Intensity-Modulated Radiation Treatment Techniques and Clinical Applications - Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

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

Chapter 10. Intensity-Modulated Radiation Treatment Techniques and Clinical Applications

K.S. Clifford Chao, Radhe Mohan, Timothy D. Marinetti, and Lei Dong

The previous edition of this chapter included literature reports through 2006. At that time intensity-modulated radiation therapy (IMRT) was still something of a novelty; 5 years later it is safe to say that the technique has become the de facto standard practice for many tumors. IMRT’s coming of age is described in thorough terms in the 2010 International Commission on Radiation Units (ICRU) report (hereafter ICRU 83), which spans 106 pages with over 350 references.¹ Readers new to the field will find this report an excellent synthetic introduction to IMRT; experienced practitioners should also note that it contains new reporting guidelines for clinical treatments.

The use of ionizing radiation for diagnosis and treatment goes back over a century; for a wonderfully concise review see Bernier et al.² An enduring clinical problem has been to achieve high levels of irradiation at the tumor site without causing extremely toxic or even fatal consequences in normal tissues in the path of the treatment beam. Advances in technology—especially fast, affordable computers—opened the prospect of true three-dimensional (3D) tailoring of radiation fluence with equipment and a planning timescale usable in the clinic. Since its introduction into clinical use,³^–⁴^,⁵ IMRT has generated widespread interest. IMRT optimally assigns nonuniform intensities (i.e., weights) to tiny subdivisions of beams, which have been called rays or “beamlets.” The ability to optimally manipulate the intensities of individual rays within each beam permits greatly increased control over the radiation fluence, enabling custom design of optimum dose distributions. These improved dose distributions potentially may lead to improved tumor control and reduced normal tissue toxicity. For example, tumors of the head and neck often require concave-shaped treatment volumes to spare closely adjacent sensitive critical structures (e.g., brainstem, spinal cord). Such fluence distributions are easily done with IMRT but may be difficult or impossible by other techniques, including three-dimensional conformal radiation therapy (3DCRT). This is illustrated in Figure 10.1, which is taken from ICRU 83.

IMRT requires setting the relative intensities of tens of thousands of rays which make up an intensity-modulated treatment plan. This task cannot be accomplished manually and requires the use of specialized computer-aided optimization methods. The optimum beamlet intensities are determined using a systematic iterative process during which the computer sequentially generates intensity-modulated plans one by one, evaluates each of them according to user-selected criteria (“desired objectives”), and makes incremental changes in the ray intensities based on the deviation from the desired objectives. The quality of an intensity-modulated treatment plan produced in this manner depends on a number of factors. These include the mathematical function and parameters used by the optimization process to evaluate and compare competing treatment plans; the mathematics and algorithms of optimization; the number, orientation, and energy of radiation beams; margins assigned to the planning target volume (PTV) and to normal structures; dose-calculation algorithms; and so on. We will discuss many of these in this chapter.

The 2010 ICRU 83 report has some important conceptual changes. The previous ICRU reports for photon therapy (No. 50 in 1993 and its supplement, No. 62, in 1999) defined a reference point within the treatment volume, one that was easily located with anatomic landmarks and where dosage could be accurately measured. The prescription dose was something of an ideal to be sought. However, with IMRT, treatment volumes are more relevant, and doses are given and bounds set within those volumes. Also, the prescription dose itself is now taken to be the final result of treatment planning by the physicists and radiation oncologists. With literally thousands of degrees of freedom available to the planner, the dosage to a single point is no longer adequate to describe or evaluate a plan.

ICRU 83 cites the increase in the clinical impact and use of IMRT in the recent past: “In a survey performed in 2003 in the USA, among 168 radiation oncologists randomly selected, one-third was using IMRT. In 2005, a similar survey showed that more than two-thirds of radiation oncologists were using some form of IMRT, mainly for increased normal-tissue sparing or target-dose escalation”.¹^,⁶^,⁷ Another noteworthy metric is the number of research reports in the peer-reviewed literature concerning IMRT. A scan of the Web of Science database showed full papers with IMRT in the title as numbering <50 per year through 2001. It reached 100 in 2005 and has plateaued at about 140 for the years 2009–2011. One presumes the flattening of the publication rate has more to do with the fiscal woes plaguing the industrial countries since 2008 than a loss of interest in IMRT.

FIGURE 10.1. Comparison of conformal radiation therapy (CRT) (left) and intensity-modulated radiation therapy (IMRT) (right). The ability for CRT to alter isodose lines was limited to shaping of field boundaries with multileaf collimators (MLCs) or blocks, the use of wedges or compensators for missing tissues, and the use of central blocks for shielding critical structures. The IMRT beams can have highly nonuniform beam intensities (fluences) and are capable of producing a more concave-shaped absorbed-dose distribution. With neither conformal therapy nor IMRT can the planning organ at risk volume (PRV) always be completely avoided, but with IMRT the concave isodose curve that includes the planning target volume (PTV) better avoids the PRV. The black region indicates the PTV, the gray region indicates a PRV, and the line surrounding the PTV is a typical isodose contour. (Reprinted from ICRU Report 83: prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy [IMRT]. J ICRU 2010;10[1]:1–106, with permission.)

IMRT RATIONALE

The term IMRT is used to mean much more than its literal meaning might suggest. Strictly speaking, the use of wedges and conventional compensators for surface curvature is also intensity modulation. In this chapter, IMRT is a form of 3DCRT in which a computer-aided optimization process is used to determine customized nonuniform fluence distributions to attain certain specified dosimetric and clinical objectives.

Viewed in this light, IMRT is intimately tied to 3D imaging. As ICRU 83 states: “Three-dimensional CRT, in general, and IMRT, in particular, increase the need for accurate anatomic delineation. This requires an adequate specification of the tumor location and a thorough knowledge of the processes of likely infiltration and spread”.¹

IMRT has many potential advantages. It can be used to produce dose distributions that are far more conformal than those possible with standard 3DCRT. Dose distributions within the PTV, in theory, can be made more homogeneous, and, if so desired, a sharper fall-off of dose at the PTV boundary can be achieved. Experience with current IMRT systems has led to an impression among many that IMRT inherently produces inhomogeneous dose distribution within the target volume. Inhomogeneity commonly observed is the result of the overriding need to partially or wholly protect one or more critical organs. In other words, the dose distributions tend to be more heterogeneous because the homogeneity criterion is made less important than the normal structure avoidance criterion. If all things were equal, the IMRT plan always should produce more homogeneous dose distribution than a plan made with uniform beams. A sharper fall-off of dose at the PTV boundary, in turn, means that the volume of normal tissues exposed to high doses may be reduced significantly. These factors may allow escalation of tumor dose, reduction of normal tissue dose, or both, hopefully leading to an improved outcome, including lower morbidity. A lower rate of complications also may mean lower cost of patient care following the treatment. In addition, IMRT has the potential to be more efficient with regard to treatment planning and delivery than standard 3DCRT, although gains in this direction are being realized rather slowly. The treatment design process is relatively insensitive to the choice of planning parameters, such as beam direction.⁸^–¹⁰ There are no secondary field-shaping devices other than the computer-controlled multileaf collimator (MLC). Furthermore, large fields and boosts can be integrated into a single treatment plan, and, in many cases, electrons can be dispensed with, permitting the use of the same integrated boost plan for the entire course of treatment.¹¹^,¹² An integrated boost treatment may offer an additional radiobiologic advantage¹³ in terms of lower dose per fraction to normal tissues while delivering higher dose per fraction to the target volume. Higher dose per fraction also reduces the number of fractions and hence lowers the cost and burden to the patient for a treatment course. IMRT also offers the potential of adaptive therapy—revision of the treatment plan according to imaging of tumor reduction and organ movement during the course of radiation therapy. Mechalakos et al. present a case study where weekly cone beam computed tomography (CBCT) was used to track treatment of a recurrent neck mass from a nasopharyngeal cancer.¹⁴

IMRT Limitations and Risks

We should recognize, however, that IMRT has limitations. There are many dose distributions (or dose–volume combinations) that are simply not physically achievable. Furthermore, our knowledge about what is clinically optimal and achievable and how best to define clinical and dosimetric objectives of IMRT is often limited. Moreover, the best solution may elude us because of the limitations of the mathematical formalism used or because of the practical limits of computer speed and the time required for finding it.

Uncertainties of various types (e.g., those related to daily, or interfraction, positioning; displacement and distortions of internal anatomy; intrafraction motion; and changes in physical and radiobiologic characteristics of tumors and normal tissues during the course of treatment) may limit the applicability and efficacy of IMRT. Dosimetry characteristics of a delivery device, such as radiation scattering and transmission through the MLC leaves, introduce some limitations in the accuracy and deliverability of IMRT fluence distributions. In addition, the limited spatial and temporal coverage and overall accuracy of current IMRT dosimetric verification systems, based principally on radiographic and radiochromic film, diminish the confidence in the delivered dose. Furthermore, most current dose-calculation models are limited in their accuracy, especially for the small, complex shapes required for IMRT. It is quite conceivable that inaccuracies in dose calculations may yield a solution different from the one derived if dose calculations were accurate. However, the most important factor that may limit the immediate success of IMRT is the inadequacy of imaging technology to define the true extent of the tumor, its extensions, and radiobiologic characteristics as well as geometric, dose-response, and functional characteristics of normal tissues.

We also should be aware of the risks of IMRT. The effect of large fraction sizes used in integral boost IMRT on tissues embedded within the gross tumor volume is uncertain and may present an increased risk of injury.¹⁵ There also may be an increased risk that improper use of spatial margins, coupled with the high degree of conformality with IMRT, may lead to geographic misses of the disease and recurrences, especially for disease sites where positioning and motion uncertainties play a large role or where there are significant changes in anatomy and radiobiology during the course of radiotherapy. Similarly, high doses in close proximity to normal critical structures may pose a greater risk of normal tissue injury. In addition, IMRT dose distributions are unusual and highly complex, and existing experience is too limited to interpret them properly and evaluate their efficacy. Finally, while IMRT can spare specific tissues compared to conventional radiation therapy, the use of many more beams and irradiation angles means that a larger volume of normal tissue is being exposed, albeit at lower accumulated doses. This may lead to unforeseen sequelae.

IMRT—An Unconventional Paradigm

The application, process, and dose distributions of IMRT are significantly different from those of conventional two-dimensional (2D) CRT or 3DCRT. This means the traditional methods of specification and fractionation of treatments, evaluation of treatment plans, and reporting of results are limited and new methods need to be introduced.

The traditional 3DCRT process involves “forward planning,” in which beam parameters (directions, apertures and their margins, beam weights, beam modifiers) are specified and dose distributions are computed. The treatment plan is evaluated by a human being, and, if necessary, beam parameters are modified to achieve a satisfactory dose distribution. In IMRT, an inverse process (“inverse planning”) is used in which the desired dosimetric and clinical objectives are stated mathematically (in the form of an “objective function”).⁹^,¹⁶^–¹⁸ The term inverse planning should not be confused with the mathematical operation of matrix inversion. In the present context the word inverse is used to distinguish it from forward planning for conventional 3DCRT. As ICRU 83 concisely notes:

The word “inverse” is used in reference to the established body of mathematical inverse problem-solving techniques, which start at the final or desired result and work backwards to establish the best way to achieve it. So-called inverse treatment planning starts by describing a goal, i.e., a series of descriptors characterizing the desired absorbed-dose distribution within the tumor, with additional descriptors designed to spare normal tissues.

The inverse-planning process works iteratively to determine beam shapes and fluence patterns to achieve an optimal or acceptable absorbed-dose distribution. The IMRT optimization software iteratively adjusts beam parameters with the aim of obtaining the best possible approximation of the desired dose distribution. In each optimization iteration, the optimization software computes the value of the objective function (i.e., the IMRT plan score) to judge the overall quality of each of a large number of plans to choose the optimum one. However, it must be kept in mind that limitations of planning time may preclude full exploration of all the degrees of freedom (there can be many thousands), so whether the optimization is done by a variant of gradient or stochastic methods, the computed solution may not be the true global one. Final review by the radiation oncologist of any plan, of course, is required.

IMRT is most conformal and most efficient when all target volumes (gross disease, subclinical extensions, and electively treated nodes) are treated simultaneously using different fraction sizes. Such a treatment strategy has been called the simultaneous integrated boost.¹⁵^,¹⁹ This is in contrast to conventional radiotherapy in which the same fraction size (typically 1.8 or 2 Gy) is used for all target volumes with successive reductions in field sizes to protect critical normal structures and to limit the dose to electively treated and subclinical disease regions.

