head and neck, and upper spine. Subsequently, the ability to track implanted fiducial markers was introduced, allowing treatment of lower spinal tumors with submillimeter precision.²¹⁶ More recently, software has been developed that obviates the need for implanted fiducials in spine patients and enables respiratory tracking.

Several preclinical studies have been published reporting high levels of accuracy of CyberKnife. Murphy and Cox²¹⁷ noted a mechanical accuracy of the beams of 0.7 mm with a calibration accuracy of plus or minus 0.5 mm along each axis. Yu et al.²¹⁸ reported submillimeter accuracy in a phantom study using fiducial markers. Many clinical studies have described favorable outcomes for patients treated with CyberKnife, including adenoma,^219,220schwannoma,²²¹ glioma,^222,223 brain metastases,²²⁴ meningioma,²²⁵ trigeminal neuralgia,^226,227 AVM,²²⁸ and tumors abutting the optic nerves or chiasm.^229,230

A provocative use of the CyberKnife is for pediatric brain tumors. CyberKnife avoids the need for a rigid head frame and, in select children, general anesthesia. Moreover, frameless treatment can be fractionated. Investigators at Baylor University reported promising results with the CyberKnife in infants²³¹ and the general pediatric population.²³² Giller et al.²³² treated 21 children (median age, 6 years) with CNS tumors, with a median dose of 18.8 Gy primarily delivered in a single fraction. At a median follow-up of 18 months, 10 children had evidence of decreased tumor size or stable disease on follow-up imaging.

Many studies have focused on CyberKnife for spinal lesions (Table 11.1).^{233,234–237,238,239,240,241–244,245,246,247,248} Dodd et al.²³³ treated 51 patients with 55 benign intradural extramedullary spinal tumors, with a median dose of 19.6 Gy delivered primarily in 1 or 2 fractions. All patients with more than 2 years of follow-up had either stable or smaller tumors on repeat imaging. Most patients had stable or improved symptoms. One developed a spinal cord injury 8 months following treatment. Investigators at the University of Pittsburgh reported on 125 primarily malignant spinal lesions (115 patients) treated to a median dose of 14 Gy in 3 to 5 fractions (Fig. 11.9).²³⁸ At a median follow-up of 18 months, no patient developed new symptoms or had evidence of RT sequelae, despite the fact that 68% had received prior RT. Of 79 patients presenting with pain, 74 (94%) noted improvement. Others have reported similarly promising results in patients with benign and malignant spinal tumors.^235–249

Recently, CyberKnife has been used to treat extracraniospinal sites.^250–258 However, outcome data remain limited. King et al.²⁵² treated 41 low-risk prostate cancer patients, prescribing 36.25 Gy in 5 fractions of 7.25 Gy. At a median follow-up of 33 months, two patients developed grade 3 GU toxicity and no patients developed grade 3 or higher GI toxicity. Less rectal toxicity was observed with an every-other-day approach versus 5 consecutive days (0% vs. 38%; P = .0035). At last follow-up, all patients remained biochemically controlled. Of 32 patients with 1-year minimum follow-up, 25 (78%) achieved a PSA nadir of 0.4 ng/mL or less.

Several investigators have explored the use of CyberKnife in patients with lung cancer.^251,254 Nuyttens et al.²⁵¹ treated 20 patients with lung tumors in whom fiducial markers had been implanted for tumor tracking. A system of light-emitting diodes placed on the patient’s abdomen was used to monitor the location of fiducials with respect to respiratory motion and provide feedback to the robotic arm of the CyberKnife for tracking. Four-dimensional CT simulation scans were acquired, and patients were treated with hypofractionated radiation (36 to 60 Gy in 3 fractions). With a median follow-up of 4 months, no local failures were observed.

FIGURE 11.8. CyberKnife radiosurgery system. Two amorphous silicon x-ray detectors are positioned orthogonally to the treatment couch. (From Gerszten PC, Ozhasoglu C, Burton SA, et al. Cyberknife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery2004;55:89–99, with permission.)

FIGURE 11.9. X-ray with isodose lines of a treatment plan for a renal cell metastasis to C5 in a 70-year-old woman (arrow). The patient had severe pain that recurred after initial external beam irradiation. The tumor was treated with 14 Gy to the 80% isodose line in a single fraction (orange line). Notice the conformality of the isodose lines around the spinal cord. The patient had significant pain relief within 1 month of treatment. (From Gerszten PC, Ozhasoglu C, Burton SA, et al. Cyberknife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery 2004;55:89–99, with permission.)

TABLE 11.1 OUTCOMES FROM SELECTED SERIES OF SPINAL TUMORS TREATED WITH CYBERKNIFE

Novalis

The Novalis system (BrainLab Inc, Westchester, IL) consists of a 6 MV linear accelerator equipped with a micro-multileaf collimator (MLC). Infrared camera and stereoscopic kilovoltage x-ray imaging technologies are used for patient positioning. Two 80 to 100 kV x-ray tubes mounted in the floor of the treatment room are used to acquire images of internal anatomy (e.g., the vertebral bodies), which are automatically compared with the DRRs from the planning CT scan. The cameras are used to detect the positions of sensors on the patient’s skin, which are automatically compared with their position at simulation to determine necessary couch shifts.

In an analysis of the positional accuracy of the Novalis system, simulated infrared marker shifts revealed that positioning errors of the planned isocenter were 0.6 ± 0.3, 0.5 ± 0.2, and 0.7 ± 0.2 mm along the lateral, longitudinal, and vertical axes, respectively.²⁵⁹ Simulated target shifts indicated that positioning errors of the planned isocenter were 0.6 ± 0.3, 0.7 ± 0.2, and 0.5 ± 0.2 mm along the three axes. Others studies have similarly reported submillimeter accuracy with the Novalis system.²⁶⁰

Various investigators have reported outcomes of patients with intracranial tumors and conditions treated with Novalis.^{261,262–268} In a series of 32 trigeminal neuralgia patients, Chen et al.²⁶¹ found good-to-excellent pain relief in 78%. Pedroso et al.²⁶³ treated 44 cranial AVM patients to a median dose of 15 Gy in a single fraction. The obliteration rate was 53%. Three patients (7%) bled following treatment; however, none developed significant late sequelae.

Others have reported on the use of Novalis in spinal tumors.^269–272 Investigators at Henry Ford Hospital treated 10 spinal metastases with external beam RT (25 Gy in 10 fractions) followed by a 6 to 8 Gy SRS boost on a Novalis unit (Fig. 11.10).²⁷¹ All patients presenting with pain experienced significant relief. No acute or chronic sequelae were noted at a median follow-up of 6 months. These same investigators reported their experience with SRS alone (10 to 16 Gy) in 49 patients with 61 spinal metastases.²⁷² Complete and partial pain relief was noted in 85% of patients. Others have reported similarly promising results in malignant and benign spinal tumors.^269,270

The Novalis system is being increasingly used in other tumor sites.^{273–274,275–279} Ryu et al.²⁷⁷ treated 13 HNC tumors with either SRS (12 to 18 Gy in 1 fraction) or hypofractionated RT (30 to 36 Gy in 6 fractions). Six patients achieved a complete and three a partial response. Soete et al.²⁷⁸ reported short-term outcomes of prostate cancer patients treated with hypofractionated RT (56 Gy in 3.5 Gy daily fractions). Acute grade 2 rectal and bladder toxicity was noted in 12% and 29% of patients, respectively, with no grade 3 or higher toxicities. In a separate study, Soete et al.²⁷⁹ noted significant improvements in positioning of prostate cancer patients using Novalis compared to conventional setup techniques. Setup errors of 5 mm or more occurred in 2% to 14% of patient positionings, versus 28% to 53% with conventional positionings.

FIGURE 11.10. An intensity-modulated stereotactic spinal radiosurgery plan in a patient treated on a Novalis unit. The patient had multiple myeloma involving the seventh and eighth thoracic vertebral bodies. (From Ryu S, Yin FF, Rock J, et al. Image-guided and intensity-modulated radiosurgery for patients with spinal metastasis. Cancer 2003;97:2013–2018, with permission.)

FIGURE 11.11. The real-time tumor-tracking radiation therapy (RTRT) system. (From Harada T, Shirato H, Ogura S, et al. Real-time tumor-tracking radiation therapy for lung carcinoma by the aid of insertion of a gold marker using broncho-fiberoscopy. Cancer 2002;95:1720–1727, with permission.)

Real-Time Tumor Tracking

The real-time tumor-tracking radiation treatment (RTRT) system (Mitsubishi Electronics Co Ltd, Tokyo, Japan) consists of four sets of diagnostic x-ray tubes and imagers (Fig. 11.11).²⁸⁰ Each x-ray unit has a 1.5 MHU x-ray tube with a fixed collimator mounted in the floor with a corresponding imager mounted in the ceiling. During treatment, two of the four x-ray systems are selected to track an implanted fiducial marker using motion-tracking software.²⁸¹The treatment beam is gated to irradiate when the position of the marker coincides with its planned position.

Phantom experiments demonstrate that the RTRT system is highly accurate, with geometric accuracy better than 1.5 mm for moving targets up to a speed of 40 mm per second. Dose due to the diagnostic x-ray monitoring ranges from 0.01% to 1% of the target dose measured in a chest phantom.²⁸⁰ A 4D RTRT system has also been developed.²⁸²

Investigators at Hokkaido University in Japan have presented a number of clinical studies using the RTRT system.^280–293 In an early report, Shirato et al.²⁸⁰ described the treatment of 14 patients with a variety of tumors, including lung, bladder, prostate, liver and rectal cancers. All patients were treated with tight planning target volume (PTV) margins (<10 mm). At a median follow-up of 6 months, no local or marginal recurrences were noted. These investigators and others have explored the RTRT system in tumors of the lung,^{281,286,289–291} prostate,^283,285 GI tract,^287,293,294 and female genital tract.^288,290 In a study of 18 lung cancer patients, Harada et al.²⁸¹ placed gold markers via bronchofiberoscopy under video guidance. Markers were shown to be stable in 65% of tumors throughout treatment. All patients received 35 to 40 Gy in 4 fractions, with tight (5 mm) margins around the tumor. At a median follow-up of 9 months, all were locally controlled, with only one patient developing symptomatic pneumonitis.