Alternative IMRT Approaches

During the past 15 years, a variety of techniques have been explored for designing and delivering optimized IMRT.⁴^,⁵^,⁸^,¹⁵^,²⁰^–⁴⁹ Many of these are implemented in commercial IMRT systems. The most significant differences among the various approaches are in terms of the mechanisms they use for the delivery of nonuniform fluences. Although the merits of each often are speculated, the superiority of any of the approaches is difficult to assess because there have been no systematic comparisons of clinical treatment plans.

Of the various approaches proposed, two dominant but significantly different methods have emerged. Mackie et al.³⁴ proposed an approach called tomotherapy in which intensity-modulated photon therapy is delivered using a rotating slit beam. A temporally modulated slit MLC is used to rapidly move leaves in or out of the slit. Like a CT unit, the radiation source and the collimator continuously revolve around the patient. The patient is translated either stepwise between successive rotations (serial tomotherapy) or continuously during rotation (helical tomotherapy). For helical tomotherapy, the system looks like a conventional CT scanner and includes a megavoltage portal detector to provide for the tomographic reconstruction of the delivered dose distribution.

A commercial slit collimator (called MIMiC) of the type proposed by Mackie et al.³⁴ has been designed and built by the NOMOS Corporation (North American Scientific, Chatsworth, CA). It has been incorporated into the company’s serial tomotherapy system, known as Peacock, for planning and rotational delivery of intensity-modulated treatments.²⁶^,²⁷ Figure 10.2 shows an original “binary” collimator built by NOMOS and as mounted on a linac. The figure also shows a modern tomotherapy machine.

In the second approach, implemented first into clinical use at Memorial Sloan-Kettering Cancer Center,⁴^,⁵^,³⁵^,³⁷^,⁴⁴^,⁴⁵^,⁵⁰ a standard MLC is used to deliver the optimized fluence distribution in either dynamic mode (defined as the leaves moving while the radiation is on) or static mode (i.e., “step-and-shoot” mode, defined as sequential delivery of radiation subportals that combine to deliver the desired fluence distribution), to deliver a set of intensity-modulated fields incident from fixed-gantry angles (see Fig. 10.3). These techniques are gaining wide acceptance rapidly. Every major commercial treatment-planning system manufacturer has implemented one or both of these.

A third approach, called intensity-modulated arc therapy or IMAT, developed by Yu,⁴⁹ uses a combination of dynamic multileaf collimation and arc therapy. The shape of the field formed by the MLC changes continuously during gantry rotation. Multiple superimposing arcs are used, and the field shape for a specific gantry angle changes from one arc to the next appropriately so that the cumulative fluence distribution of all arcs is equal to the desired distribution. Arc therapy is discussed in a recent review of various intensity-modulated techniques.⁵¹

In addition to these approaches, the University of Michigan has used the so-called multisegment approach in which each of a number of beams is divided into multiple segments.⁵² One segment for each beam frames the entire target while the others spare one or more normal structures. Each segment is uniform in intensity. The weights of segments of all beams are optimized to produce the desired treatment plan. The treatments are delivered as a sequence of multiple uniform field segments. A similar approach previously was proposed by Mohan et al.⁵³ In almost all of these significantly different treatment-delivery approaches, the underlying principles of optimization are similar, although the specifics may be quite different.

FIGURE 10.2. Commercial serial tomotherapy delivery hardware mounted on a conventional linear accelerator. A: View looking into the collimator toward the radiation source. A leaf pattern is shown that highlights the system’s capability for delivering complex fluence patterns. B: The multileaf collimator mounted to a conventional linear accelerator. C: Modern tomotherapy TomoHD^® machine. (C used with permission by Accuray, Incorporated, Madison, WI.)

FIGURE 10.3. A: A typical multileaf collimator used for delivery of intensity-modulated radiation therapy looking toward the radiation source. In the dynamic mode, the leaves move back and forth or sweep across the field continuously to form the sequence of required field shapes while the beam is on. In the static or step-and-shoot mode, the beam is turned off when the leaves move to form the required field shapes. B: Cutaway diagram of linac head, Varian Clinac^®. (Courtesy of Varian Medical Systems, Palo Alto, CA.)

FIGURE 10.4. Overview of a typical intensity-modulated radiation therapy planning and delivery process.

FIGURE 10.5. Comparison between traditional (left) and intensity-modulated radiation therapy (IMRT) (right) optimization processes. (Reprinted from ICRU Report 83: prescribing, recording, and reporting photon-beam intensity-modulated radiation therapy [IMRT]. J ICRU2010;10[1]:1–106, with permission.)

THE IMRT PROCESS OVERVIEW

As mentioned previously, there are significant differences in 3DCRT and IMRT concepts and processes. However, there are also many similarities. In particular, IMRT relies on many of the same imaging, dose calculations, plan evaluation, quality assurance (QA), and delivery tools as 3DCRT.

The IMRT planning, QA, and delivery phases of the dynamic or static MLC process are summarized in Figure 10.4. Figure 10.5 shows the steps in each phase of the IMRT optimization process. The tomotherapy process is similar, except that the fixed-beam angle selection is replaced by selection of the slice thickness and, for serial tomotherapy, the gantry rotation angles.

In the preparatory phase of the IMRT process, volumes of interest (such as tumors and normal organs) are delineated on 3D CT images,⁵⁴ often with assistance from other coregistered imaging modalities. The second imaging technique most often used is magnetic resonance imaging (MRI); the latter has an advantage over CT in that it can provide both structural and physiologic information.⁵⁵ Other imaging modalities such as positron emission tomography (PET) use intrinsic or externally added molecular markers to visualize specific metabolic processes or cellular phenotypes.⁵⁶^–⁶⁰ Also, the desired objectives in the form of an objective function, its parameter values, and the IMRT fractionation strategy are specified, and beam configuration is defined. Typically the objective function⁶¹ assigns a weighted “cost” to the square of the difference between the desired 3D fluence distribution and that calculated at a given iteration. The software attempts to minimize the costs—maximizing dosage to the tumor volume and minimizing exposure of normal tissues.

In the treatment-plan optimization phase, an iterative process is used to adjust and set the intensities of rays of each beam (or portion of the arc) so that the resulting intensity distributions yield the best approximation of the desired objectives. The IMRT plan then is evaluated to ensure that the trade-offs made by the optimization system are acceptable. If further improvement is deemed necessary and possible, the objective function parameters are modified and the optimization process is repeated until a satisfactory treatment plan is achieved.

In the leaf sequence-generation phase, the intensity distributions are converted into sequences of leaf positions. It is conceivable that certain dose distributions cannot be delivered as a result of the leakage characteristics of the delivery devices. Therefore, in most treatment-planning systems, the leaf sequences are used in a reverse process to calculate the dose distributions they are expected to deliver. These dose distributions, called the deliverable dose distributions, are evaluated for clinical adequacy. If necessary, objective function parameters are further adjusted to produce an intensity distribution that leads to a deliverable dose distribution that meets the desired objectives. This is the practice in most systems. However, in some systems, the leaf sequence-generation process is incorporated into the IMRT plan optimization loop so that the optimized and deliverable dose distributions are identical. More details on this are given later in this chapter.

The leaf sequences then are transmitted to the treatment machine and used to verify that the dose distribution that will be delivered to the patient is correct and accurate. The patient then is set up in the usual fashion and treated. In general, the entire treatment is delivered remotely without the need to re-enter the treatment room in between fields.

PREPARATORY AND IMRT PLANNING PHASES

This section discusses each of the steps of the preparatory and IMRT plan design phases. For reasons of clarity, the order in which these steps are discussed is not the same as the order in which they occur as shown in Figure 10.5. Figure 10.6 sketches the quality assurance process.

Imaging and Volumes of Interest

ICRU 83 presents updated definitions for the assorted volumes that will form the skeleton of the treatment plan.¹ Conceptually, the volumes contain three types of tissue: (a) malignant lesion, (b) otherwise normal tissue near the tumor that is already or likely to be infiltrated by microscopic disease, and (c) more distant normal tissue and organs. The quoted definitions that follow are from ICRU 83.

• Gross tumor volume (GTV): “The GTV is the gross demonstrable extent and location of the tumor. The GTV may consist of a primary tumor (primary tumor GTV or GTV-T), metastatic regional node(s) (nodal GTV or GTV-N), or distant metastasis (metastatic GTV, or GTV-M)”.¹ They note that in some cases it may not be possible to differentiate expanding primary lesions from nearby metastatic disease. The GTV for IMRT is always defined from anatomic images, usually CT with or without MRI, and increasingly supplemented by PET.

• Clinical target volume (CTV): “The CTV is a volume of tissue that contains a demonstrable GTV and/or subclinical malignant disease with a certain probability of occurrence considered relevant for therapy. There is no general consensus on what probability is considered relevant for therapy, but typically a probability of occult disease higher than from 5% to 10% is assumed to require treatment”.¹ The volumes outside the GTV encompassed by the CTV will depend a great deal on the particular tumor (e.g., with high or low propensity for lymph node extension). In the past, the CTV was effectively the GTV (including affected nodes) plus a 1- to 2-cm margin. The current definition stresses more the physiologic criteria based on the specifics of disease spread for each tumor. Gregroire et al. have compiled studies on CTV margins into a book.⁶² In postoperative situations, following an R0 or R1 resection, there is no gross tumor so only the CTV need be defined. Readers are strongly encouraged to consult ICRU 83 for details.

• Planning target volume (PTV): “The PTV is a geometrical concept introduced for treatment planning and evaluation. It is the recommended tool to shape absorbed-dose distributions to ensure that the prescribed absorbed dose will actually be delivered to all parts of the CTV with a clinically acceptable probability, despite geometrical uncertainties such as organ motion and setup variations”.¹

• Organ at risk (OAR): “The OAR or critical normal structures are tissues that if irradiated could suffer significant morbidity and thus might influence the treatment planning and/or the absorbed-dose prescription. In principle, all non-target tissues could be OARs. However, normal tissues considered as OARs typically depend on the location of the CTV and/or the prescribed absorbed dose”.¹ All normal tissue exposed to radiation during treatment is at risk, but the OAR is generally taken to be rather more specific—structures in the immediate vicinity of the PTV, sparing of which may demand specific recontouring of the CTV or PTV. Historically, OARs have been loosely grouped into “serial” or “parallel” organs or a combination of the two, following the work of Withers et al. using the concept of functional subunits in each organ.⁶⁴^,⁶⁵ Serial organs, such as the spinal cord, can suffer unacceptable damage if only a small portion is irradiated, whereas parallel organs, such as the liver, can suffer loss of a portion without total loss of function.

• Planning organ at risk volume (PRV): “As is the case with the PTV, uncertainties and variations in the position of the OAR during treatment must be considered to avoid serious complications. For this reason, margins have to be added to the OARs to compensate for these uncertainties and variations, using similar principles as for the PTV. This leads, in analogy with the PTV, to the concept of PRV”.¹ As with the OAR itself, margins in the PRV will be affected by the serial or parallel attributes of the adjacent tissues.

• Remaining volume at risk (RVR): “The RVR is operationally defined by the difference between the volume enclosed by the external contour of the patient and that of the CTVs and OARs on the slices that have been imaged”.¹Definition of an RVR and its inclusion in the treatment plan (at least in the form of dose constraints) is essential in IMRT. Without such limits, the optimization software could craft excellent dose distributions for the CTV and OAR but cause toxic irradiation levels in otherwise uncontoured tissues.

• Treated volume (TV): “The TV is the volume of tissue enclosed within a specific isodose envelope, with the absorbed dose specified by the radiation oncology team as appropriate to achieve tumor eradication or palliation, within the bounds of acceptable complications”.¹ The TV is what is physically deliverable given limitations of beam collimation and homogeneity and, more importantly, the risks of treatment-associated morbidity acceptable to the oncologist and the patient. ICRU 83 proposes that, in conformity with its proposal for proton therapy, the TV be defined as the dosage received by 98% of the PTV. This serves as a measure of the minimum absorbed dose, and is also referred to as D_{near minimum}. In an analogous manner, a D_{near maximum} is defined as D_2%, the dose received by 2% of the PTV receiving the highest fluence. Readers are referred to Section 3 of ICRU 83.

It should be noted that the GTV, CTV, and OAR represent volumes based on anatomic and physiologic judgments on the location of malignant growths or normal tissues in danger from metastatic spread and/or treatment-induced toxicity. These are independent of the particular irradiation protocol employed (i.e., 3DCRT, IMRT, or particle beams). The PTV, PRV, and TV are intimately tied to the specific radiation therapy used.

FIGURE 10.6. Intensity-modulated radiation therapy (IMRT) process: Quality Assurance (QA) and delivery phase.

Beam Configurations

Systems Using Fixed Intensity-Modulated Fields

The beam configuration can have a significant impact on the quality of an optimized IMRT plan. It may be argued that, because of the greater control over dose distributions afforded by optimized intensity modulation, the fine-tuning of beam angles may not be as important for IMRT as it is for standard radiotherapy. However, optimization of beam angles may find paths least obstructed by critical normal tissues, thus facilitating the achievement of desired distribution with a minimum of compromise.