Hashimoto et al.²⁸⁷ treated 20 GI patients (14 esophagus, 2 stomach, and 4 duodenum) with the RTRT system. Markers were placed either intraoperatively or via endoscopy and tight (5 mm) margins were used. At a median follow-up of 10 months, no grade 3 or higher late toxicities were noted. Ahn et al.²⁹⁴ used the RTRT system in three unresectable pancreatic cancer patients. All received intraoperative electrons and external beam RT. None developed grade 2 or higher acute toxicity. At a median follow-up of 3 months, three partial responses and one stable disease were noted. The RTRT system is discussed further in the section “Respiratory Gating” below.

University of Michigan System

Investigators at the University of Michigan developed an IGRT system for high-dose irradiation of intrahepatic tumors comprising a racetrack microtron and diagnostic x-ray tubes mounted on the floor and ceiling of the treatment room.²⁹⁵ An in-room shielded control booth allows direct visual contact of the patient during kilovoltage imaging. This system was designed for use in conjunction with an active breathing control (ABC) apparatus to reduce tumor motion due to respiration. In a feasibility study, daily orthogonal images were obtained under ABC and aligned to the planning CT, using the diaphragm for SI alignment and the vertebral bodies for LR and AP alignment.²⁹⁶ Overall, 171 of 262 (65%) fractions required repositioning. Setup errors were reduced from 3.8 mm (AP), 6.7 mm (SI), and 4.0 mm (RL) to 2.3 mm (AP), 3.5 mm (SI), and 2.1 mm (RL). Treatment time was 25 to 30 minutes, with breath holds of up to 35 seconds.

In a review of the 128 patients with unresectable intrahepatic tumors treated with high-dose conformal RT and hepatic artery floxuridine, Ben-Josef et al.²⁹⁷ reported a median survival of 15.8 months, which was significantly improved over historical controls. Grade 3 and 4 toxicities were noted in 21% and 9% of patients, respectively. However, outcomes of patients treated with or without online setup corrections were not compared, so the direct effect of IGRT on patient outcome is not clear.

FIGURE 11.12. The prototype gantry-mounted image-guided radiation therapy (IGRT) system developed by Takai et al. at Tohoku University in Japan. (From Takai Y, Mitsuya M, Nemoto K, et al. Development of a new linear accelerator mounted with dual x-ray flouroscopy using amorphous silicon flat panel x-ray sensors to detect a gold seed in a tumor at real treatment position [abstr]. Int J Radiat Oncol Biol Phys 2001;51[Suppl]:381, with permission.)

FIGURE 11.13. The integrated radiotherapy imaging system developed at Massachusetts General Hospital. (Courtesy of Steve Jiang, PhD.)

Prototype Gantry-Mounted Systems

Investigators at Tohoku University in Japan have modified a commercial linear accelerator to include x-ray generators (mounted on the gantry at plus or minus 45 degrees from the beam axis) opposite two sets of aSi flat panel sensors with images obtained at 15 frames per second (Fig. 11.12).²⁹⁸ In a subsequent study, Takai et al.²⁹⁹ used this system to image a gold seed on a rotating disc and a seed implanted in a metastatic lung tumor and reported excellent visualization of both. This system was combined with a dynamic MLC approach, potentially allowing tracking and continuously irradiating a moving target.

Inter- and intrafractional prostate organ motion has been evaluated using this system in eight patients with implanted gold markers.²⁹⁹ After alignment using skin marks, images were obtained and isocenter shifts were calculated. Images were also obtained prior to every field with corrections of intrafractional displacements greater than 1 mm. The mean magnitudes of interfractional displacements were 1.76, 3.14, and 3.78 mm in the LR, SI, and AP directions, respectively. Corresponding intrafractional displacements were 0.45, 1.08, and 1.45 mm, respectively. Of 214 fractions, 84 (39%) required intrafractional corrections.

An integrated radiotherapy imaging system (IRIS) comprising two gantry-mounted diagnostic x-ray units mounted on either side of the machine head opposite two aSi flat panel detectors has been developed at Massachusetts General Hospital (Fig. 11.13).³⁰⁰ The system co-rotates with the gantry, maintaining relative positions between the megavoltage and kilovoltage x-ray beams. It is also integrated with the pulsing of the LINAC to limit the amount of megavoltage noise during imaging. Each flat panel has an active area of 39.7 cm by 29.8 cm. To accommodate larger coverage for cone-beam CT acquisition (see “Volumetric Imaging” below), the panels are able to slide 13.2 cm along their long axes from their home position. Unlike commercially available systems, the dual-imager IRIS provides a stereoscopic view of the tumor, allowing assessment of the 3D trajectory of tumor motion. To date, no clinical studies have been published using this system.

Commercial Gantry-Mounted Systems

Two commercially gantry-mounted planar imaging systems are currently available: the Varian On-Board Imaging (OBI) system (Varian Medical Systems, Palo Alto, CA) and the Elekta Synergy (Elekta Oncology Systems, Norcross, GA). Both produce high-resolution diagnostic quality x-ray images of the patient in treatment position with considerably less dose than EPID. The Varian OBI system consists of an x-ray tube opposed to an aSi flat panel detector, both mounted to the LINAC gantry orthogonal to the treatment beam axis. The x-ray tube and aSi detector panel can be retracted from the imaging position via robotic arms (Fig. 11.14). The x-ray tube produces 40 to 150 kV x-rays with an image size of 40 by 30 cm². Images are acquired at 7.5 frames per second at 0.195 mm per pixel and 15.0 frames per second at 0.390 mm per pixel.

Fox et al.³⁰¹ presented an overview of OBI software and hardware and a performance evaluation of the automated image registration algorithm. In phantom verification tests, the registration algorithm was capable of detecting known translations and rotations with an accuracy of less than 1.4 mm for a 3D vector offset (0.4 mm, 1.1 mm, and 0.8 mm in the lateral, longitudinal, and vertical dimensions, respectively). Earlier work demonstrated that the isocenter stability of the LINAC with the OBI arms extended is less than 1 mm.³⁰²

The Elekta Synergy system consists of an x-ray tube opposed to an aSi flat panel detector, both mounted to the LINAC gantry orthogonal to the treatment beam axis. Similar to the Varian system, the x-ray tube and aSi detector panel can be retracted via mechanical arms. The x-ray tube produces 60 to 150 kV x-rays with an image size of 41 by 41 cm². Modern day LINAC-based kilovolt imaging systems were originally developed by investigators at the William Beaumont Hospital (Fig. 11.15). A full description of their original system is provided by Jaffray et al.³⁰³

Commercial gantry kilovoltage planar systems are becoming increasing used clinically in the radiation oncology community.¹³¹ Lawson et al.³⁰⁴ presented their early clinical experience using the OBI system in 117 patients (2,088 sessions) with a wide variety of tumors. Overall, the great majority of alignments based on either bones or implanted fiducial markers were small; however, 10% of lateral, longitudinal, and vertical shifts were 0.8 cm or more, 0.6 cm, and 0.7 cm, respectively. Median vector shifts varied between anatomic sites: 0.42 cm (HNC), 0.40 cm (brain), 0.59 (prostate), and 0.73 cm (breast). Pisani et al.³⁰⁵ evaluated the accuracy of online setup errors using a kilovoltage and megavoltage dual-beam imaging system mounted on an Elekta SL-20 linear accelerator. Inter- and intraobserver variability was less with kilovoltage imaging in most cases.

Perkins et al.³⁰⁶ presented the outcome of 13 GI tumor patients undergoing IMRT and concomitant chemotherapy with daily online setup corrections based on bony landmarks or surgical clips using the OBI system. Of 276 fractions, average isocenter shifts were 0.30 ± 0.42 cm (vertical), 0.33 ± 0.34 cm (longitudinal), and 0.35 ± 0.39 cm (lateral). Maximum corresponding shifts were 4.0, 2.3, and 2.4 cm, respectively. Grade 2 or higher acute nausea and diarrhea were noted in five and two patients, respectively. At a median follow-up of 6 months, 21% had disease regression and 71% stable disease. Investigators at Karolinska University reported on OBI in prostate cancer patients with implanted gold markers.³⁰⁷ Shifts were determined by comparing daily orthogonal films of the patient on the treatment couch with reference DRRs at simulation, using a 2D matching algorithm with couch movements made remotely. The entire process added less than 1 minute to the treatment.

Others have presented their initial experiences using OBI in patients with prostate,³⁰⁸ pancreas,^309,310 HNC,^311,312 and gynecologic cancers.^313–330 This system has also been used in patients undergoing SRS,³¹⁴ stereotactic body RT (SBRT),³¹⁵ and intracavitary brachytherapy.³¹⁶ An intriguing use of OBI is the daily localization of select normal tissues. Willis et al.³¹⁷ used daily OBI for verifying the location of kidneys in patients undergoing abdominal irradiation. In that study, kidneys were well visualized in 60% of the images. Ability to visualize the kidneys depended on multiple factors, including the relative anterior-posterior patient and kidney separation, axial profile of the kidneys, and relative contrast between the kidneys and surrounding structures.

FIGURE 11.14. The Varian On-Board Imaging (OBI) system. (From Fox T, Huntzinger C, Johnstone P, et al. Performance evaluation of an automated image registration algorithm using an integrated kilovoltage imaging and guidance system. J Appl Clin Med Phys 2006;7:97–104, with permission.)

FIGURE 11.15. A modified Elekta linear accelerator (LINAC) with dual kilovoltage and megavoltage imaging capability. (From Jaffray SA, Drake DG, Moreau M, et al. A radiographic and tomographic imaging system integrated into a medical linear accelerator for localization of bone and soft-tissue targets. Int J Radiat Oncol Biol Phys 1999;45:773–789, with permission from Elsevier.)

Volumetric Imaging

In the IGRT survey, 59% of practicing radiation oncologists reported using volumetric imaging approaches clinically, most commonly in HNC, lung, GI, and prostate cancers.¹³¹ Compared to other in-room IGRT approaches, volumetric IGRT technologies had been adopted more recently, with the majority of users having adopted them only since 2007.

Fusion of Computed Tomography and Linear Accelerator

The fusion of CT and LINAC (FOCAL) system comprises a Mitsubishi EXL-15DP linear accelerator (Mitsubishi Electric, Tokyo, Japan), a high-speed DX/I General Electric CT scanner (GE Medical Systems, Tokyo, Japan), and conventional x-ray simulator (Fig. 11.16). Developed at the National Defense Medical College in Japan, this system was designed primarily for stereotactic irradiation of lung tumors.³¹⁸ The gantry axes of the LINAC, CT scanner, and simulator are all coaxial, and the table can be rotated in three directions, allowing imaging with the CT scanner and simulator and treatment with the LINAC. Accuracy of the matching of the LINAC isocenter with the CT image is 0.5 mm or less.

Uematsu et al.^318–321 published a series of reports on the utility of FOCAL. Lung cancer patients are immobilized supine and instructed to perform shallow breathing, often with the aid of an oxygen mask. The position and motion of the lung tumor are first evaluated using planar x-rays. The table is then rotated to the CT and serial thin-slice scans are performed at 4 seconds per slice to ensure capturing of the full extent of tumor motion. The target volume is determined, the plan generated, and the table is rotated to the LINAC for treatment. Using this approach, Uematsu et al.³¹⁹ treated 50 stage I or II lung cancer patients, primarily with 50 to 60 Gy in 5 to 10 fractions. At a median follow-up of 36 months, local control was 94%. No adverse sequelae were noted, apart from minor bone fractures and temporary pleural pain in two and six patients, respectively.

In a separate study, FOCAL was used to evaluate intrafraction tumor stability in 38 lung and 12 liver tumor patients.³²⁰ Overall, no intrafraction movements greater than 10 mm were noted, and 68% of lesions had clinically negligible changes in position (0 to 5 mm). The percentage of upper lung, lower lung, and liver tumors with 5 mm or less movements were 100%, 50%, and 25%, respectively. However, in addition to coaching all patients on shallow breathing, abdominal belts were used in select patients to further reduce motion.

FIGURE 11.16. Fusion of computed tomography (CT) and linear accelerator (LINAC) unit (top). The table is rotated to the x-ray simulator to monitor respiratory motion, then to the CT for scanning (middle), and finally to the LINAC for treatment (bottom). (From Uematsu M, Shioda A, Suda A, et al. Intrafractional tumor position stability during computed tomography (CT)-guided frameless stereotactic radiation therapy for lung or liver cancers with a fusion of CT and linear accelerator (FOCAL) unit. Int J Radiat Oncol Biol Phys 2000;48:443–448, with permission from Elsevier.)

Memorial Sloan-Kettering Cancer Center System

Investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) have constructed a treatment system consisting of a conventional CT scanner (Phillips Medical Systems, Milpitas, CA) and a Clinac 2100EX linear accelerator (Varian Medical Systems, Palo Alto, CA).^322,323 The CT scanner couch and LINAC table are aligned, permitting a smooth transfer to the LINAC after the CT is performed. In an initial report, Yenice et al.³²² described the treatment of paraspinal patients with this system. Patients were first immobilized in a stereotactic body frame, using pressures points on select skeletal structures. A planning CT scan was then performed and an IMRT plan generated. A CT scan in the treatment room was then obtained and automatically registered using bony landmarks and surgical hardware to the planning CT scan. Prior to treatment, a second registration was performed using fiducial markers on the frame and patient. The entire process required approximately 60 to 85 minutes for the initial fraction. Overall 3D accuracy of the system was 1.3 ± 0.8 mm.

The outcome of 35 paraspinal tumor patients (14 primary, 21 metastatic) undergoing IMRT using the MSKCC system has been presented.³²³ Overall, 24 (68%) had received prior RT. A planning margin of 10 mm was used, except at the spinal cord interface where 5 mm was used. The median prescribed dose was 20 Gy in 5 fractions. At a median follow-up of 11 months, the 2-year local control for primary and metastatic tumors was 75% and 81%, respectively. Of 30 patients with more than 3 months follow-up, 90% experienced excellent palliation. No patient developed late RT-related sequelae. In their latest report focusing on previously irradiated patients,³²⁴ daily CT myelograms were performed to improve localization of the spinal cord and cauda equina.

Recently, investigators at MSKCC published a study of patients with extracranial metastases treated with either single fraction or hypofractionated SBRT regimens.³²⁵ The 3-year actuarial local progression-free survival for the entire group was 44%. However, lesions that were treated with high-dose single fraction sizes (≥24 Gy) had a local progression-free survival of 88%, compared to 21% in lesions treated with lower single fraction doses (<24 Gy) and 17% in those undergoing hypofractionated RT.

Computed Tomography on Rails

The initial CT-on-rails system was developed at the University of Yamanashi in Japan. It consists of a linear accelerator, a CT scanner, and a common treatment couch, with the LINAC and the CT gantries positioned at opposite ends of the patient couch.³²⁶ This system minimizes patient movement and displacement by moving the gantry of the CT scanner instead of the couch within the gantry. The basis of this system is the Smart Gantry system (GE Medical Systems, Tokyo, Japan), which comprises one middle and two side rails. The side rails ensure controlled horizontal gantry movement, whereas the middle rail guides the gantry forward and backward in the direction of scanning. Kuriyama et al.³²⁶ reported that the positional accuracy of the common couch was 0.2, 0.18, and 0.39 mm in the lateral, longitudinal, and vertical directions, respectively. The scan-position accuracy of the CT gantry was less than 0.4 mm in all three axes.

In a series of reports, Onishi et al.^327,328 described the utility of the CT-on-rails system in patients with unresected lung cancer. Twenty-two stages I to IIIB patients were treated using voluntary breath hold and self-directed beam control. Patients were able to turn the beam on or off using a hand-held switch.³²⁷ Using fluoroscopy, a comfortable degree of breath hold was identified, which maintained tumor position. Tumor position was found to be highly reproducible, with average positional differences of 2.2, 1.4, and 1.3 mm in the SI, AP, and RL positions, respectively, between the daily and planning CT scans. In a separate report, they treated 35 stage I lung cancer patients with 60 Gy in 10 fractions.³²⁸ At a median follow-up of 13 months, 94% of tumors were locally controlled. Five patients developed mild (grade 1 or 2) late respiratory symptoms.

Recently, several investigators have published experiences using commercial CT-on-rails systems. Investigators at M.D. Anderson Cancer Center used Varian ExaCT Targeting System (Varian Medical Systems, Palo Alto, CA), which integrates a high-speed CT scanner on rails (GE Medical Systems, Milwaukee, WI) with a Varian dual-energy LINAC equipped with a 120 MLC.^329,330 The couch base is rotated to position the patient for either treatment or scanning, without the need to transfer onto the CT couch. Court et al.³³¹ reviewed the accuracy of this system and noted that the largest single uncertainty was the couch position on the CT side after a rotation (0.5 mm in the lateral direction). All other sources of uncertainty, including the difference in couch sag between the CT and LINAC, were less than 0.3 mm.

Chang et al.³³⁰ treated 15 patients with spine metastases with IMRT on a phase I clinical trial using ExaCT. All patients were immobilized in a stereotactic body frame and received 30 Gy in 5 fractions, with a maximum cord dose of 10 Gy. On average, the duration of the daily procedure was 1.5 hours. At a median follow-up of 9 months, no patient developed significant RT-related sequelae. These investigators reported the outcome of 63 patients with 74 spine lesions treated using CT-on-rails on the phase I trial and a subsequent phase II trial.³³² At a median follow-up of 21.3 months, the 1-year local progression-free survival was 82%, with 52% of patients pain free at 12 months. No patient developed late grade 3 or higher neurologic sequelae. Favorable results have similarly been reported using this approach in patients with renal cell spine metastases³³³ and those undergoing reirradiation.³³⁴

Others have reported their experiences using the Siemens Primatom CT-on-rails (Siemens Oncology Systems, Concord, CA). This system consists of a Somatom CT scanner and a Primus linear accelerator in the same vault sharing a common table or couch (Fig. 11.17).^335–338 As with other systems, the CT scanner is moved on a pair of horizontal rails. Wong et al.³³⁵ used Primatom to deliver the boost treatments in 108 prostate cancer patients undergoing IMRT. Overall, isocenter adjustments were common. The percentage of adjustments in the AP, SI, and LR directions were 54%, 27%, and 34%, respectively. Corresponding shifts of 1 cm or greater were noted in 15%, 4%, and 5% of patients, respectively.

Ma and Paskalev³³⁹ provided an excellent review of in-room CT systems and techniques. The future of such systems remains unclear given the increasing availability of other commercial volumetric imaging systems, including on-board CBCT and helical tomotherapy.³⁴⁰ However, the value and possible applications of high-quality in-room conventional CT images remains an interesting area for clinical research.

Megavoltage Systems

Early Megavoltage Computed Tomography Systems

The underlying principle of megavoltage CT (MVCT) is analogous to kilovoltage CT, namely an x-ray source and detectors are used to reconstruct 2D images into 3D datasets. The first MVCT system was developed in 1982, consisting of a modified 4 MV linear accelerator with a detector array mounted on the LINAC gantry.³⁴¹ In addition to the appeal of using the megavoltage beam for imaging, MVCT has the added benefit of producing images free of the streaking artifacts common in kilovoltage CT, secondary to dental fillings or hip prostheses.