Beam-angle optimization, however, is not a trivial problem. There have been some attempts to solve this problem,⁶⁶^–⁶⁷^,⁶⁸ and advances in mathematical operations research applied to the problem have been reviewed recently.⁶⁹ To appreciate the magnitude of the problem, consider the following example. If the angle range is divided into 5-degree steps, nearly 60,000 combinations would need to be tested for three beams, nearly 14 million combinations for five beams, nearly 1.5 billion combinations for seven beams, and so on. Considering the magnitude of the search space, none of the optimization methods is likely to be able to demonstrate a significant improvement in treatment plans, let alone find a truly optimum combination when the number of beams is five or more. Furthermore, the beam-angle optimization problem is known to have multiple minima,⁷⁰ which means that fast gradient-based optimization techniques may fail. Stochastic methods,⁷¹^,⁷² in principle, should avoid the local minimum problem but may present excessive computing time demands. These should prove less of a problem in the near future, especially with the use of dedicated parallel processors, which can drastically reduce computation time. For a review see Pratx and Xing.⁷³

Another question that may be asked is how many beams are optimal. In principle, a larger number of beams would provide a larger number of parameters to adjust and therefore a greater opportunity to achieve desired dose distributions. (Thus, in theory, a rotational beam would be the ultimate.) However, for fixed-beam IMRT, it may be desirable to minimize the number of beams to reduce the time and effort required for planning, QA, dosimetric verification, and delivery of treatments. Fewer intensity-modulated beams would be needed if beam angles were optimized than if the beams were placed at equiangular steps. Calculations by Webb⁹ indicate that seven or nine fields give adequate conformal dose distributions for both serial tomography and fixed-gantry IMRT.

Figure 10.7 compares prostate treatment plans employing different numbers of fields using 3DCRT, serial tomography, and step-and-shoot IMRT. Consistent with published experience, the plan quality improves but the incremental improvement diminishes with increasing number of beams. Optimum nonuniform placement of beams can further improve dose distribution. Figure 10.8A, B shows a head and neck IMRT case for two different beam angles. The patient, treated with the beam configuration shown in Figure 10.8A, developed significant mucositis at the early phase of treatment. This was consistent with the “horn” in dose distribution shown by the arrow. Revising the beam-angle arrangement as shown in Figure 10.8C led to improved dose distribution, shown in Figure 10.8D.

In general, it is most advantageous to place beams so that they are maximally avoiding each other and the opposing beams with the stipulation that directions that overlap significant obstructions, such as heavily attenuating bars in the treatment couch, be avoided. For simplicity, beams often are constrained to lie in the same transverse plane. However, noncoplanar beams will provide an additional degree of freedom and potentially an additional gain in the quality of treatments. It should be noted that the beam configurations used for 3DCRT may not be optimal for IMRT.⁷⁴

Although reducing the number of beams is a desirable goal for IMRT delivered with several fixed-gantry angles and dynamic MLC, it should not be the overriding consideration. IMRT can be planned and delivered automatically in times not significantly different from the times for much simpler conventional treatments. Therefore, the delivery times for six to 20 beams may be quite acceptable. Keep in mind, however, that some of the current linear accelerators are limited in their ability to accurately deliver a large number of intensity-modulated beams each with a very small number of monitor units.⁷⁵

FIGURE 10.7. Typical isodose distributions for treating prostate cancer from (1) a four-field three-dimensional conformal radiation therapy (3DCRT) plan; (2) a seven-field 3DCRT plan; (3) an intensity-modulated radiation therapy (IMRT) plan delivered by serial tomotherapy using MIMiC (NOMOS Corp, Sewicky, PA); and (4) a 10-field step-and-shoot segmental multileaf collimator (SMLC) plan. (Reprinted from Chao et al. Practical essentials of IMRT, 2nd edition. Philadelphia: Lippincott Williams & Wilkins, 2005, with permission.)

Systems Using Rotating Slit (Tomotherapy) Approach

Tomotherapy delivery has substantial differences from fixed-portal IMRT. Mackie has published a historical review of tomotherapy, intertwined as it is with his career.⁷⁶ The linear accelerator rotates during delivery, and the beam is modulated during rotation. Typically, the modulation is subdivided into small gantry angle ranges (e.g., 5 degrees) and the beam is independently modulated at each gantry angle. Each leaf is used to deliver a single rotating pencil. The pencil-beam modulation is conducted for each leaf by opening that leaf for a fraction of the gantry range consistent with the fractional fluence to be delivered from that gantry angle. For example, for a 5-degree-angle-range bin, if a leaf is to deliver 50% fluence, the leaf will be open for 2.5 degrees over the 5-degree range. Because of geometric constraints of modulating the radiation fan beams, only one or two thin planes can be treated with each rotation. The Peacock system,²⁶ for instance, uses two banks of opposing leaves projecting to 1.7 or 3.4 cm, depending on user-selected mechanical stops. This delivers modulated beams to two abutting, independently modulated planes. The helical tomotherapy unit uses a single leaf bank with a backup collimator that allows the radiation field width to be continuously adjusted. Narrower leaf widths provide higher spatial resolution for modulation but require more treatment arcs and consequently more delivery time. The current TomoHD MLC uses tungsten leaves 10 cm thick (in beam direction) and with a width of 0.625 cm. Leaves are driven pneumatically and switch in 20 msec.

Aperture Margins

IMRT has the inherent capacity to reduce margins attributable to the beam penumbra. When a photon beam traverses the body, it is scattered, depositing dose not only along the path of each ray of the beam but also at points away from it. The electrons knocked out by the incident photons travel laterally to points in the neighborhood of each ray, depositing dose along the way. Near the middle of a uniform beam, outgoing electrons are offset by incoming electrons and equilibrium exists. However, at and just inside the boundaries of the beam, there are no incoming electrons to balance electrons flowing out of the beam. Therefore, a “lateral electronic disequilibrium” exists that leads to a dose deficit inside the boundaries of beams. For lower-energy beams and at large depths, scattered photons significantly contribute to this effect also. The conventional approach to overcome this deficiency is to add a margin for the “beam penumbra” to the PTV so that the tumor dose is maintained at the required level.

For IMRT plans, there is another method to counterbalance the dose deficit. The intensity of rays just inside the beam boundary may be increased. Because some of the increased energy must also flow out, a very large increase would be required if the margin for the penumbra were set to zero or to a very small value. Therefore, an increase in boundary fluence alone is not enough. A combination of an increased fluence and the addition of a margin, albeit a much smaller one, is a better solution. This reduction in margin can be exploited quite usefully to reduce the volume of normal tissues exposed to high doses of radiation with a corresponding reduction in toxicity and a further potential for dose escalation.

The beam–boundary-sharpening and margin-reduction feature of IMRT can be taken advantage of only if the dose-computation method is able to adequately take into account the lateral transport of radiation⁷⁷ and if the intensity matrix grid size is sufficiently small. Initially, dose distribution for a given configuration of beams is computed by taking lateral transport into consideration. In each optimization iteration, the intensity distribution first is designed ignoring lateral transport. At the end of the iteration, the dose distribution is recalculated, thereby incorporating the effects of field-shaping devices on lateral transport and revealing the resulting deviations from the anticipated dose distribution. In the next iteration, ray intensities are adjusted further to rectify the deviations, and so on.⁵⁰^,⁷⁸ Carrasco et al. compared several dose-computation algorithms in lung phantoms.⁷⁷

A schematic example shown in Figure 10.9 illustrates the issues involved. Figure 10.9A shows a normal organ overlapping the target volume. The target volume is being irradiated by two parallel-opposed beams. It is desired that the dose to the region of overlap be 60% of the target dose. If more dose is delivered, damage to the normal organ may result; but lower than the desired dose may cause local failure. If the role of lateral transport in optimization is ignored, the intensity resulting from the optimization process is essentially a step function, as shown in Figure 10.9B (solid curve). The corresponding dose distribution (the dotted curve) shows a dose deficit inside the high-dose target volume as well as the outside edge of the region of overlap and an excess of dose in the region of overlap adjacent to the high-dose volume. If lateral transport is incorporated by adjusting fluence, the fluence and dose patterns shown in Figure 10.9C result. Fluence is increased at both boundaries. It also is increased in the high-dose side of the interface with the overlap region and decreased on the lower-dose side. The dose is now much closer to the desired dose. Comparing Figures 10.9B and 10.9C, it also appears that a modest increase in fluence just inside the boundary does not lead to a perceptible increase in dose outside the beam boundary. This is presumably the result of the fact that the excess dose flowing out of the target periphery is deposited in a much larger volume of tissue. A reduction of margins attributable to penumbra by as much as 8 mm has been found to be feasible for prostate treatments.⁵⁰^,⁷⁸

FIGURE 10.8. A patient with carcinoma of the base of the tongue was treated with intensity-modulated radiation therapy. A and B depict the beam angle arrangement and the resulting isodose distribution. Arrow on (C) indicated a “horn” of high dose to the left oral tongue and buccal mucosa. Rearrangement of anterior beam placement as shown in (B) led to improvement of dose distribution to the normal mucosa of the left anterior oral cavity (D).

FIGURE 10.9. A schematic example illustrating the sharpening of penumbra with intensity-modulated radiation therapy.

IMRT Fractionation

In principle, conventional fractionation strategies can be used to design IMRT plans as well. For example, in a strategy similar to the conventional 1.8-Gy to 2-Gy/fx schedule, a major portion of the dose could be delivered in the initial phase using uniform fields designed with standard 3D conformal methods followed by an IMRT boost. Alternatively, separate IMRT plans could be designed for both the initial large-field treatment and the boost treatment. It may be intuitively obvious that, if a large portion of the dose already has been delivered using large fields, it may be very difficult, if not impossible, to achieve a high level of dose conformation with the remaining fractions in the IMRT-boost phase.¹⁵ As indicated earlier in this chapter, IMRT may be most conformal if all target volumes (gross disease, subclinical extensions, and electively treated nodes) are treated simultaneously using different fraction sizes.¹⁵ Such a treatment strategy has been called the simultaneous integrated boost (SIB).¹¹^,¹²^,¹⁵^,¹⁹ Mackie et al. had also indicated the possibilities for irradiation boost in their first paper on serial tomography.⁷⁹ The SIB IMRT strategy not only produces superior dose distributions but also is an easier, more efficient, and perhaps less error-prone way of planning and delivering IMRT because it involves the use of the same plan for the entire course of treatment. Furthermore, in many cases, there is no need for electron fields, and the nodal volumes can be included in the IMRT fields; thus, the perennial problem of field matching⁸⁰ encountered in the treatment of many sites is thereby avoided.

Because each of the target regions receives different doses per fraction in the SIB IMRT strategy, prescribed nominal (physical) dose and dose per fraction must be adjusted appropriately. The adjusted nominal dose and fraction size for each target region depend on the number of IMRT fractions. The fraction sizes may be estimated using an isoeffect relationship based on the linear-quadratic model and the values of its parameters (such as α/β ratios, tumor doubling time).

The effect of the modified fractionation on acute and late toxicity of normal tissues both outside and within the volumes to be treated also should be considered. Because of the improved conformality of IMRT plans, dose to normal tissues outside the target volume is typically lower than for conventional treatment plans. In addition, if the number of fractions is greater than the number of fractions used to deliver large fields in conventional therapy, the dose per fraction to normal tissues is lower. Therefore, the biologically effective dose would be lower still. However, normal tissues embedded within or adjacent to the target volumes would receive high doses per fraction and may be at higher risk. Isoeffect formulae for normal tissues also may be derived to estimate the effect of a particular fractionation strategy (see ICRU 83, pp. 36–38). These formalisms would need to incorporate regeneration and change in sensitivity over the treatment course.

The values of parameters for the computation of altered fractionation may, in theory, be obtained from published studies. Studies by Maciejewski et al.⁸¹ and Withers et al.⁸²^–⁸⁴ for example, have yielded important information for estimating tumor parameters for head and neck carcinoma. In general, the data available are limited. Furthermore, there is considerable uncertainty in the data, and there are concerns about the validity of numerous assumptions in the linear-quadratic model and the isoeffect formalism, especially with regard to normal tissues. (For an early review of the linear-quadratic model see Fowler⁸⁵). Much of the accumulated data on normal tissue complications comes from clinical experience in the era of wide-field radiation therapy, so the dosage limits reported from such studies may not be immediately applicable to IMRT. Nevertheless, various investigators have carried out the necessary calculations and adopted SIB IMRT fractionation strategies. Continued investigations and clinical trials are needed to develop more reliable time-dose fractionation models, to produce better estimates of their parameters, and to evaluate alternate SIB IMRT fractionation strategies for all sites.¹³ The following are some examples of IMRT fractionation strategies that have been used for IMRT of head and neck cancers.