More recently, investigators at the University of Tokyo mounted a small detector on the gantry of a 6 MV LINAC in order to generate MVCT images in lung tumor patients undergoing SRS.^342,343 All patients were instructed to maintain shallow breathing during planning and treatment to minimize organ motion. Moreover, at simulation, tumor motion was assessed by fluoroscopy, and, if greater than 1 cm, an oxygen mask and a belt compressing the chest and abdomen were used. Immediately prior to treatment, a MVCT was obtained on the treatment table and appropriate shifts are made. In a series of 14 patients treated with a median single fraction dose of 20 Gy using this approach, the overall local control was 95%. Moreover, although all patients with greater than 3 months follow-up had interstitial lung changes, only one developed symptomatic pneumonitis.

FIGURE 11.17. The Siemens Primatom computed tomography-on-rails system. (From Wong JR, Grimm L, Uematsu M, et al. Image-guided radiotherapy for prostate cancer by CT-linear accelerator combination: prostate movements and dosimetric considerations. Int J Radiat Oncol Biol Phys 2005;61:561–569, with permission from Elsevier.)

FIGURE 11.18. The helical Tomotherapy system. (From Tomsej M. The Tomotherapy Hi-Art System for sophisticated IMRT and IGRT with helical delivery: recent developments and clinical applications. Cancer Radiother 2006;10:288–295, with permission from Elsevier.)

FIGURE 11.19. Color wash showing dose distribution for a 20-year-old female patient treated with targeted total body irradiation using Tomotherapy. The target structure is skeletal bone. Relative sparing of the brain, oral cavity, thyroid, lungs, heart, soft tissue, and gastrointestinal tract is seen. (From Wong JYC, Rosenthal K, Liu A, et al. Image guided total marrow irradiation (TMI) using helical Tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation. Int J Radiat Oncol Biol Phys 2009;73:273–279, with permission from Elsevier.)

Helical Tomotherapy

The Tomotherapy system (Tomotherapy Inc., Madison, WI) has a 6 MV LINAC and a detector array mounted opposite each other on a ring gantry that continuously rotates while the couch is translated through the gantry (Fig. 11.18).^344,345 MVCT imaging on the Tomotherapy system is performed by reducing the nominal energy of the incident electron beam to 3.5 MeV.³⁴⁶ Three acquisition modes are available (fine, normal, and coarse).

Investigators at the University of Wisconsin evaluated Tomotherapy MVCT imaging for optimizing setup in eight dogs undergoing RT.³⁴⁷ Prior to treatment, a MVCT scan was obtained and aligned with the planning kilovoltage CT scan in the transverse and sagittal planes. MVCT images were of sufficient quality for verification of treatment setup in all eight animals, although soft tissue contrast was inferior to that of the kilovoltage CT scans. Both the primary tumor and adjacent bony landmarks were used for alignment. The entire process took approximately 5 to 12 minutes, including 3 minutes for image acquisition.

Mahan et al.³⁴⁸ reported on Tomotherapy for optimizing patient setup in eight patients undergoing reirradiation of spinal metastases. The mean retreatment dose was 28 Gy, with the maximum cord dose of 27% to 56% of the prescribed dose. Prior to treatment, MVCT images were acquired and autofused with the planning CT scan, allowing calculation of couch translations. The range of interfraction displacement was as great as 1.5 cm, with standard deviations of ± 4 mm (AP), ± 4.3 (SI), and ± 4.1 (RL). At a median follow-up of 15.2 months, all eight patients responded (two partial, six complete). None developed an in-field recurrence or significant late toxicity. Others have reported the value of daily setup verification using the Tomotherapy system in other sites, notably lung cancer.^349,350

A concern with the use of the Tomotherapy system for daily setup verification is image quality. Although less of a concern when bony landmarks are used, this is important when alignment is based solely on soft tissues. Song et al.³⁵¹ evaluated the feasibility of Tomotherapy for daily prostate localization. MVCT images were acquired and compared to the planning kilovoltage CT images in five patients. Of note, prostate volumes were smaller and more consistent on kilovoltage CT scans. Moreover, inter- and intraobserver contouring uncertainty was greater for MVCT. Daily alignment can be improved in prostate patients, however, with implanted fiducials, which are well visualized on the Tomotherapy system.³⁵²

Tomotherapy is a popular IGRT treatment approach, with multiple dosimetric studies supporting its potential benefits.^{353,354–360} Multiple investigators have reported favorable results using the Tomotherapy system for HNC³⁶¹ and CNS,³⁶² pediatric,³⁶³ GI,³⁶⁴ gynecologic,³⁶⁵ and GU³⁶⁶ tumors. An intriguing use of Tomotherapy is in the delivery of total marrow irradiation in place of total body irradiation in leukemia patients undergoing allogeneic stem cell transplantation (Fig. 11.19).³⁶⁷

Megavoltage Cone-Beam Computed Tomography Systems

Megavoltage CBCT imaging is accomplished by first generating a series of 2D projections around the patient with the megavoltage beam and a detector.³⁶⁸ A 3D dataset is then reconstructed using the Feldkamp algorithm,³⁶⁹ in a process analogous to conventional CT imaging, whereby an x-ray source and a detector are mounted on a rotating gantry. However, whereas a conventional CT system uses a 1D linear detector array, the CBCT system uses a 2D array.

Multiple investigators have evaluated the utility of megavoltage CBCT,^{370,371–373,374,375} with the largest published experience from UCSF.^{370,374,375–376} Pouliot et al.³⁷⁴ described patient alignment and dose verification using a 6-MV Primus linear accelerator (Siemens Oncology Systems, Concord, CA) operating in arc mode equipped with an aSi flat-panel EPID. Megavoltage CBCT scans were generated using an anthropomorphic head phantom, frozen sheep or pig cadaver heads, and HNC patients, requiring doses of 0.05 to 0.15 Gy. Acquisition and processing times were both on the order of 90 seconds. Megavoltage CBCT and conventional CT datasets were registered with millimeter and degree accuracy.

Morin et al.³⁷⁰ evaluated the potential benefits of megavoltage CBCT imaging in HNC, lung, and pelvic cancer patients treated on a prospective clinical trial. In a locally advanced HNC patient, megavoltage CBCT detected a misalignment of the vertebral bodies and spinal cord in the neck not seen on portal imaging (Fig. 11.20). Megavoltage CBCT has also been found to complement treatment planning in patients with implanted metallic objects.³⁷⁷

Outcomes of patients specifically undergoing megavoltage CBCT imaging during treatment are limited. Swamy et al.³⁷⁸ evaluated the use of dose-escalated IMRT treatment in 12 intact prostate cancer patients. Following implantation of fiducials, patients underwent megavoltage CBCT daily to localize the prostate. At a mean follow-up of 12.2 months, 92% of patients were biochemically controlled. Only one patient developed grade 2 proctitis following treatment; no grade 3 or higher toxicities were seen.

Kilovoltage Systems

Mobile Fluoroscopic C-Arm Systems

Several groups have reported on kilovoltage CBCT scanning using a mobile fluoroscopic C-arm imager.^378–380 Swamy et al.^378,380 modified a commercial mobile isocentric fluoroscopic C-arm (Power-Mobil, Siemens Medical Solutions, Erlangen, Germany), replacing the standard image intensifier with an aSi flat-panel detector. A projection set of 100 to 1,000 images are obtained while the C-arm rotates around the patient in a 180-degree arc. Similar to megavoltage CBCT imaging, kilovoltage CBCT images are reconstructed using the Feldkamp algorithm, modified due to the limited projection arc.³⁸¹ Similar units have been developed at other centers.³⁸²

The feasibility of using kilovoltage CBCT imaging produced by a mobile C-arm system in patients with prostate and HNC to improve setup and target localization has been presented.³⁷⁸ Patients underwent kilovoltage CBCT imaging weekly and the images were assessed offline. Overall, the imaging procedure was performed in less than 5 minutes with less dose than conventional CT. Although spatial resolution was good, image quality was not ideal (e.g., differentiation of the prostate from the rectum in the area of the prostate-rectum interface was poor). In sites prone to respiratory-induced motion, image quality can be improved by correlating the CBCT acquisition with breathing.³⁸⁰

FIGURE 11.20. Comparison of a kilovoltage computed tomography (CT) scan (left) with a megavoltage cone-beam CT (right) of a head-and-neck cancer patient. The window level of both images was adjusted to provide the best soft-tissue contrast. (From Morin O, Gillis A, Chen J, et al. Megavoltage cone-beam CT: system description and clinical applications. Med Dosim 2006;31:51–61, with permission from Elsevier.)

Gantry-Mounted Cone-Beam Computed Tomography Systems

Most major linear accelerator vendors currently offer gantry-mounted kilovoltage CBCT solutions. The Elekta Synergy and Varian OBI systems consist of kilovoltage x-ray tubes mounted opposite flat panel detectors orthogonal to the treatment beam on retractable arms.^383,384 In collaboration with investigators at the University of Heidelberg, Siemens is developing an “in-line” system that places the diagnostic x-ray tube at 180 degrees to the megavoltage source (Fig. 11.21).^385,386 All three systems acquire kilovoltage projections during a 360-degree gantry rotation, which are reconstructed into a 3D dataset.³⁸⁷

The initial prototype (and its corresponding commercial counterpart) of the Elekta kilovoltage CBCT system has been presented in reports from William Beaumont Hospital.^388,389 In a phantom study in prostate cancer, kilovoltage CBCT was found to achieve a setup accuracy of 1 mm or less in the LR, AP, and SI directions. Setup error was reduced in nearly all cases and was generally within ± 1.5 mm. The entire image-guided process required 23 to 35 minutes. Others have presented their experiences using the Elekta kilovoltage CBCT system.^390–394 In 20 patients with various tumors, McBain et al.³⁹⁰ noted sufficient image quality in all patients, including those in whom full gantry rotations were not possible (extremity and breast tumor patients). In general, soft tissue delineation was sufficient to allow assessment of the target and normal tissues. However, prostate images were not sufficiently distinct to allow organ contouring, compensation for small (<3 mm) movements, or for verification of small PTV margins.