In the Radiation Therapy Oncology Group H-0022 protocol for early-stage oropharyngeal cancer, 30 daily fractions (5 per week × 6 weeks) are used to simultaneously deliver 66 Gy (2.2. Gy per fraction) to the PTV, 60 Gy (2 Gy per fraction) to the high-risk subclinical disease (“levels II–IV bilaterally, Ib ipsilaterally, and level V and retropharyngeal nodes if the jugular nodes were involved”), and 54 Gy (1.8 Gy per fraction) to subclinical disease. These are biologically equivalent to 70, 60, and 50 Gy, respectively, if given in 2 Gy per fraction. For normal structures, brainstem, spinal cord, and mandible are maintained below 54, 45, and 70 Gy, respectively. The mean dose to the parotid glands is maintained below 26 Gy and/or 50% of one of the parotids is maintained below 30 Gy and/or at least 20 mL of the combined volume of both parotids is constrained to receive no more than 20 Gy. Sixty-nine patients were accrued at 14 institutions. Treatment-associated xerostomia improved following therapy, in contrast to regular radiation therapy. High locoregional control was achieved with stringent adherence to protocol guidelines.⁸⁶

The SIB strategy at Virginia Commonwealth University involves a dose-escalation protocol in which primary nominal dose levels of 68.1, 70.8, and 73.8 Gy, given in 30 fractions (biologically equivalent to 74, 79, and 85 Gy, respectively, if given in 2 Gy per fraction), are used.⁸⁷ Simultaneously, the subclinical disease and electively treated nodes were prescribed 60 and 54 Gy, respectively (biologically equivalent to 60 and 50 Gy, respectively, if given in 2 Gy fractions). Spinal cord and brainstem are maintained below 45 and 55 Gy, respectively, and an attempt is made to allow no more than 50% of at least one parotid to receive higher than 26 Gy.

At the Mallinckrodt Institute of Radiology, the SIB strategy for definitive IMRT prescribes 70 Gy in 35 fractions in 2 Gy per fraction to the volume of gross disease with margins. The adjacent soft tissue and nodal volumes at high risk were treated to 63 Gy in 1.8 Gy per fraction and simultaneously 56 Gy in 1.6 Gy per fraction to the elective nodal regions. This regimen has been shown to be well tolerated when combined with concurrent chemotherapy.⁷⁸

The most conservative normal tissue constraints for head and neck sites based on the most recent RTOG protocols (1016, 1008, 0920, and 0912) are: optic nerve and chiasm <30 Gy; eyes <30 Gy; brainstem <48–52 Gy to any 0.03 cc volume; brain <60 Gy to any 0.03 cc volume; spinal cord <45–48 Gy to any 0.03 cc volume; ipsilateral cochlea <50 Gy; parotid glands <26 Gy and at least 20 cc volume <20 Gy; submandibular glands mean <39 Gy; mandible <60 Gy; cervical esophagus mean <35 Gy; pharynx mean <40–45 Gy (for details, see www.rtog.org). Other workers⁸⁸^–⁹⁰ have determined dose levels to the pharyngeal constrictors above which severe dysphagia will occur: V65 Gy >30%, V55 Gy >80%, and a mean dose >60 Gy were predictive of feeding tube dependence.

Optimization of Intensity Maps

The optimization of ray intensities may be carried out using one of several mathematical formalisms and algorithms, also termed optimization engines.⁶⁹ Each method has its strengths and weaknesses. The choice depends in part on the nature of the objective function and in part on individual preference. Although the details are complex, the basic principles are not difficult to comprehend. Each ray of each beam is traced from the source of radiation through the patient. Only the rays that pass through the target volume need to be traced (plus through a small margin assigned to ensure that the lateral loss of scattered radiation does not compromise the treatment). Others are set to a weight of zero.

The patient’s 3D image is divided into voxels. The dose at every voxel in the patient is calculated for an initial set of ray weights. The resulting dose distribution is used to compute the “score” of the treatment plan (i.e., the value of the objective function that mathematically states the clinical objectives of the intended treatment).

The ray-tracing process identifies the tumor and normal tissue voxels that lie along the path of the ray. The effect of a small change in a ray weight on the score then is calculated. If the increase in ray weight would result in favorable consequences for the patient, the weight is increased, and vice versa. Mathematically speaking, the ray weight is changed by an amount proportional to the gradient of the score with respect to the ray weight. Realizing that the improvement in the plan at each point comes from rays from many beams and that each ray affects many points, only a small change in ray weight may be permitted at a time. This process is repeated for each ray. At the end of each complete cycle (an iteration), a small improvement in the treatment plan results. The new pattern of ray intensities then is used to calculate a new dose distribution and the new score of the plan, which then is used as the basis of further improvement in the next iteration. The iterative process continues until no further improvement takes place, the optimization process is assumed to have converged, and the optimum plan is assumed to have been achieved.

Many current optimization systems use variations of gradient techniques to optimize IMRT plans. These calculations are prodigious given the thousands of free parameters in variation—it was only with the advent of powerful and affordable computers that such calculations could become clinically realistic. Direct aperture optimization has been proposed as an alternative that reduces the parameter space and eliminates nonphysical dose distributions at the start; for a review see Broderick.⁹¹ The use of gradient techniques assumes that there is a single extremum (a minimum or a maximum, depending on the form of the objective function). This is indeed the case for objective functions based on variance of dose and when only ray weights are optimized. For other cases, it would be necessary to determine whether multiple extrema exist and whether such multiple extrema have an impact on the quality of the solution found. Multiple extrema have been found to exist when beam directions are optimized or when dose–response-based objective functions are used to optimize weights of uniform beams.⁵³^,⁹²^,⁹³ One can expect that multiple minima also exist when dose–response-based objective functions are used to optimize IMRT plans. Using simple schematic examples, it also has been shown that multiple minima exist when dose–volume-based objectives are used.⁹⁴Although this may be the case in theory, the existence of multiple minima has not been found to be a serious impediment in dose–volume-based or dose–response-based optimization using gradient techniques. In fact, in a study of dose–volume-based IMRT optimization, Wu and Mohan⁹⁵ found that, starting from vastly different initial intensities, the solutions converged to nearly the same plans. The reasons for this have been speculated but not conclusively proven and need to be investigated further.

If multiple minima are discovered to be a factor, then some form of stochastic optimization technique may need to be considered. At the simplest, one may use a random search technique in conjunction with one of the gradient techniques. A more sophisticated stochastic technique is “simulated annealing” or its variation, the “fast simulated annealing”.⁸^,⁴⁶^,⁵³^,⁹² These techniques allow the optimization process to escape from the local minima traps. Other forms of stochastic approaches, such as “genetic algorithms,” also have been proposed.⁹⁶ In principle, the simulated annealing technique and other stochastic approaches can find the global minimum, but, practically, there is no guarantee that the absolute optimum has been found, only that the best among the solutions examined has been found. (This, of course, is true for gradient techniques as well.) Stochastic techniques tend to be extremely slow and should be used in routine work only if it is established that they are necessary. Nevertheless, some commercial systems have implemented the simulated annealing approach for IMRT optimization.³ Also, as noted earlier, rapid advances in parallel processing using off-the-shelf components can dramatically reduce computation times.⁷³ In 2005, Xu and Mueller reported an order of magnitude decrease in the time to process a CT image on a PC when equipped with a dedicated graphics board.⁹⁷

OBJECTIVE FUNCTIONS

Dose-Based Objective Functions

A simple example of an objective function is the criteria stated in terms of the sum of the squares of the differences of desired dose and computed dose at each point within each of the volumes of interest. That is,

This type of objective function is called the quadratic or variance objective function. The optimization process attempts to minimize the treatment plan score S. D_T_,0 in expression Eq. (1) is the desired dose to the target volume and D_n_,0 is the tolerance dose of the nth normal structure. D_T,i is the computed dose at the ith voxel of the target and D_n,j is the computed dose at the jth voxel of the nth normal structure. For normal organs, the function H(D_n,j –D_n,₀) is a Heaviside step function defined as follows:

In other words, so long as the dose in a normal tissue voxel does not exceed the tolerance limit, the voxel does not contribute to the score function. The quantity p_n is the “relative penalty” for exceeding the tolerance dose.

Dose–Volume-Based Objective Functions

Purely dose-based criteria, such as the one previously described, are not sufficient. In general, the response of the tumor and normal tissues is a function of not only radiation dose but also (to varying degrees depending on the tissue type) the volume subjected to each level of dose. Currently, dose–volume-based objective functions are the most widely used clinically. Dose–volume-based objective functions are expressed in terms of the limits on the volumes of each structure that may be allowed to receive a certain dose or higher. ICRU 83 sets its IMRT reporting guidelines in terms of dose–volume criteria, and dose–volume histograms (DVHs) are a mandatory part of treatment planning.

A practical scheme to incorporate dose–volume-based objectives has been suggested by Bortfeld et al.⁹⁸ It is explained in Figure 10.10 using a simple schematic example of one organ at risk. The dose–volume constraint is specified as V(>D₁) < V₁. In other words, the volume receiving dose greater than D₁ should be less than V₁. To implement such a constraint into the objective function, we seek another dose value D₂ so that in the current dose–volume histogram V(D₂) = V₁. The objective function component for this OAR then may be written as:

That is, only the points with dose values between D₁ and D₂ contribute to the score. Therefore, they are the only ones penalized.

For the target volumes, two types of dose–volume criteria may be specified to limit both the hot and cold spots. For instance, for the desired target dose of 80 Gy, we may specify V (>85 Gy) ≤ 5% and V (>79 Gy) ≥ 95%. In other words, the volume of the target receiving dose >85 Gy should be no more than 5%, and the volume of target receiving 79 Gy or higher should be at least 95%. Dose-based criteria can be considered as a subset of the dose–volume criteria in which the volume is set to an extreme value (0% or 100%, as appropriate). Dose–volume criteria provide more flexibility for the optimization process and greater control over dose distributions. The reason is that dose-based optimization penalizes all the points above the dose limit, whereas the dose–volume-based optimization penalizes only the subset of points within the lower end of range of dose values above the dose limit. For the example of Figure 10.10A, the dose–volume-based optimization process attempts to bring only the points between D₁ and D₂ into compliance with the constraint. In contrast, the dose-based optimization process attempts to constrain all of the points above D₁. Furthermore, dose–volume criteria are highly “degenerate” functions of dose distributions (i.e., there is a very large number of dose distributions that correspond to the same dose–volume constraint). Therefore, the optimization system has a large solution space to choose from, making it easier to find a better solution.

FIGURE 10.10. A: Incorporation of dose–volume constraints in intensity-modulated radiation therapy optimization. (Adapted from Wu Q, Mohan R. Multiple local minima in IMRT optimization based on dose-volume criteria. Med Phys 2002;29[7]:1514–1527.) B, C: Limitations of dose–volume-based criteria (see text).

Limitations of Dose–Volume-Based Objective Functions

Dose–volume-based criteria have been demonstrated to have limitations. To illustrate one such limitation, consider the example in Figure 10.10B of a normal structure for which a constraint has been specified that no more than 25% of the volume is to receive 50 Gy or higher. All three DVHs shown meet this criteria. However, the DVH represented by the solid curve clearly causes the least damage. One can argue that we can overcome this limitation by specifying multiple dose–volume constraints or even the entire DVH. However, as illustrated in Figure 10.10C, this would be too limiting. Multiple DVHs could lead to an equivalent injury to a particular organ, but each DVH may produce a different effect on other organs and the tumor. When this happens, DVHs usually cross each other, as shown in Figure 10.10C. Only one of them is optimum so far as the tumor and other organs are concerned.

To overcome the limitations of dose–volume-based criteria, they may be supplemented with biologic (or dose–response-based) criteria, for instance, in terms of such indices as tumor control probability (TCP), normal tissue complication probabilities (NTCPs), and equivalent uniform dose (EUD).⁷⁷ Dose–response-based objective functions are the subject of ongoing investigations.⁵³^,⁹⁹ The ICRU currently includes NTCP and EUD projections in its Level 3 reporting (i.e., still investigative). The report (see p. 51) notes that most of the tissue tolerance data go back to the period before 3D imaging, but they do cite newer prospective studies involving 3DCRT or IMRT.^100,101

FIGURE 10.11. Effect of adjusting dose-prescription parameters on the resulting treatment plan. The parotid gland and target are shown in green and blue, respectively. Plan C emphasizes parotid sparing, and plan F emphasizes tumor coverage. (Interested readers should view the full set of six plans as presented in the original paper. From Chao KS, Low DA, Perez CA, et al. Intensity-modulated radiation therapy in head and neck cancers: the Mallinckrodt experience. Int J Cancer 2000;90[2]:92–103.)