Guckenberger et al.³⁹¹ compared the utility of the Elekta kilovoltage CBCT system with EPID in terms of setup accuracy in 24 patients with a variety of tumors. Kilovoltage CBCT was found to add little in the assessment of translational errors. Translational errors detected with either approach differed by less than 1 mm in 70.7% and less than 2 mm in 93.2% of measurements. However, CBCT was superior in the detection of rotational errors. Rotational errors greater than 2 degrees were noted in 3.7%, 26.4%, and 12.4% of pelvic cancers, thoracic cancers, and HNC, respectively. Such rotational errors led to poorer target coverage and increased normal tissue dose in cases with elongated targets in close proximity to normal tissues. Several authors have presented their experience using the Varian kilovoltage CBCT system in the treatment of a variety of tumors including neuroblastoma³⁹⁵ and bladder cancer.³⁹⁶

Thilmann et al.³⁸⁶ evaluated the utility of the in-line kilovoltage CBCT system developed in collaboration with Siemens. In a study of various tumor sites, bony landmarks were easily visualized on all images, allowing table shifts to be automatically calculated. Soft tissue contrast was acceptable except in one morbidly obese patient. Using an action level of 2 mm, setup corrections were performed in four of six patients. Approximately 10 to 12 minutes were required to perform imaging, reconstruction, analysis, and positional corrections.

No detailed clinical outcome studies are yet available in patients treated using kilovoltage CBCT for either setup or target localization. However, Groh et al.³⁹⁷ compared the performance of megavoltage and kilovoltage CBCT technologies. Megavoltage CBCT was found to offer an advantage in terms of simplicity of mechanical integration with a linear accelerator. In contrast, kilovoltage CBCT was found to be superior in terms of imaging of soft tissue structures and the signal-to-noise ratio per unit dose.

In the coming years, numerous advancements are expected in kilovoltage CBCT technology. One area of active research is digital tomosynthesis (DTS), a method of reconstructing 3D slices from 2D cone beam x-ray projections data acquired with limited source angulation (e.g., 40 degrees). Unlike conventional kilovoltage CBCT approaches, DTS requires less scan time and results in less radiation exposure to the patient. Investigators from Duke University recently illustrated the ability to generate high-quality images using the DTS approach in patients with prostate, HNC, and liver tumors.³⁹⁸

FIGURE 11.21. Comparison of a conventional computed tomography (CT) scan (left) with a kilovoltage cone-beam CT scan (right) obtained using a mobile fluoroscopic C-arm imager in a patient with prostate cancer. (From Sorensen SP, Chow PE, Kriminiski S, et al. Image-guided radiotherapy using a mobile kilovoltage x-ray device. Med Dosim 2006;31:40–50, with permission from Elsevier.)

Electromagnetic Localization Systems

Electromagnetic localization systems are typically based on a magnetic dipole source and one or more sensors to detect a magnetic field created by the dipole. The dipole source is excited by a radiofrequency (RF) signal that creates a magnetic field. Overall, the system operates such that when the RF signal is removed, a capacitor is discharged, resulting in an oscillating magnetic dipole. A transponder is an electric device used to wirelessly transmit and receive electrical signals. The dipole sources in clinical electromagnetic systems are generally referred to as transponders. Each transponder is similar in size to a gold fiducial marker. The transponders are permanently implanted within the tissue to be treated. To date, the only commercial system is supplied by Calypso Medical Technologies, Inc. (Seattle, WA). An excellent review of this technology and its clinical use in IGRT is given by Litzenberg.³⁹⁹ The benefits of electromagnetic tracking systems are: (a) transponders can be implanted directly into the target, (b) nonionizing radiation is used, and (c) real-time positional determination is possible during the treatment fraction.

Particular attention has been focused on the use of the Calypso system for prostate cancer patients undergoing definitive RT.^400–404 Kupelian et al.⁴⁰⁰ reported a multi-institutional study of 35 patients undergoing prostate localization and continuous monitoring during treatment. An average initial displacement (from setup skin marks) exceeding 5 mm was seen in more than 75% of sessions analyzed. Displacement of 3 mm or move and 5 mm or more for 30 seconds or longer occurred during 41% and 15% of sessions, respectively. The percentage of fractions in an individual patient with displacements of 3 mm or more varied considerably (3% to 87%). In a study of 28 patients with implanted Calypso transponders, Rajendran et al.⁴⁰¹ noted that the average number of treatment days with shifts beyond 0.5 cm in the vertical, longitudinal, and lateral directions were 62%, 35%, and 38%, respectively. No outcome comparisons have been performed of prostate cancer patients treated with and without the Calypso system; hence, the clinical importance of this intrafraction displacement remains unclear.

Less attention has been focused on the use of the Calypso system in other tumor sites. Shinohara et al.⁴⁰⁵ recently evaluated the potential of using the Calypso system in five patients with locally advanced pancreatic cancer. Overall, the markers were well tolerated, with minimal migration noted, except in one patient who expulsed a single transponder. The mean initial shifts (from the setup markers) were 4.5 mm, 6.4 mm, and 3.9 mm in the x, y, and zdirections, respectively. Mean intrafraction motion was significant in all directions: superior (7.2 mm), inferior (11.9 mm), anterior (4.9 mm), posterior (2.9 mm), left (2.2 mm), and right (3.1 mm).

Few in-room IGRT systems provide the ability to perform continuous monitoring of target position. Thus, particularly in sites in which intrafraction motion is a concern, the use of the Calypso system remains appealing.

Emerging In-Room Imaging Technologies

Increasing interest has focused on the combining treatment devices with advanced imaging modalities to create novel in-room IGRT platforms. These platforms can incorporate functional and high-resolution imaging to facilitate better setup and target delineation than is possible with CT-based techniques. Such technologies may provide the possibility for improved adaptive RT techniques in the future.

Magnetic Resonance–Linear Accelerator Systems

MRI provides superior soft-tissue resolution compared to CT. Because linear accelerators are the dominant radiation delivery device in developed radiotherapy programs, in-room MR-LINAC systems are being developed, but to date no commercial systems are available. An early proposal for an integrated MR-LINAC was from the University Medical Center Utrecht.⁴⁰⁶ This system was designed as a 1.5-T MRI scanner with diagnostic quality imaging integrated with a 6-MV LINAC. More recently, simultaneous MRI and megavoltage transmission images were acquired with the imaging systems without interfering with each other.⁴⁰⁷ The first operational prototype system reported in the literature was at the Cross Cancer Institute.⁴⁰⁸ This prototype used a fixed gantry 6-MV LINAC in conjunction with a 0.2-T MRI system and fully operational MRIs were acquired during LINAC beam-on. There are issues with MR-LINAC systems such as magnetic interference at the LINAC due to the MR fringe fields, beam losses with the electron gun and RF noise from MLC motors. However, these are active areas of research and do not appear to be insurmountable hurdles toward the clinical implementation of MR-LINAC systems.^409–411

Magnetic Resonance–Cobalt Systems

Due to some of the technical issues limiting MR-LINAC systems, MR-cobalt systems have also been developed.⁴¹² MR-cobalt systems consist of one or more high-dose-rate cobalt sources, an MRI system, and MLCs for IMRT (the same issues exist with RF noise from MLC motors as for MR-LINAC systems). A commercial cobalt-MR system has been developed by ViewRay Inc. (Oakwood Village, OH) and utilizes a 0.35-T MR, 3 KCi cobalt sources and three double-focused MLCs (Fig. 11.22).

As with MR-LINAC systems, the dose distributions can be significantly affected by high magnetic fields. The effect is a significant increase in dose at tissue air boundaries, due to returning electrons in the presence of magnetic fields, known as the electron return effect. The magnitude of this effect depends on the strength of the magnetic field. It has been demonstrated that this effect is minimal for lower magnetic fields of about 0.2 T.⁴¹³ Therefore, it is advantageous to use the lowest possible magnetic field strength while still obtaining MR images with sufficient spatial resolution.

On-Board Single-Photon Emission Computed Tomography Imaging Systems

SPECT imaging uses a radiotracer attached to a biologically active molecule, which is injected into the patient. The energy of γ-ray emission depends on the radionuclide used in the procedure. A gamma camera is used in SPECT imaging to create 3D images. The gamma camera collects γ-rays that are emitted from within the patient. An image of the radionuclide location within the patient is generated from the data collected by the gamma camera. The aspects making up the gamma camera are the collimator, detector crystal, photomultiplier tube array, and reconstruction algorithm such as filtered back projection or iterative reconstruction. SPECT uses collimation (e.g., lead block containing many tiny holes that is positioned between the patient and the detector) to permit only photons of essentially parallel trajectory to pass through the collimator and reach the detector. Given knowledge of the orientation of a collimator’s holes, the original path of a detected photon is linearly extrapolated and thus used in the reconstruction algorithm to create the 3D image. Simulation studies have been performed to determine the potential localization accuracy for on-board SPECT-LINAC systems. It was determined that conventional SPECT systems were too cumbersome, and realization of such a system would be better accomplished using a smaller gamma camera with a limited imaging region that would also be mobile to move it closer to the patient and to enhance the spatial resolution.⁴¹⁴

Proton–Positron Emission Tomography Systems

PET, similar to SPECT, is an imaging technique in which a radionuclide is synthetically introduced into a molecule of potential biological relevance and administered to a patient. However, the physics of photon emission is different from that for SPECT. In PET, the photons emitted from the radiotracer are coincident, that is, nearly back to back. Locating the source of an annihilation event is a method known as coincident detection. PET systems have similar components as SPECT systems (e.g., detectors, photomultiplier tube, collimators, and a reconstruction algorithm), except that a PET camera is constructed so that opposing detectors are used. Each annihilation event is presumed to have occurred at some point along an imaginary line between the two. This information is registered in the reconstruction algorithm. Coincidence detection is a very efficient technique and contributes to PET’s superior sampling rates and sensitivity compared to SPECT.