Objective Function Parameters

The desired IMRT dose distributions are specified in terms of parameters of the objective function. In Eq. (1), for instance, the parameters of the objective function are the desired dose limits D_T_,0 and D_n_,0 for target and normal structures, respectively, and the relative importance (or penalty) factors p_n for deviating from desired dose limits. Most often, the objective functions are specified in terms of one or more “soft” dose–volume constraints for each volume of interest, one for each constraint. That is, if the computed dose deviates from the desired value, the plan is not rejected, but it is assessed a penalty. The optimization software computes a “subscore” corresponding to each constraint. The subscore value depends on the deviation of dose distribution from the desired dose distributions and the penalty factor. The overall score of an IMRT plan is an accumulation of subscores of individual volumes of interest. The IMRT optimization system uses the IMRT plan score to arrive at the optimum plan according to the specified objective function. The optimized solution involves trade-offs that balance specified normal tissue objectives against each other and against tumor objectives. An IMRT treatment-planning system should provide parameters that allow the treatment planner to adjust the trade-off for each critical structure in a straightforward manner. An example of this is shown in Figure 10.11, where a head and neck target volume nearly abuts the parotid gland.¹⁰² Two of six plans are shown—Plans C and F use parameters that emphasize parotid-gland sparing and tumor coverage, respectively. This is an excellent example of the flexibility of moving the steep dose gradient in and out of the target volume.

The plan considered to be the best by the computer may not be judged the best (or even good enough) by the treatment planner. Parameters are adjusted by trial and error to obtain a satisfactory plan. A confounding factor is that a change in a parameter of one volume of interest affects not only its own subscore and DVH but also the subscores and DVHs of other structures in a complicated manner. For a complex IMRT problem, in which there may be several dozen parameters, their adjustment is an extremely difficult task. The trial-and-error approach used currently is time consuming and leads to suboptimal results. Future research based on artificial intelligence techniques may provide a systematic means of determining optimum parameter values.

Treatment Plan Evaluation

IMRT dose distributions tend to be highly conformal but complex and unconventional. Traditional methods of evaluation and reporting may be too limited for such dose distributions. In principle, the target dose distributions for IMRT should be more homogeneous than for 3DCRT. In practice, the opposite is the case, due in part to the competing demands of sparing of normal tissues and in part to the inadequacy of objective functions. Dose distributions in normal structures as well are, in general, more nonuniform than for 3DCRT.

In the current practice of radiotherapy, treatment plans are evaluated using dose and dose–volume parameters including such quantities as dose to a point in the volume of interest, minimum dose, maximum dose, minimum dose to a specified fractional volume, or the volume of the structure receiving a specified dose or higher. Monitor units (MUs) are set to deliver the prescribed dose to a specified point or to an isodose line (or surface) just enclosing the target volume. For some sites and techniques (e.g., stereotactic radiosurgery of brain tumors), an index of conformality (the ratio of volume occupied by the prescription isodose surface and the volume of the target) is used for plan evaluation. Cumulative dose and dose–volume data are reported as a part of the patient’s chart and used for correlation with outcome.

Because of the unconventional nature of IMRT dose distributions, especially the high degree of dose heterogeneity and fluctuations in dose as a function of position in volumes of interest, indices such as dose to a point, minimum dose, or maximum dose may not correlate well with dose response. Instead, dose to a specified fractional volume is more appropriate, and this is the approach taken by ICRU 83. ICRU reporting now specifies a D_98% or D_{near minimum}(dose to at least 98% of the PTV) and a corresponding D_2% (dose received by the most heavily irradiated 2% of the PTV).¹

Limitations of dose and dose–volume plan evaluation parameters have been articulated in the literature.¹⁰³ These limitations become more significant for the complex dose distributions of IMRT. It has been argued that biophysical dose-response indices, which summarize complex dose distributions using a single clinically relevant index in each volume of interest, may be more appropriate. Currently, indices such as TCP, NTCPs, and biologically EUD often are computed and recorded but rarely are used for routine plan evaluation. This is because of the unreliability of published dose-response data and weaknesses of models to compute these indices. This is, in turn, the result of the various sources of uncertainty both in the quantification of response and in doses delivered to the structures. Levegrun et al.¹⁰⁴ analyzed data from patients with prostate cancer treated at Memorial Sloan-Kettering Cancer Center and concluded that the biopsy-based response did not correlate with minimum tumor dose, EUD, or TCP. Instead, they found the mean dose to be a very good predictor of response. They attributed this observation to large treatment margins for PTV, substantial target motion, and relatively homogeneous dose distributions. As functional imaging (e.g., PET and nanoparticle optical probes) becomes more widespread, treatment will become more adaptive, with planning readjusted to reflect tumor regression or persistence. Recently, Moeller et al. reported a prospective study using 18-fluorodeoxyglucose (FDG)-PET to assess tumor response in head and neck cancers.⁶⁰ PET was seen to be superior to CT in the subset of patients with high-risk disease.

FIGURE 10.12. Intensity profile of the left lateral beam of an intensity-modulated radiation therapy plan designed for the treatment of the cervix. Intensity distribution in a plane through the isocenter and normal to the direction of the beam is plotted. The grid size along the y-axis is 1 cm, corresponding to the width of multileaf collimator leaves. Each intensity curve along the x-axis corresponds to one pair of opposing leaves.

GENERATION OF LEAF SEQUENCES

Fixed Intensity-Modulated Fields

For the IMRT mode using multiple fixed fields, the plan optimization process produces nonuniform intensity distributions (see Fig. 10.12) for each set of fields. In principle, such intensity distributions can be delivered using custom-fabricated compensators made of lead alloys to attenuate the appropriate amount of radiation along each ray of the beam. Such devices would have to be produced using computerized milling machines. In addition, to use them it would be necessary for the operator (radiation therapist) to enter the treatment room to insert the device for each field. This process would be highly labor intensive and impractical considering that a large number of beams often may be needed for optimum intensity-modulated treatments.

The most efficient means of delivering fixed-field IMRT is the standard MLC in dynamic mode using such methods as the “sliding-window” technique or the step-and-shoot technique. In either case, leaf position sequences as a function of MUs need to be generated. The MLC leaves are made of approximately 5- or 6-cm-thick tungsten and are typically 0.5 or 1 cm wide (projected to isocenter). MLCs with leaves of a width as small as 1 mm have been introduced. Smaller leaf width may be of greater value for IMRT than for standard 3DCRT. For the former, the leaf width affects the dose delivered to the entire slice, whereas for the latter, it affects only the shape of the boundary. A smaller leaf width undoubtedly would produce more conformal dose distributions, but the electromechanical complexity and cost of the device would increase. Because of the smearing caused by finite-sized radiation sources, lateral secondary electron transport, and the use of multiple fields, and because of motion and positioning uncertainties, an acceptable leaf width may not need to be very small. The minimum desirable leaf width would depend on numerous factors including shapes and locations of volumes of interest, dose gradients desired, and number and orientations of beams. Although the issue of leaf width has been debated for quite some time, there are no definitive studies to guide the choice of the most suitable width.

MLCs transmit only 0.5% to 2% of incident radiation (except through small interleaf gaps and the rounded ends of some MLCs). However, as discussed later in this chapter, because intensity-modulated treatments require a substantially larger number of MUs than do the conventional uniform field treatments, the cumulative effective transmission may be considerably larger.

FIGURE 10.13. A typical trajectory of one of the pairs of leaves used to deliver intensity-modulated beam profiles of the type shown in Fig. 10.12. Intensity-modulated radiation therapy optimization based on deliverable dose distributions using the sliding-window technique. Positions of the leading and following leaves are plotted as a function of monitor units (MUs). The gap formed by the pair of leaves moves from left to right. Its width and speed are adjusted by the computer to allow a predetermined amount of radiation to reach each point within the field. Note that the fluence is the differences in MUs for the left leaf and the right leaf.

Leaf Sequence Generation—Sliding-Window Technique

In the sliding-window method, the gap formed by each pair of opposing leaves is swept across the target volume under computer control while the radiation is on. The gap opening and its speed are optimally adjusted. Because the dose rate of the treatment machine might fluctuate slightly, the motion is indexed to MUs rather than time. The basic principle is that as the gap slides across a point, the radiation received by the point is proportional to the number of MUs delivered during the time the tip of the leading leaf goes past the point and exposes it until the tip of the trailing leaf moves in to block it again. (The point also receives additional radiation transmitted through or scattered from the leaves, which must be accounted for. See later discussion in this chapter.) The setting of the gap opening and its speed for each pair at any instant are determined by a technique first introduced by Convery and Rosenbloom¹⁰⁵ and refined and studied further by Bortfeld et al.,²³ Spirou and Chui,⁴⁰^,⁴¹ Stein et al.,⁴² Svensson et al.,¹⁰⁶ and others.⁴⁴^,¹⁰⁷ Knowledge of the maximum leaf speed is taken advantage of to maximize the gap between the opposing pair of leaves and, therefore, to minimize the treatment time. The number of leaves participating in the delivery of a beam depends on the projected size of the target volume. The data describing leaf trajectories, produced by the leaf sequence-generation process, are in the form of a table of positions of leaves versus the corresponding MUs (depicted graphically in Fig. 10.13).

Leaf Sequence Generation—Step-and-Shoot and Multisegment Techniques

With the step-and-shoot technique (as well as for multisegment technique), the fixed-gantry radiation beam is composed of multiple static MLC segments, with each segment having its own aperture shape and weight or monitor (MU) settings. The leaf sequence-generation algorithms take the optimized intensity pattern as the input and decompose it into multiple segments, each to be shaped as an aperture formed by the MLC. Fluence intensity throughout each MLC segment is relatively uniform. The summation of all static segments yields the required intensity-modulated dose distributions. Ideally, the segments are sorted to minimize the MLC leaf travel time between the segments. Note that such sorting is neither necessary nor possible for the sliding-window technique.

The first step of the leaf sequence-generation process is the discretization of the continuous intensity distribution into a limited number of intensity levels. These intensity levels then are converted into leaf sequences using one of several methods described in the literature. Bortfeld et al.,²³ for example, have proposed a method in which each row of intensity is handled separately, similar to the sliding-window algorithm. The advantage is that the total number of MUs is small but at the cost of possibly large numbers of segments. Xia and Verhey¹⁰⁸ proposed the so-called areal algorithm. Instead of dividing the intensities into levels of equal steps, they divided them into levels in powers of 2 to reduce the number of steps and to gain efficiency. Wu et al.⁹⁹ proposed a technique called the K-means clustering in which the intensity levels are grouped together based on their values and the user-specified error tolerance levels. The intensity levels are not equally spaced and can be arbitrary.

Unlike the sliding-window algorithm, the maximum leaf speed is not important for the step-and-shoot and multisegment techniques. Similarly, while the number of segments is not an issue for the sliding-window techniques, it could affect the step-and-shoot delivery efficiency significantly. For the former, the only penalty of the large number of segments is the size of computer storage, whereas for the latter it leads to inefficiency because the beam is off during the transition between the segments. Furthermore, for some linear accelerators, there is an overhead time associated with each segment.

Que¹⁰⁹ compared several step-and-shoot algorithms and found that the algorithm used by Xia and Verhey¹⁰⁸ frequently, but not always, produces the least number of segments. Other investigators have reported methods to minimize the number of segments as well. The algorithm of Dai and Zhu¹¹⁰ checks numerous candidates for each segment, and the candidate that would result in a residual intensity matrix with the least complexity is selected. If more than one candidate exists with the same complexity, the one with the largest size is chosen. Langer et al.¹¹¹ reported a technique based on the integer programming that can minimize the number of segments under the constraints that the MUs do not exceed a certain limit. It was found that the technique produces considerably fewer segments than the algorithms of Bortfeld et al.⁸^,⁹⁸ and Xia and Verhey¹⁰⁸ for the same or fewer MUs.

Monitor Units of IMRT Beams

Based on methods similar to those previously described, software systems have been developed to convert intensity distributions to leaf trajectories. The input to this software is the intensity distribution for each field in terms of MUs or, to be more precise, “effective” MUs. Effective MUs are fractions of MUs transmitted through the intensity modulation or compensation device. The intensity distribution-to-leaf trajectory conversion software not only produces trajectories but also computes actual MU settings for each beam as a natural by-product of the conversion process. Trajectories of leaves and the MUs for each beam are transmitted to the computer-controlled radiation treatment machine for dosimetric verification and the delivery of treatment.

It is important to note that the relationship between the prescribed dose and MUs required for delivering each of the intensity-modulated beams is highly complex and not obvious. There is no practical way to calculate MUs by hand as is done for traditional treatments as an independent check of the predicted MU values. To ensure patient safety and to satisfy the requirements of the independent check, some systems have implemented independent software for a second MU calculation. Others have adopted the policy to measure the dose or dose distribution for each of the beams before the first treatment.

Impact of MLC Characteristics

ICRU 83 notes that the tolerances for MLC operation must be more stringent than even those required for beam blockage in 3DCRT. This stems from the steep dose gradients made possible by and employed with IMRT. Slippage of leaf position would cause a cumulative degradation of the dose distribution actually delivered. Leakage through closed leaves may also pose a problem for which consideration in planning must be taken.¹¹² Adjustments to leaf trajectories are required to account for the various effects associated with MLC characteristics, including the rounded leaf tips, tongue-and-groove leaf design, interleaf and intraleaf transmission, leaf scatter, and collimator scatter upstream from the MLC. The accuracy of dose delivered and the agreement between calculated and measured dose distributions depend on the adequate accounting of these effects. Approximate empirical corrections are applied for these effects by algorithms and software that convert optimized intensity distributions into leaf trajectories.

MLCs have an interlocking tongue-and-groove leaf design to minimize interleaf leakage. However, there is a difference in interleaf leakage and leakage through the leaves. This difference can become significant for beams that require a large number of MUs and in portions of the beams that receive large fractions of their dose through leakage. Currently, this effect is ignored, although the use of Monte Carlo techniques to account for it is being investigated.¹¹³^,¹¹⁴

In addition, there are circumstances during creation of intensity profiles when a thin strip of the irradiated medium is shielded by the tongue of one leaf pair or the groove of the adjacent leaf pair rather than being completely exposed or completely blocked. van Santvoort and Heijmen⁴³ have demonstrated that this leads to an underdosage in the thin strip. They, and subsequently Webb et al.,⁴⁸ also showed that this effect could be removed by the use of leaf motion-synchronizing techniques. However, such techniques result in an increase in the number of MUs. Furthermore, this effect is not considered to be of significant clinical consequence because of the smearing caused by multiple fields and the positioning and motion uncertainties. Using different collimator angles for each field can reduce this effect further.

Depending on the complexity (the frequency and amplitudes of peaks and valleys) of the intensity pattern, points within the field aperture may receive a substantial portion of the dose as a result of radiation transmitted through or scattered from the leaves when the points are in the shadow of the leaves. Points outside the leaf aperture receive their entire dose through these “indirect” sources. The complexity of intensity distributions produced by the IMRT optimization process depends on a combination of several clinical factors including the shapes, sizes, and relative locations of tumor and normal tissues; required tumor dose; dose homogeneity; and dose–volume limits of normal tissues. Intensity distributions for head and neck cases, for example, tend to be considerably more complex than for prostate cases. For beams with highly complex intensity patterns, the average window width to deliver the treatment tends to be small and, for the same dose received by the tumor, the treatment time (i.e., the number of MUs) is long. Consequently, the contribution of radiation transmitted through and scattered from the leaves may form a significant fraction of the total dose delivered. Because these contributions are accounted for approximately, the uncertainty in dose delivered is increased. In addition, the differences between interleaf and intraleaf transmissions may no longer be negligible. Another consequence of complex intensity patterns is that the lower limit of the deliverable intensity is high.

The deliverable dose distributions may be significantly different from the original optimized ones. There are different ways to overcome the difficulties resulting from the differences in desired and deliverable dose distributions. For example, if the deliverable dose to a particular normal structure is higher than the original optimized dose, the planner could modify the objective function to demand an appropriately lower dose. Alternatively, the optimization loop could include a pass-through leaf sequence generation and calculation of deliverable dose distributions. The optimizer then adjusts ray weights based on deliverable dose distributions rather than the idealized ones. This scheme has been investigated by Siebers et al.¹¹⁵

QA FOR INTENSITY-MODULATED TREATMENTS

A number of QA steps unique to IMRT are needed to ensure the accuracy and safety of treatments. These include QA of the MLC in dynamic mode, dosimetric verification for each dynamic beam as well as for the composite treatment plans, portal imaging, treatment verification, in vivo dosimetry, and reduction in uncertainty associated with daily positioning and internal organ motion during irradiation. In recognition of the special demands of IMRT, the American Association of Physicists in Medicine (AAPM) recently commissioned Task Force 142 to recommend new QA guidelines and these have been published.¹¹⁶

When using conventional 3DCRT, MLC leaf position calibration errors influence the accuracy of the radiation distribution at the portal boundary. Because of PTV and beam penumbra margins, small errors in leaf calibration will have a minimal effect on the target volume dose. The accepted leaf calibration accuracy is 2 mm, but this is too large¹ because in IMRT the MLCs are used to generate inhomogeneous fluence distributions. In the sliding-window technique, for instance, this is done by adjusting the velocity and width of leaf gaps during radiation delivery. If the MLC calibration is inaccurate, the delivered dose distribution will be in error. The error is a function of the ratio of leaf calibration error to the sliding-window width. For example, a 1-mm imprecision in the gap would result in a 10% error in dose if a uniform field were to be delivered using a sliding window of 1 cm. For step-and-shoot delivery, magnitudes of dose errors are greater (owing to the steep dose gradients near the MLC leaf edges), but they are confined to the subfield edges. Thus, it is important that the manufacturers of MLCs used for IMRT ensure that the leaves can be positioned with accuracy of better than 0.25 mm, and the physicists must ensure through routine QA procedures that such precise positioning is achieved and maintained. It is interesting that integral dose error is similar for both the step-and-shoot and sliding-window techniques, but the distribution of the error is different.

Because MLC leaf calibration and the accuracy of MLC operations influence the delivered dose distribution, new, more rigorous MLC QA procedures have been developed. Chui et al.,¹¹⁷ LoSasso and Chui,¹¹⁸ and Ling et al.,⁵among others, have developed QA procedures specifically for MLCs used in dynamic mode. Periodic QA checks must ensure that the leaves of the MLC do indeed move to their designated positions at the specified values of MUs. Moreover, to ensure safe and accurate delivery of treatments with an MLC, the manufacturers must include redundant and independent sensors for the leaves of the MLC. Furthermore, in the event of treatment field interruption and resumption, there should be no perceptible change in dose delivered.

Another aspect of QA important for IMRT is the daily positioning uncertainty and motion during irradiation. IMRT is a highly conformal and highly precise form of radiotherapy frequently used to escalate dose. Dose distributions may have steep dose gradients between the target and the neighboring normal structures. Furthermore, margins may be much smaller than in conventional treatments. Patient positioning and immobilization requirements are more stringent than ever to ensure that the target volumes are covered adequately and the normal tissues are spared adequately. In fact, special immobilization devices and techniques are being developed to reproducibly and accurately position the target volume and normal anatomy. Many of these devices already are available commercially (e.g., rectal inserts to improve positioning for prostate IMRT).

Similarly, motion during treatment, mainly as a consequence of respiration, also can be a serious problem for IMRT of sites in the thorax and abdomen. Because IMRT is delivered dynamically, the moving target volume may move in and out of the instantaneous field of radiation. Some portions of the target volume may get more than the planned dose, whereas others may get less. A way to minimize effects of respiratory motion would be to use “gated treatments” in which radiation and leaf motion are turned on only during a specific, reproducible portion of the respiratory cycle or in an interval during which the patient’s breath is voluntarily, or involuntarily, held.¹¹⁹ New methodologies, typically employing CT imaging, are being used to synchronize patient breathing motion with the irradiation beam.¹²⁰^–¹²²

FIGURE 10.14. Overview of intensity-modulated radiation therapy quality assurance (QA) includes patient-specific and equipment-specific procedures. MLC, multileaf collimator.

FIGURE 10.15. Diagram illustrating dosimetric verification of individual intensity-modulated radiation therapy fields. DMLC, dynamic multileaf collimator; IMRT, intensity-modulated radiation therapy.

DOSIMETRIC VERIFICATION OF INTENSITY-MODULATED TREATMENTS

To implement a new treatment technology into routine clinical use, there are usually three distinct but closely related phases: Acceptance tests: This is the initial set of tests that ensures the hardware and software meet the factory- or customer-provided specifications. Usually, but not always, the written specifications contain the necessary instructions or guidelines for these tests (in order to avoid legal ambiguity in the measurements). It is also a good opportunity for the users to establish some performance baselines, especially for the hardware purchased. Commissioning tests: The IMRT commissioning is a process to implement IMRT treatments using the customer’s hardware and beam data. Various groups have studied the general guidelines for commissioning a treatment-planning system, and the AAPM issued a new report on IMRT commissioning in 2009.¹²³ The process usually starts with collection of essential beam data for beam modeling. The parameters of the dose-calculation algorithm are then tuned to provide the best performance for the user’s beam. Additional tests should be performed to evaluate the limitations of the treatment-planning system and a solution or a work-around should be found if the problem is clearly identified. Then IMRT phantom measurements should be performed to test the accuracy of the delivery system and data connectivity. If the accuracy is judged to be acceptable, the system can be released to the clinic after the necessary user training and procedural implementations. It is recommended that a small (interdisciplinary) focus group should be assigned to lead the IMRT implementation in the clinic. The “train-the-trainer” approach has proven to be effective in translating new technology into routine clinical practice.

Ongoing QA: After the system is released to the clinic, it is important to establish a routine QA program. The performance of various steps involved in performing IMRT treatments needs to be tracked so that the quality of the treatments can be maintained. The ongoing QA program can be separated into patient-specific QA and equipment QA, which will be described in more detail in the following section.

Patient- and Equipment-Specific QA

Because of the complexity of irregular field shapes, small-field dosimetry, and time-dependent deliverable leaf sequences, it is recommended by the AAPM and ASTRO that patient-specific QA should be performed as a part of the IMRT management process and a requirement for billing for IMRT services. Figure 10.14 shows the general categories of patient- and equipment-specific QA, which are detailed in the following.

Patient setup, although not specific to IMRT dosimetry, is considered a key step in ensuring accurate IMRT treatments. A variety of image-guided localization techniques have been proposed for use with IMRT treatments, from simple orthogonal portal films to the beam’s eye view portal film with IMRT intensity pattern overlays,¹²⁴ imaging of implanted fiducials,¹²⁵^,¹²⁶ daily ultrasound-guided localization,¹²⁷^–¹²⁹ and to the most integrated tomotherapy solutions.¹³⁰ The detailed discussion of these specific image-guided procedures is out of the scope of this chapter, but QA in patient positioning remains an important issue for IMRT. A somewhat related problem of organ motion due to breathing has been discussed earlier. Several recent studies have examined the use of cone beam CT for patient setup or respiratory gating.¹³¹^–¹³⁴ The implementation of patient-specific QA depends highly on each institution. For example, dosimetric measurements of MU settings can be verified for each beam individually (usually in a flat [slab] phantom geometry) or for the composite treatment plan (usually in a specially designed phantom, but it is also possible to use the simple slab phantom setup). Unlike single-beam verification in which the single-beam dose distribution can be significantly different from the original patient plan, the advantage of measuring the composite treatment plan in a phantom (regardless of the shape of the phantom) is that the composite dose distribution or the dose “pattern” generated in a phantom is usually similar to those in the original patient plan. This can be useful in selecting the measurement points or in visualizing potential dose errors. Absolute dosimetry is usually referred to as “MU verification” for IMRT. The traditional manual process for MU verification is virtually impossible to perform because of the large number of fields involved and the irregular shape and size of the treatment segments. Attempts have been made to verify MU settings in an IMRT plan using alternative calculation methods.¹³⁵ However, these alternative calculation methods cannot predict the uncertainties during the actual delivery at the treatment machines and are also subject to limitations and approximations in their dose-calculation models. The most reliable and practical technique currently for IMRT MU verification is still the ion chamber-based point dose measurement in a phantom. Absolute dose measurement in a phantom is usually performed through a process called the hybrid phantom plan. In this plan, all beam angles and deliverable intensity patterns for a patient plan are transferred to the phantom, and doses in the phantom are computed for QA. The basic assumption in this process is that if the dose calculated in the phantom agrees with the measurement in the phantom, then the dose delivered to the patient agrees with the dose calculated in the patient. Relative dosimetry is usually performed using radiographic films or 2D array detectors. The process is similar to absolute dose measurement using the hybrid phantom plan technique. For film dosimetry, it is important to convert film density into relative dose using a film calibration process. Because of the additional dimensionality, it becomes difficult to define good numerical criteria for evaluating relative 2D/3D measurements. Various numerical indicators (such as the distance to agreement, and gamma, or normalized agreement test) were proposed. In particular, the concept of gamma, combining the dose difference and distance to agreement, is appealing in evaluating 2D or 3D dose distributions. For clinical applications, the most reliable and practical way to evaluate 2D distribution is to overlay the measurement isodose lines with the calculated ones. Special attention should be paid to the low-dose regions near critical structures in the original patient plan. Attention should also be paid to the systematic shifts of isodose lines, which may reveal if the isocenter or any reference setup point may be off. The relative dosimetry verification for IMRT should be performed in conjunction with the absolute dose verification for IMRT. It would be useful if the relative dose distribution can be normalized to the absolute dose measurement point, which converts the relative dose measurement into absolute dose distributions.