During proton therapy, inelastic reactions between the treatment protons and nuclei of the tissues in the patient produce small amounts of short-lived positron-emitting isotopes. PET imaging has been suggested as a method to determine the geometric accuracy of the treatment delivery. The threshold of inelastic nuclear reactions leading to tissue positron activation is in the energy range of 15 to 20 MeV. The distal activity falloff is not exactly matched to the dose falloff at the end of the proton range. Nonetheless, a clinical study was completed to investigate proton-PET IGRT for offline proton treatment verification.⁴¹⁵ This pilot study was followed by further development of this approach to include efficient analytical models to accurately predict the expected PET images based on the treatment plan.⁴¹⁶ Furthermore, mobile PET scanners have been investigated to provide a low-cost solution for in-room PET imaging, which also has the advantage of increasing the imaging sensitivity partly due to lower biological washout.⁴¹⁷

FIGURE 11.22. Viewray cobalt magnetic resonance system. (Courtesy of Timothy Sokolich.)

FIGURE 11.23. Tumor trajectories in 20 liver cancer patients, measured using a total of 49 implanted markers during cone-beam computed tomography acquisition: (A) Anterior-to-posterior, (B) Posterior-to-anterior, (C) Left-to-right, and (D) Right-to-left projection view. An average motion of up to 3.0 ± 0.4 cm was observed for a patient, in 1 fraction.

FOUR-DIMENSIONAL IMAGING AND MOTION MANAGEMENT

Respiratory Motion

Respiratory-induced organ motion presents a significant challenge. Particularly for tumors in the thorax and upper abdomen, movements can be greater than 3 cm if the motion is not actively controlled (Fig. 11.23).^285,418 Respiratory motion can result in imaging artifacts on both the planning CT and the CBCT used for treatment guidance. If left uncorrected, this can lead to target delineation and beam placement uncertainties that compromise the overall effectiveness of the treatment. There are numerous ways to compensate for motion and minimize its impact on the treatment integrity, including 4D imaging, 4D target delineation, increased planning margins, voluntary breath-hold and shallow breathing, abdominal compression, respiratory gating, and real-time tumor tracking. Although most of these approaches have been in clinical use in various forms, each has pros and cons that need to be weighed for use in an individual clinic.

Four-Dimensional Imaging

Four-dimensional imaging refers to the acquisition of spatial motion information over time. This can be done with CT,^419,420 PET,⁴²¹ or MRI.⁴²² All have all been successfully used for RT planning. Only 4D CT has seen widespread use in the past decade, although 4D PET is gaining more interest, especially used in combination with 4D CT.^423,424 The need for 4D CT is nicely illustrated in Figure 11.24. As can be seen, without 4D imaging, significant and unpredictable artifacts can render tumor visualization difficult. Depending on the scanning speed relative to the tumor motion speed, artifacts appear in different ways.⁴²⁵ If the scan speed is much slower than the tumor speed, a smeared image is captured. If the scan speed is much faster, tumor position and shape are captured at an arbitrary breathing phase. If the scan and tumor speeds are comparable, which is the case in Figure 11.2 and in most currently available CT scanners, the tumor position and shape are heavily distorted. Based on an experiment and computer simulations, it was found that distortions along the axis of motion could result in either a lengthening or shortening of the target. In addition to shape distortion, the center of the imaged target can be displaced by as much as the amplitude of the motion.⁴²⁵

To overcome these problems, a respiratory-correlated or 4D CT is performed. The idea behind 4D CT is that at every position of interest along the patient’s long axis, images are oversampled and each image is tagged with breathing phase information (Fig. 11.25). The instantaneous breathing phase information can be obtained through the real-time position management (RPM) system,⁴²⁶ (GateCT, VisionRT, London, UK),⁴²⁷ spirometry,⁴²⁸ and pressure belts,⁴²⁹ among others. After the scan is done, images are sorted based on the corresponding breathing phase or amplitude signals. Many 3D CT sets are thus obtained, each corresponding to a particular breathing phase, and together they constitute a 4D CT set covering the whole breathing cycle. Four-dimensional CT decreases motion-induced artifacts and accurately assesses the extent of intrafraction motion. Downsides to 4D CT include the increased time for image acquisition and increased dose to the patient from multiple CT scans. An excellent review of 4D CT scanning was presented by Keall.⁴³⁰

Four-Dimensional Target Delineation and Planning

There are several approaches to internal target volume (ITV) delineation of moving lung tumors.^431–437 Lagerwaard et al.⁴³² used multiple “slow” CT scans to define the ITV, showing that this volume provided better target coverage than a free-breathing CT-derived ITV with isotropic margins. This method is old and limited, however, by the presence of motion-induced artifacts in 3D CT that hamper accurate target delineation. Breath-hold or forced shallow breathing during a 3D CT acquisition can theoretically minimize the motion-induced artifacts.⁴³³ However, such approaches may not be well tolerated in many patients, particularly those with poor pulmonary function. More sophisticated methods to improve target delineation are based on 4D CT imaging.

Various investigators have proposed numerous 4D CT-based techniques, which can largely be classified into four categories: (a) maximum intensity projection (MIP)-based ITV delineation,^434–436 (b) using two extrema phases with a margin,⁴³⁴ (c) time-weighted mean tumor position with a margin,⁴³⁷ and (d) using all 10 phases to create composite volume.^434,436 The MIP-based ITV technique is popular due to the simple and rapid construction of the ITV, based on a single 3D image. It has been shown to have good agreement with the “two extrema phases” and “all 10 phases” techniques.⁴³⁵ Wolthaus et al.⁴³⁷ have found, however, that the MIP-based ITV technique can overtreat normal tissues by up to 33% compared with a mean tumor position approach. In addition, Muirhead et al.⁴³⁶ have found that, although the MIP-based ITV technique is safe in most cases, compared with the all 10 phases technique as a gold standard, there are still special cases when the tumor is at or near the diaphragm, the MIP-based ITV technique would lead to underestimation of the actual ITV. This occurs because the tumor is similar in electron density with the diaphragm and other surrounding healthy tissues, such that when an MIP is generated, one cannot distinguish the borders between the overlapping tumor and its similar-density surroundings (Fig. 11.26). Therefore, the MIP-based ITV technique should not be entrusted in all situations, and the all 10 phases technique may be preferable in cases of doubt.

For liver cancers, the authors discourage the use of the MIP-base ITV technique, because the electron density of the liver tumor is generally lower than the surrounding normal liver tissue. Thus, the MIP image underestimates the ITV volume. The remedy for this is to use the minimum intensity projection (MinIP) instead. In terms of planning and dose calculations, the authors recommend using the average intensity projection images over a MIP, MinIP, or free-breathing CT images, due to the fact that it more closely represents the time-averaged anatomy of the patient than the other images. To be most accurate, 4D planning (Fig. 11.27) is desired (i.e., calculating dose on each 4D CT phase image and accumulating the dose using a deformable dose tracking technique).^438,439 However, full implementation of the 4D planning approach is currently limited due to the computational resources needed to perform the increased number of dose calculations and deformable image registrations. If computational burden is not an issue, then a fully integrated 4D IMRT optimization based on the 4D CT phase images and 4D dose accumulations would be the best approach.⁴⁴⁰

The ways to treat a moving tumor can largely be classified into five categories⁴⁴¹: (a) motion-encompassing, (b) respiratory gating, (c) breath-hold, (d) forced shallow breathing with abdominal compression, and (e) real-time tumor tracking. Motion-encompassing methods refer to treating the entire ITV, without intervention to minimize the treatment volume, in a patient’s natural breathing state. Once the ITV is delineated, the beam portal can be made large enough to adequately cover the volume during the planning stage. During treatment, it is necessary to monitor the patient to ensure that the patient breathes consistently without any drifts or sudden change in the amplitude. One should also be aware that presently most linear accelerator systems do not offer 4D imaging for patient setup (e.g., 4D CBCT).^442,443 Therefore, adequate training to properly recognize the motion-induced blurring effects in 3D CBCT is critical to the image registration accuracy and the overall treatment effectiveness. Figure 11.28 illustrates blurring of the 3D CBCT images that can result due to breathing pattern (i.e., inspiration-to-expiration duration ratio).⁴⁴⁴

FIGURE 11.24. Computed tomography (CT) images of a spherical object in periodic motion in the axial direction. Top row: artifacts obtained in helical CT. Such artifacts depend on the relative phase between CT data acquisition and object motion. To evaluate different artifacts, CT scans were started at different phases. The right image shows the disconnected top and bottom of the sphere. Bottom row: On the left is a CT scan of the static object. The other images show three positions of the moving sphere as imaged by four-dimensional CT. Only small residual artifacts (on the surface) remain on the images at different positions of the motion cycle. (From Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography image formation and clinical protocol. Med Phys 2005;32:874–889, with permission).

FIGURE 11.25. Data acquisition and processing in four-dimensional computed tomography (CT). The x-ray “on” duration during each step of data acquisition is greater than or equal to the average breathing cycle plus the duration of data acquisition for an image reconstruction. The dots on the respiratory signal trace represent the midscan time of the CT image reconstructions. Each dot represents four image reconstructions on a four-slice CT. There is an x-ray “off” period for table translation from one position to the next. (From Pan T, Lee TY, Rietzel E, et al. 4D-CT imaging of a volume influenced by respiratory motion on multi-slice CT. Med Phys 2004;31:333–340, with permission.)