Two-dimensional fluence verification of intensity patterns gained popularity with the invention of 2D array detectors and the necessary software.¹³⁵^–¹³⁷ Fluence verification usually is performed for each IMRT beam at a fixed-gantry angle with or without a flat phantom geometry. The purpose of fluence verification is to make sure the intensity patterns created in each IMRT plan can be faithfully delivered under ideal conditions (2D, beam’s eye view). Fluence verification should be combined with other patient-specific and equipment QAs to make sure that IMRT treatments are executed accurately.

Figure 10.14 also illustrates equipment-specific QA procedures. In general, IMRT QA is a subset of general equipment QA processes. The technology of IMRT and techniques for QA are also evolving. It is strongly suggested that users of IMRT should attempt to attend national meetings and technology conferences or training courses so that their knowledge about the use of IMRT can be updated regularly.

IMRT has been variously termed as opaque, unintuitive, and nontransparent, partly because it is delivered using dynamic techniques. Many are skeptical about whether the dose distribution displayed on an IMRT plan is, in fact, delivered. Furthermore, because of the complexity of computations involved, there is no practical way to verify the MU settings by hand calculations, as is done for conventional treatments. Moreover, because of the inherent nonuniformity of IMRT fields, it is important to know the dose accurately at every point within the beam. One way to check if the intended dose would be delivered to the patient at the time of the treatment is to conduct dosimetric verification measurements.

Two broad categories of IMRT treatment-plan verification approaches have been developed for MLC-based IMRT. First, the dose distribution from radiation fields is independently measured and evaluated. This often is accomplished by using a flat homogeneous water-equivalent phantom and irradiating each field independently. The film-measured dose distributions are compared against calculations conducted by the treatment-planning system under the same geometric conditions. The process is explained in Figure 10.15. For calculation of dose distributions, each field is transferred to a treatment plan with a flat homogeneous phantom. A typical example for a sliding-window intensity-modulated beam dosimetric verification is shown in Figure 10.16. This technique has the advantage that discrepancies between the planned and delivered dose can be attributed to individual radiation portals. However, the total integrated dose distribution is not checked.

The second method uses a phantom that is irradiated by all beam portals, allowing the evaluation of the total dose distribution delivered.¹³⁸^,¹³⁹ Typically, ionization chambers and radiographic film are the dosimeters used for these measurements. Although ionization chambers can be benchmark-quality dosimeters, they suffer from volume averaging and are inefficient for measuring multiple points. Because of the complexity of the dose distributions being measured, a 2D dosimeter is required for thorough evaluations of nonuniform dose distribution. Quantitative radiographic film measurements require careful dose calibrations using independently measured sensitometric curves. The film optical densities are measured and converted to absolute dose using film calibration data and compared with the predictions of the treatment-planning system.⁴⁴

In vivo dosimetry commonly is used to verify the dose delivered by conformal therapy radiation fields. The complex fluence distribution of IMRT fields makes quantitative use of in vivo dosimetry, specifically the use of skin surface–mounted dosimeters, difficult.

Film, thermoluminescent dosimeters, and diodes may not be sufficiently accurate; are laborious to use; and, in the case of thermoluminescent dosimeters and diodes, are incapable of providing detailed information. In the long run, the most efficient way to verify fixed intensity-modulated fields is expected to be with real-time 2D dosimetry systems using appropriately calibrated electronic portal imaging devices (EPIDs). A general review of EPIDs has appeared recently.¹⁴⁰ Such devices could be used for dosimetric verification of IMRT beams before treatment delivery and for exit dosimetry using transmitted portal dose images (PDIs). For electronic portal imaging devices to be used for pretreatment dosimetric verification and exit dosimetry, they must operate in the integration mode to capture the transmitted radiation over the entire exposure of each beam. The result is a PDI that can be compared with an intensity-modulated digitally reconstructed PDI. For pretreatment dosimetric verification of a given beam, a PDI may be created using a 3D treatment-planning system to compute dose deposited in the electronic portal imaging device detector. For exit dosimetry, the PDI may be calculated using the 3D CT image of the patient. In either case, for accurate dosimetric verification, the effect of scattered radiation and the variation in response of the detector with energy must be included. The former effect can be taken into account with dose-spread kernel superposition methods, but both can be accounted for using Monte Carlo techniques.

FIGURE 10.16. Dosimetric verification example comparing measured and calculated dose profiles of a right-lateral field generated with sliding-window technique for the intensity-modulated radiation therapy of gynecologic cancer.

TREATMENT SETUP AND DELIVERY

Fixed-Gantry Intensity-Modulated Fields

As for conventional radiotherapy, for IMRT techniques using fixed intensity-modulated fields, it is necessary to verify the patient alignment using portal images with beams used for actual treatment before the delivery of the first treatment and then periodically thereafter. However, no beam apertures are required for IMRT. Therefore, special fields for portal imaging with apertures are created in which the shape of each aperture is defined by the terminal positions of the leading leaf tips and the starting positions of the trailing leaf tips.

Intensity-modulated treatments may be delivered remotely or automatically under computer control. The treatment machine computer may automatically set up the various components of the machine and switch on the radiation beam. For the sliding-window technique, it moves leaves during irradiation in the sequence specified in the leaf motion dataset. In the step-and-shoot mode, the radiation pauses while the leaves move. At the completion of the first field, the computer sets the machine for the next field and again goes through its leaf motion sequence and irradiation. This process is repeated until all fields are delivered. The treatment times may vary somewhat and depend on the number of fields involved and the complexity of the fluence distribution. Current time estimates range from 5 to 20 minutes, excluding patient setup.⁴^,⁵^,⁴⁴

SETUP AND IMRT DELIVERY WITH SERIAL TOMOTHERAPY

Current delivery of serial tomotherapy is concisely described in a recent review.¹⁴¹ A new-generation serial treatment machine with multiple photon heads as well as an electron source has been described by Achterberg and Müller.¹⁴² Because there are no specific beam directions or portals associated with serial tomotherapy beam delivery, the treatment QA concentrates on patient positioning and immobilization. The add-on multileaf collimator (MIMiC) is relatively heavy and its removal is time consuming, so portal films often are acquired with the MIMiC in place. This limits the portal fields to a roughly 3.4 × 20 cm² field size. Therefore, the imaging of useful, immobile, bony anatomic landmarks is critical for each port film, meaning that the selection of the portal film locations is critical to the accurate determination of patient-treated indices, but the digitally reconstructed radiograph that is used to compare against the portal film must be simulated at the same relative couch position as the portal film is acquired. Typically, anteroposterior and lateral films are acquired, and if the target is longer than 10 cm and is in a location where patient structures are flexible (e.g., in the neck), portal films may be required at multiple couch positions to ensure the patient is in the correct orientation throughout the length of treatment.

Treatments are conducted by placing the patient on the couch and aligning the patient to the linear accelerator in the standard fashion. Once the patient is aligned (to a point analogous to isocenter for conventional treatments), the couch translation device (called CRANE) coordinates are set to zero and the couch is moved to the location of the first index. This position is determined by the treatment-planning system. The gantry is rotated to the starting arc position, and the patient treatment plan is loaded onto the MIMiC control computer. The linear accelerator is operated in normal arc mode, and the MIMiC control computer determines if the treatment can proceed. If the gantry speed is within acceptable limits, the MLC leaves are opened in their programmed sequence. The MIMiC communicates with the linear accelerator using the conventional door interlock. If the MIMiC control computer determines the treatment should not continue, the door interlock circuit is interrupted and the linear accelerator ceases operation just as if the door had been opened (the door interlock fault is tripped on the accelerator). Once the arc is delivered, the therapist enters the room to move the CRANE to the next couch position and reprograms the MIMiC control computer by following the screen prompts.

TOMOTHERAPY VERSUS FIXED-GANTRY IMRT

The physical and operational differences between tomotherapy and fixed-gantry IMRT lead to trade-offs when considering each system. The rotational beams used in tomotherapy could be a significant advantage until robust beam configuration optimization tools are developed, particularly those involving noncoplanar beams.

For serial tomotherapy delivery, one of the difficulties is the requirement of precisely moving the patient between successive arc deliveries (couch indexes). The dose-delivery error made for an incorrect junction move is similar to the errors in abutting conventional fields. Studies have shown that the maximum dose error is 25% mm⁻¹ in the abutment region for errors in couch index movement or intrajunction patient motion.¹⁴³ When conventional fields are abutted, feathering often is used to reduce the risk of systematic dose errors. A similar technique has been suggested for distributing the abutment regions for serial tomotherapy¹⁴⁴ by creating multiple treatment plans with modified target volumes to force a redistribution of indexes.

Even when perfectly abutted, there are dose heterogeneities within the abutment region caused by the divergent radiation fields, especially when arcs of less than 360 degrees are used. Low et al.¹⁴³ studied the abutment region dose distributions for arcs ranging from 180 degrees to 340 degrees and determined that the tumor doses can have significant cold spots when short arcs are used. These become more severe when the longer leaf setting (1.7 cm) is used. The accuracy of the treatment-planning system in predicting these heterogeneities was not evaluated, but the system tends to underestimate the severity of the heterogeneities. Although the divergence in the radiation beams is still present in helical tomotherapy, the helical path of the field edge distributes the diverging distribution such that dose errors caused by inaccuracies in couch motion, or by patient movement, are significantly smaller than with serial tomotherapy.

One of the advantages of fixed-gantry IMRT is the availability of noncoplanar directions. The commercial hardware device used to precisely move the couch between successive indexes also is produced in a model that attaches directly to the couch, allowing for couch rotations. Although limited noncoplanar dose delivery is possible when using serial tomotherapy, especially when treating the brain, this has not been widely adopted.

Gating for serial tomotherapy is impractical because of the use of conventional linear accelerators and the lack of shared information between the MLC and the linear accelerator control computers. Breath-hold techniques are also impractical because of the relatively long time to rotate the linear accelerator gantry. Because of the potentially large abutment-region dosimetry errors, it is important to consider the immobilization accuracy of targets and critical structures when selecting targets for serial tomotherapy. Gating for helical tomotherapy is possible by pausing the radiation beam and the couch motion when the gating circuitry dictates that no treatment should be delivered. However, there will be a delay in restarting the treatment after the gating signal has been restarted while waiting for the gantry to return to its position when the gating signal was interrupted.

Because the dose is delivered over many indexes or gantry rotations, there are many more MUs used when treating with tomotherapy than for conventional 3DCRT or MLC-based IMRT. The ratio of MUs can be as high as 10:1 even when compared with MLC-based IMRT.¹⁴⁵ This increase in MUs leads to increases in whole-body dose that may yield a significant increase in secondary radiation-induced malignancies. The solution to this is to improve the linear accelerator head shielding, the source of most of the whole-body dose in tomotherapy.

Another limitation of tomotherapy is the lack of electron beams. Electron beams (including energy and intensity-modulated electron beams), by themselves or in combination with intensity-modulated photon beams, currently are employed in the treatment of both breast and skin cancers.

A major advantage of helical tomotherapy is that it is a dedicated IMRT device. However, MLC-based IMRT is likely to compete as a delivery mode resulting in part from the limitations of tomotherapy discussed earlier. Furthermore, the large base of MLC-mounted linear accelerators will mean that the adoption of tomotherapy for significant numbers of IMRT patient treatments will take many years.

SPECIAL REQUIREMENTS OF FACILITY DESIGN FOR IMRT

The room-shielding design characteristics for IMRT delivery are different than those for conventional radiotherapy. Shielding requirements are determined separately for primary and scattered radiation barriers and for tomotherapy and MLC-based IMRT. For MLC-based IMRT, the total integrated radiation fluence remains similar to that used in conformal therapy, so no change in primary barrier thicknesses is expected. However, the increase in MUs of about a factor of 3 is expected to increase the required secondary shielding barrier attenuation, at least until the linear accelerator manufacturers improve the head leakage characteristics. For serial tomotherapy without a beam stopper, the same primary barrier is struck for each couch index, indicating that an increase in primary barrier thickness may be required. However, the use of a rotating beam, and the relatively small angle subtended by the MIMiC, reduces the effective use factor to the point that it almost exactly cancels the number of times the beam strikes the primary barrier. Increases in secondary shielding, however, may be greater than for IMRT because the total number of MUs is significantly greater.