FIGURE 11.26. An example difference in the internal target volumes generated based on the maximum intensity projection (blue) and the 10-phase four-dimensional computed tomography (purple) images, when the tumor is adjacent to the diaphragmatic tissue of similar density. (From Muirhead R, McNee SG, Featherstone C, et al. Use of maximum intensity projections (MIPs) for target outlining in 4DCT radiotherapy planning. J Thoracic Oncol 2008;3:1433–1438, with permission.)

FIGURE 11.27. Dose–volume histograms for target volumes for two patients, showing three-dimensional and four-dimensional dose calculations. (From Starkschall G, Britton K, McAleer, et al. Potential dosimetric benefits of four-dimensional radiation treatment planning. Int J Radiat Oncol Biol Phys2009;73:1560–1565, with permission from Elsevier.)

FIGURE 11.28. Three-dimensional cone-beam computed tomography (3D CBCT) images of five simulated respiratory profiles. The ratio of time spent in inspiration to expiration is indicated on the bottom right corner of each 3D CBCT. (From Vergalasova I, Maurer J, Yin FF. Potential underestimation of the internal target volume (ITV) from free-breathing CBCT. Med Phys 2011;38:4689–4699, with permission.)

Respiratory Gating

There are two main approaches to respiratory gating—internal^445,446 and external^176,433,447—although a combination is also possible.^448,449 Internal gating utilizes internal tumor motion surrogates such as implanted fiducial markers or marker-less imaging of internal anatomy, whereas external gating uses external respiratory surrogates such as markers placed on the surface of the patient’s abdomen, a compression belt, or spirometer signals.

The only internal gating system currently in clinical use is the RTRT system.²⁸¹ Its major strength is its precise and real-time localization of the tumor position during treatment. Implanted markers are often good surrogates for tumor position, and marker migration is usually not an issue, particularly if multiple markers are used. Major weaknesses include its invasiveness and the high imaging dose required for fluoroscopic tracking.

The RPM system (Varian Medical Systems, Palo Alto, CA) can be viewed as representative of external gating systems. This system consists of a lightweight plastic block with two or six passive infrared reflective markers placed on the patient’s anterior abdominal surface and monitored by a charge-coupled–device video camera mounted on the treatment room wall. The surrogate signal is the abdominal surface motion. Both amplitude and phase gating are allowed. During treatment, a periodicity filter checks the regularity of the breathing waveform and disables the beam when the waveform becomes irregular, such as with patient motion or coughing, and re-enables the beam after establishing breathing is again regular. The RPM system is also used during simulation to acquire the patient’s geometry in the gating window and to set up the gating window.

Major strengths of external gating are that it is noninvasive, relatively easy to use, and well tolerated by patients. Moreover, it does not require any radiation dose for imaging. However, it should be noted that tracking the external marker is not equivalent to tracking the tumor, and blindly trusting the external surrogate can result in errors.⁴⁴⁸ In particular, the relation between the tumor motion and the surrogate signal may change over time, inter- and intrafractionally.

BrainLab (Westchester, IL) has a U.S. Food and Drug Administration–cleared respiratory gating device called ExacTrac Gating/Novalis Gating.⁴⁴⁹ This device uses external markers for gating the radiation beam, however, it uses x-ray imaging to determine the internal anatomy position and to verify its reproducibility during treatment. By updating the correlation between the internal and external signals in a reasonable frequency, x-ray exposure to the patient is minimized, while the external gating signal accuracy is maintained.

Breath-hold and deep inspiration breath-hold techniques^450–453 are attractive options for patients who are capable of repeatedly holding for greater than 15 seconds due to reduced setup uncertainty (and hence, planning margins). The technique is useful for thoracic and upper abdominal targets as well as left-sided breast cancers, due to heart sparing. Setup reproducibility is challenging, due to the different levels of inspiration that are possible. Breathing coaching is helpful, and a monitoring device is essential. Any of the monitoring techniques involving internal and external signals (discussed earlier) can be used, including the spirometer,⁴⁵⁰ ABC device,^450–452 RPM,^449,450 and AlignRT surface tracking system.⁴⁵⁴

Forced shallow breathing in combination with abdominal compression devices is an effective technique for controlling the motion in upper abdominal tumors and inferior lung tumors.^{452,455–457} This was originally developed by Lax et al.⁴⁵⁵ and has since been replicated around the world. Eccles et al.⁴⁵⁶ has thoroughly analyzed the impact of the abdominal compression on the liver motion of 60 patients using cine MRI. They have found that more than 90% of patients showed reduction in motion along at least one direction and that more than 40% of patients showed greater than 3-mm motion reduction. However, this technique can be quite uncomfortable and even painful for some patients, and thus the level of compression should be balanced between patient comfort and a reasonable motion reduction (Fig. 11.29). Also, due to the difficulty in reproducibly positioning the abdominal compression device, couch indexed positioning and the subsequent imaging is essential at each treatment fraction. The technique is most appropriate for SBRT for early-stage lung and liver tumors without mediastinal involvement or nodal disease.

FIGURE 11.29. Examples of abdominal compression devices on the market: a plastic plate (left) and a pressure belt (right).

FIGURE 11.30. Flowchart of electromagnetically guided real-time dynamic multileaf collimator tracking. (From Keall PJ, Sawant A, Cho B, et al. Electromagnetic-guided dynamic multileaf collimator tracking enables motion management for intensity-modulated arc therapy. Int J Radiat Oncol Biol Phys2011;79:312–320, with permission from Elsevier.)

Tumor Tracking

Tumor tracking is perhaps the most ideal—and most technologically intense—strategy, as real-time tumor localization, fast processing and relay of information, and corresponding repositioning of the beam all need to be dynamically seamlessly integrated.^458–473 Compared to the motion “freezing” methods, tumor tracking techniques are associated with higher delivery efficiency and less residual target motion. These factors may be particularly important to SBRT of thoracic and abdominal tumor sites, where a large dose is delivered during a single or a few relatively lengthy treatment sessions. However, there are a number of technical hurdles before this approach becomes clinically feasible, including treatment planning and the accurate response of the MLC to tumor positions measured in real time. The actual tumor movement as well as its relation to surrounding critical structures during the treatment cannot be known at the time of treatment planning. Therefore, planning can only be done based on some kind of average patient geometry information or at best on 4D CT simulation data, and an adaptive scheme must be used throughout the treatment course.

As mentioned earlier, tumor tracking is presently not in widespread clinical use. Most studies carried out so far are still at an investigational stage for linear accelerator–based approaches, except for a few specialized commercial systems.^461,466 There are a number of ways one can obtain the real-time 3D position information of the tumor including: (a) marker-less imaging,^445,446,472 (b) marker-guided imaging,^{281,462,463,467–469} and (c) using implantable magnetic transponders.^465,470,473 Of these approaches, the use of implantable magnetic transponders is most promising due to lack of x-ray exposure, minimal system latency, and relative ease with which the system can be integrated in the clinical linear accelerator-based systems. The same argument in terms of x-ray exposure also applies to MRI-guided tumor tracking⁴⁷²; however, MRI implementation requires a whole new design to interface with linear accelerators. System latency is also a complex issue, due to the need to process the images and provide near real-time 3D tumor position information. Figure 11.30 illustrates a flowchart of a possible tumor tracking strategy with dynamic MLC (DMLC), based on the real-time 3D position information provided by the magnetic transponders (Calypso, Seattle, WA).

FIGURE 11.31. Tumor control probability (TCP) and rectum normal tissue complication probability (NTCP) curves for prostate cancer patients, from 50 to 100 Gy in 2-Gy per-fraction increments, for the three image-guided adaptive registration techniques: tattoo, bone, clinical target volume (CTV) registered, and CTV-registered with margin reduced to 5 mm. TCP curves are on the left and NTCP curves are on the right. Error bars are standard deviations. (From Song WY, Schaly B, Bauman G, et al. Image-guided adaptive radiation therapy (IGART): radiobiological and dose escalation considerations for localized carcinoma of the prostate. Med Phys 2005;32:2193–2220, with permission.)

ADAPTIVE RADIOTHERAPY

Radiation therapy has traditionally involved generating a static plan, based on a single snapshot of the patient’s anatomy, which is then delivered over a number of weeks. Modern IGRT technologies can transform this static process into a dynamic one, whereby plans are continuously altered throughout the treatment course or even during a single fraction. In many ways, altering the treatment plan during treatment is not new; for example, patients are often replanned due to weight loss or rapid tumor response. What is different is the speed and sophistication with which IGRT enables this process.

The term adaptive radiation therapy (ART) was first coined by Yan et al.⁴⁷⁴ in 1997. This was around the time that David Jaffray at the same institution (William Beaumont Hospital, Royal Oak, MI) was working on the integration of CBCT with a linear accelerator to enable in-room soft-tissue imaging before, during, or after treatment.⁴⁷⁵ Thus, the concept of ART was proposed based on the idea that advancements in in-room imaging technologies would make the process of target localization and definition more precise.

The optimal level of adaptation is a broad question, and it is unlikely that a global solution exists for all situations. An intriguing approach is to use the knowledge of patient setup and organ motion information to decide the prescribed “safe dose” (i.e., isotoxicity) to be delivered for each patient, rather than prescribing the same dose for all patients because normal tissue tolerance is usually what limits the prescription dose. Song et al.⁴⁷⁶ evaluated the maximum dose that can be delivered while keeping the same rectal NTCP level (i.e., iso-NTCP dose escalation) using various IGRT approaches (Fig. 11.31). It was found that the possible dose escalation levels were highly patient dependent, even if the same target localization approaches were used, and that image registration based on soft tissues provided the least discrepancy among patients.

This level of adaptation was proven to be clinically feasible.^477,478 Their approach was as follows. Based on the planning CT simulation, an initial treatment plan is generated with a 1-cm CTV–PTV margin. Each of the first 4 days of therapy, daily EPID and CT scans are acquired immediately before or after treatment. Confidence-limited PTV margins are generated based on each patient’s setup inaccuracies and internal organ motion. Rectal and bladder constraints are used to determine the individual patient’s total dose, ranging from 70.2 to 79.2 Gy. Using this isotoxicity ART strategy, they found no statistically different rectal toxicity rates across the prescription dose ranges. This was the first clinical evidence that an individualized prescription is possible indicating benefits of image-guided ART.

Deutschmann et al.⁴⁷⁹ further used online aperture adaptation to reduce planning margins in 39 prostate cancer patients, after correcting for interfraction shifts based on implanted fiducials. They found that this approach was feasible, and correcting for intrafraction 6-degree rotations could allow reduced planning margins to 3 mm. Intrafraction motion based on pretreatment kilovoltage planar imaging versus last beam EPID images showed RL rotations up to 26.9 degrees (mean, 2.5 degrees) and 3D translations up to 10.2 mm (mean, 3.0 mm).

The need to adapt to changes in the patient anatomy (tumor(s) or normal tissues) is not limited to prostate cancer. Multiple investigators have reported significant morphologic changes in tumors or normal tissues in a wide variety of tumor sites, including HNC,^480,481 lung cancer,^482,483 and gynecologic tumors.⁴⁸⁴ Barker et al.⁴⁸⁰ noted a mean volume reduction of the GTV of 0.2 cm³/day in HNC patients treated on a CT-on-rails system. Of note, the parotid gland volume decreased by 0.19 cm³/day and the glands shifted medially, on average, by 3.1 mm. In seven lung cancer patients undergoing daily MVCT imaging, Ramsey et al.⁴⁸⁵ reported a mean GTV reduction of 31%. Kupelian et al.⁴⁸² treated 10 NSCLC patients with the Tomotherapy system and observed an average decrease in GTV of 1.2% per day; five of six replanned cases demonstrated small increases in tumor dose delivery. Van de Bunt et al.⁴⁸⁴reported an average reduction in the GTV of 46% in 14 cervical cancers reimaged with MRI after the delivery of 30 Gy (Fig. 11.32).

Several investigators have reported that adapting to morphologic changes may improve treatment delivery. Ramsey et al.⁴⁸⁵ found that the lung V20 would be decreased from 23% to 17% by adapting to reductions in the GTV in lung cancer patients, corresponding to 17% less reduction in lung perfusion. Hansen et al.⁴⁸¹ evaluated the impact of replanning in a cohort of 13 HNC patients with either significant weight loss or tumor response during IMRT (Fig. 11.33). Compared to replanning, not replanning significantly decreased dose to the target volume and increased doses to normal tissues (spinal cord and brainstem). The doses to 95% of the PTVGTV and the PTVCTV decreased by up to 6.3 Gy and 7.4 Gy, respectively.

FIGURE 11.32. Magnetic resonance images of a patient with a bulky cervical cancer obtained prior to the initiation of treatment (A: sagittal; C: axial) and following 30 Gy (B: sagittal; D: axial) illustrating significant regression of the primary tumor. (From Van de Bunt L, van der Heided UA, Ketelaars M, et al. Conventional, conformal and intensity modulated radiation therapy treatment planning of external beam radiotherapy for cervical cancer: the impact of tumor regression. Int J Radiat Oncol Biol Phys 2006;64:189–196, with permission from Elsevier.)

Adaptation could potentially be extended beyond morphologic changes. An intriguing idea is to adapt the plan to functional changes of the tumor. Current IGRT technologies do not generally allow in-room functional imaging, however, increasing data suggest that functional changes in tumors are correlated with outcome.^17,486 For example, Wieder et al.⁴⁸⁶ examined changes in tumor ¹⁸FDG avidity in patients undergoing preoperative chemoradiotherapy for esophageal carcinoma (Fig. 11.34). In 27 patients undergoing midtreatment ¹⁸FDG PET, a decline in SUV greater than 30% was associated with improved 2-year overall survival and histopathologic response. Whether adapting the plan (e.g., intensifying treatment in patients with suboptimal metabolic changes) would improve patient outcomes remains unclear.

From a technical standpoint, a major concern is how exactly to adapt to changes in the tumor or normal tissues during treatment. Although it may be trivial to occasionally replan a limited number of patients offline, frequent replannings of many patients are labor and time intensive, especially if online replanning is necessary. New software tools, approaches, and fast and reliable computing are needed. This is currently an active area of research. Researchers at the University of California–San Diego have explored the potential to perform online replanning utilizing the vast computational capability of the graphics card technology (Fig. 11.35).^487–495 Graphics processing unit (GPU) cards were originally developed for the gaming industry, where a fast display of large graphics data is necessary to enhance the quality of the gaming experience. By developing new algorithms with mathematical structures suitable for GPU parallelization, it is possible to dramatically improve the computational efficiency of the traditionally computationally intense tasks in RT such as dose calculations,^{487,491,493,495} inverse planning reoptimizations,^489,493 CT reconstructions,^490,494 and deformable image registrations for fast contour mapping.⁴⁸⁹ Of note, Gu et al.^487,493 have shown that a full 3D-dose calculation based on finite-size pencil beam algorithm achieved a speed up of 200 to 400 times, taking less than 1 second for typical IMRT plans. Men et al.^488,492 found that, for a typical nine-field prostate IMRT plan with 5-by-5 mm² beamlet size and 2.5-by-2.5-by-2.5 mm³ voxel size, reoptimization would only take 2.8 seconds. Park et al.⁴⁹⁴ found that for a filtered back-projection reconstruction of a typical 3D CBCT, volume can be done in a real-time fashion (i.e., as soon as the scan is done), while Gu et al.⁴⁸⁹found that a daemons deformable image registration of a typical 3D CBCT volume can be completed in 7 to 11 seconds.

FIGURE 11.33. The benefit of replanning midway through treatment is illustrated in a patient with a T2N2C base of tongue carcinoma. A: The initial intensity modulated radiation therapy plan generated from the initial planning computed tomography (CT) scan. B: A second CT scan during treatment showing the isodose lines obtained without replanning. C: The same slice from the second CT scan, with isodose lines obtained by replanning. The second CT was obtained after 22 fractions and after a 12% weight loss from the start of treatment. The arrowdemonstrates the increased spinal cord dose without replanning. (From Hansen EK, Bucci MK, Quivey JM, et al. Repeat CT imaging and re-planning during the course of IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2006;64:355–362, with permission from Elsevier.)

Another computational acceleration approach is the utilization of Cloud computing for RT applications, pioneered by Meng et al.⁴⁹⁶ and Wang et al.⁴⁹⁷ at Stanford University. Cloud computing is a recent advancement in supercomputing technology where the end user only needs Internet access and he or she requests computations to a large network of computers (nodes) that are not visible to the end user. The task is divided up and handled in a parallel computing manner, automatically. The larger the number of nodes used, the faster the computations. Because this system does not require the computers to be physically located near the user, and they can be accessed from anywhere with an Internet connection, the potential for their use in ART applications irrespective of the location of the clinic is tremendous. The technology is new and research in RT is in its infancy; but the potential benefits remain to be seen.

Even if computational issues are completely resolved and online replanning can be technically implemented, many questions still remain to be answered before various ART strategies can be introduced into clinical practice. For example, how often should new plans be generated? Once? Weekly? Daily? Another question is whether altering the target volume would adversely impact tumor control. In the study by Hansen et al.⁴⁸¹, attempts were made to “maintain the size of the original GTV in the second plan without extending it beyond the skin contour or into adjacent normal structures,” ensuring irradiation of potential microscopic disease spread. Such concerns are quite reasonable in infiltrative tumors such as HNC, but may be less warranted in noninfiltrative tumors (e.g., bulky lymphadenopathy). Altering the target volume as the tumor responds in this situation should carry less risk. Moreover, it should reduce the risk of toxicity and allow the delivery of higher, more effective doses. The answer to these and other questions should be resolved through prospective clinical trials.

FIGURE 11.34. Coronal slices from fluorodeoxyglucose (FDG) positron emission tomographyscans in patients with histopathologically responding (A) and nonresponding (B) esophageal cancer. In the responding tumor, FDG uptake decreased to background levels 14 days after beginning chemoradiotherapy. At the same time point in the nonresponding tumor, FDG uptake is essentially unchanged. (From Wieder HA, Brucher BL, Zimmermann F, et al. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 2004;22:900–908. Reprinted with permission. © 2004 American Society of Clinical Oncology. All rights reserved.)

FIGURE 11.35. Super-Computing Online Replanning Environment (SCORE) for adaptive radiation therapy. A: SCORE workflow. B: Reoptimized dose distribution (left) and calculated dose-volume histograms (right) for a head and neck cancer patient undergoing SCORE simulation. The SCORE plan is generated then exported back to the treatment planning system for verification before treatment. (Courtesy of Xun Jia and Steve Jiang.)

CONCLUSIONS

Technological progress has been defined in economic terms as an increase in the efficiency of production. This is achieved by producing more output for a given set of inputs, or alternately, requiring fewer inputs to produce a given output. In medicine, technological progress might be defined similarly—as an increase in the efficiency of medical services—where improved patient outcomes (“outputs”) are achieved for less cost (“inputs”), and medical costs may include both economic resources and adverse events. When therapeutic outcomes are achieved for less toxicity, technological progress is tantamount to an increase in the therapeutic ratio. An ongoing challenge for the field of radiation oncology is to develop, test, and implement new technologies that meet this definition of progress.

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