CLINICAL EXPERIENCE WITH IMRT

IMRT of Head and Neck Cancer

The first report of the application of IMRT to head and neck neoplasms was from Baylor College. Kuppersmith et al.¹⁴⁶ reported a decrease in dose to the parotid glands to <30 Gy in 28 patients treated with IMRT using serial tomotherapy. They also found the incidence of acute toxicity to be drastically lower than with conventional radiation therapy. Later, Butler et al.¹⁴⁷ implemented the “simultaneous modulated accelerated radiation therapy”¹⁴⁸technique, an equivalent of the SIB technique, and found that 19 out of 20 patients treated had complete response with acceptable toxicity. Low et al.¹⁴⁹ have described the application of the serial tomotherapy technique and QA practices for head and neck treatments at Washington University in St. Louis. Preliminary results of the use of these techniques for 17 patients were reported by Chao et al.¹⁰¹ and showed that the tumor control is promising with no severe adverse acute side effects. A subsequent prospective clinical study conducted by Chao et al.¹⁵⁰ also showed that the sparing of parotid glands translated into objective and subjective improvement of both xerostomia and quality-of-life scores in patients with head and neck cancers treated with IMRT.

In another study, Chao et al.¹⁵¹ also reported the dosimetric advantage of IMRT treatment in patients with oropharyngeal carcinoma (260 with primary tumors in the tonsil and 170 with primary tumors at the base of the tongue). No adverse impact on local control or disease-free survival (DFS) was seen, but there was a significant reduction of late salivary toxicity. Fixed-field IMRT and serial tomography gave superior GTV coverage and lower parotid doses compared to conventional RT in nasopharyngeal cancer.¹⁵² Groups at Memorial Sloan-Kettering¹⁵³ and UCSF¹⁵⁴ found similar results for nasopharyngeal patients. IMRT likewise showed promise for oral and oropharyngeal caner¹⁵⁵and in dose escalation studies of head and neck squamous cell carcinoma.¹²^,⁸⁷ Examples of target delineation for nasopharyngeal and hypopharyngeal cancer are shown in Figures 10.17 and 10.18, respectively.

Since the early part of the past decade, IMRT usage in head and neck cancers has become ubiquitous. The Web of Science database records 135 papers with “head and neck” and “IMRT” in the title from 2002 through 2011. Of these, 102 appeared in or after 2006. Recent review articles pertaining to head and neck cancers include the following: Lee and Terezakis¹⁵⁶ in 2008 and Maingon et al.¹⁵⁷ in 2010. Lu and Yao found improved quality of life and survival benefit in IMRT treatment of nasopharyngeal cancer.¹⁵⁸ Reviews focused on quality-of-life issues include Scott-Brown et al.¹⁵⁹ and Tribius and Bergelt;¹⁶⁰ swallowing issues are reviewed by Roe et al.¹⁶¹ Early work by Chao et al.¹⁵⁰^,¹⁵¹ showed significant reduction in salivary gland toxicity in the IMRT-treated patients. Nutting et al.¹⁶² reported the results from a head-to-head phase III trial of IMRT versus conventional radiation therapy in patients with pharyngeal squamous cell carcinoma (T1–4, N0–3, M0). The IMRT arm showed significantly less grade 2 (or worse) xerostomia compared to radiation therapy: at 12 months, 74% for radiation therapy versus 38% for IMRT; at 24 months, 83% for radiation therapy versus 29% for IMRT. At 24 months, no significant differences were seen in other toxicities or in local control or overall survival.

FIGURE 10.17. Intensity-modulated radiation therapy (IMRT) target delineation for stage T2N2 nasopharyngeal cancer. Three axial slices are shown.

This raises a question—given the increased complexity and cost in equipment and physician time for IMRT compared to conventional radiation therapy, is the improvement in quality of life alone worth the cost? This was the raison d’être for the study by Tribus and Bergelt.¹⁶⁰ The answer is obviously yes for the patient. More to the point, what possibilities are there for improvement of outcome in survival and locoregional control? IMRT by itself is still radiation therapy—the photon sources do not have the coherence of an optical laser, so there are beam-edge effects and also beam scattering from the MLC leaves and within the patient’s body as the depth increases. This puts limits on the dose gradients that can actually be achieved, and if OAR sparing is to occur it will mean less homogeneous doses to the GTV. There are several ways to approach this problem:

1. Better imaging during a course of treatment. Changes in tumor size and/or location during treatment will require imaging to adjust the IMRT plan. Various promising imaging modalities useful for radiation oncology were reviewed by Apisarnthanarax and Chao;⁵⁷ more recently Moeller et al.⁶⁰ reported on a prospective trial using FDG-PET and CT imaging in head and neck cancer. Cone beam CT has also been reviewed recently.¹⁶³

2. Accelerated fractionation. Here one makes use of the radiobiologic advantages of IMRT¹³ to perform dose escalation to tumor while constraining the dose to critical normal tissue. Ling et al. have discussed the effects of dose rate in terms of the widely used linear-quadratic model.¹⁶⁴ Chakraborty et al.¹⁶⁵^,¹⁶⁶ observed 95% disease-free survival in 20 patients with squamous cell carcinomas at various head and neck sites, but the SIB group treated at a higher dose did have more acute toxicities.

3. Combined-modality treatment. Combined chemotherapy and radiation treatment is the current approach for locally advanced head and neck squamous cell carcinoma.¹⁶⁷ Chemoradiation for locally advanced head and neck disease has also been reviewed by Seiwert et al.¹⁶⁸ Traditionally cisplatinum compounds have been used, but attention is turning to antiangiogenesis agents and epidermal growth factor receptor inhibitors. Similar themes were expressed in the 2008 Southwest Oncology Group report.¹⁶⁹ Riesterer et al. discuss the last decade of work on chemosensitization with molecular signaling agents followed by radiation.¹⁷⁰

Thus far, we have only considered photon irradiation since that is what is used in the overwhelming majority of external radiation treatments. New technologies, in particular beams of charged heavy ions (protons or carbon), show promise due to their highly depth-dependent energy deposition profile (the spread-out Bragg peak). Thariat et al. recently published a concise review of these and other techniques as applied to head and neck cancers.¹⁷¹ Heavy ion beam therapy is very costly and available only at a few centers, so in the immediate future it will likely be limited to those cases such as malignancies close to the eyes or optic chiasm where photon beams cause unacceptable vision loss.

FIGURE 10.18. Intensity-modulated radiation therapy (IMRT) target delineation for stage T2N1 hypopharyngeal cancer. Four axial slices are shown; the spinal canal is contoured in orange.

IMRT of Prostate Cancer

The prostate is another organ with closely associated nerves and other structures (seminal vesicles, urethra, bladder, and rectal wall), the impairment of which can cause important quality-of-life issues. The prostate was in fact one of the first targets of IMRT in the work of Ling et al. at Memorial Sloan-Kettering.⁴^,⁵

Studies involving hundreds of patients followed: in 2000, Zelefsky et al.¹⁷² demonstrated superior target coverage with IMRT compared to conventional RT and 3DCRT; in 2002 they reported a larger study showing the feasibility of high-dose IMRT with reduced acute toxicities¹⁷³:

A total of 772 patients were treated: 698 to 81.0 Gy and 74 to 86.4 Gy. Acute grade 2 rectal toxicity was seen in 35 (4.5%), but none at grade 3 or above. Acute grade 2 urinary symptoms developed in 217 patients (28%), but only 1 patient with grade 3 problems. Late rectal bleeding (grade 2) was experienced by 11 patients (1.5%). PSA relapse-free survival rates (3-year actuarial) were 92%, 86%, and 81% for the favorable, intermediate, and high-risk groups, respectively. This early work was extended by other workers,¹⁷⁴^,¹⁷⁵ and the field has been extensively reviewed.¹⁷⁶^–¹⁷⁸

As with head and neck and other organ sites, concurrent chemotherapy is being used both to sensitize malignant cells for radiation treatment and to eradicate micrometastatic disease. This is used for patients at high risk, with aggressive cancers refractory to hormonal treatment or irradiation alone. For a recent review, see Sanfilippo et al.,¹⁷⁹ who reported on a phase I/II trial in 22 patients with locally advanced hormone-ablated disease (T1–3). Paclitaxel was given biweekly, with four-field 3DCRT starting at 63 Gy and escalating to 66.6, 70.2, and 73.8 Gy. Acute toxicities included diarrhea (mostly grade 1 and 2, but with grade 3 in four patients); at 38 months, 21 (95%) were alive. But six of 22 (27%) had developed relapsed disease. Tucker et al.¹⁸⁰^,¹⁸¹ analyzed Radiation Therapy Oncology Group (RTOG) 9406 data to obtain Lyman NTCP parameters and the linear-quadratic α/β ratio for late rectal toxicity in prostate-irradiated patients.

The treatment of prostate cancer has been greatly impacted by advances in magnetic resonance, both standard MRI and magnetic resonance spectroscopic imaging (MRSI). This growing field has been extensively reviewed; for two recent articles, see Sciarra et al.¹⁸² and Mazaheri et al.180.¹⁸³ MRI and MRSI are noninvasive imaging modalities that depend on the resonant absorption of radiofrequency energy by nuclei with magnetic moments (normally protons, and also 31-P). The exact resonant behavior of each nucleus depends on the total magnetic field at its location, and this in turn is a combination of the external field of the instrument and the internal magnetic variations caused by the molecular structure in which the nucleus exists. Tumor tissues can be distinguished from normal tissues by differences in the intrinsic nuclear spin relaxation times (T1 and T2), and this can be used to accentuate (or eliminate) their magnetic resonance signals. Thus, magnetic resonance can often “see” details of the prostate tumor that are not observable on a CT scan. MRI can be used for much more precise tumor target delineation for IMRT than would otherwise be possible, and this has had significant clinical impact.

IMRT of Intracranial Malignancies

With FDG-PET and/or MRI, tumors within the brain can be visualized more clearly than on CT. Given the desire to avoid extensive neurologic damage, IMRT is expected to offer some advantages in sparing normal tissues and possibly improving the often bleak prognosis of central nervous system cancer patients. For example, Gutierrez et al. reported a planning study with tomotherapy to provide an integrated boost to whole-brain irradiation in an effort to spare the hippocampus.¹⁸⁴

Iuchi et al.¹⁸⁵ from Japan published a retrospective report on 25 patients with malignant astrocytomas (World Health Organization grade III and IV) treated with IMRT using a hypofractionated regimen of 48 to 68 Gy in eight fractions. Thirteen patients were treated to 68 Gy and 12 patients received doses of 48 to 65 Gy. The IMRT group was compared to 60 patients treated with conventional techniques to doses of 40 to 60 Gy using 2 Gy daily fractions. The 2-year overall survival was significantly improved (p = .043) in patients treated with hypofractionated IMRT (55.6%) compared to those patients treated with conventional techniques (19.4%).

Huang et al.¹⁸⁶ reported on 15 patients with pediatric medulloblastoma treated with conventional craniospinal radiotherapy followed by a boost to the posterior fossa using IMRT. IMRT delivered much lower doses of radiation to the auditory apparatus while maintaining full doses to the desired target volume. Their findings suggested that, despite receiving higher doses of cisplatin and despite receiving radiotherapy before cisplatin therapy, IMRT can significantly decrease the rate of hearing loss in children treated for medulloblastoma.

Glioblastoma multiforme (GBM) has a very poor outcome, with a median survival of 9 to 11 months following resection.¹⁸⁷ Floyd et al.¹⁸⁸ used hypofractionated IMRT tomotherapy to treat 20 patients with primary disease. Fifty Gy in 10 daily fractions was given with 30 Gy (10 fx) to surrounding edema. Time to disease progression was 7 months, so no gain in survival was seen, but the treatment time was reduced from 6 to 2 weeks. Stupp et al.¹⁸⁹ studied outcomes in GBM patients after resection who were treated with RT with or without adjuvant temozolomide: the chemoradiation group had a median survival of 14.6 months compared to 12.1 months with RT alone. A review of temozolomide therapy for brain tumors was recently done by Koukourakis et al.¹⁹⁰ Amelio et al.¹⁹¹ have recently reviewed the use of IMRT, including hypofractionation, in the treatment of glioblastoma. They concluded that there is clinical advantage with IMRT because higher doses can be given in shorter times without increasing toxicity.

IMRT of Breast Cancer

RT for breast cancer poses challenges, in particular large differences in tissue thickness in the radiation field and the close proximity of the lung apex and the heart, coupled with target motion during the breathing cycle. Taylor et al.¹⁹² reviewed excess mortality due to cardiac damage in patients treated from 1950 through 1990, when cardiac doses of up to 14 to 17 Gy were given. In addition, part of the radiation field contains the skin boundary between tissue and air. Because air scatters much less of the x-ray fluence, there can be significant dose inhomogeneities and overdosing of the skin (“skin flash”). Commercial systems are now available that can autocontour the volume of breast tissue within conventionally designed tangential photon portals and then use an inverse-planning algorithm to optimize dose homogeneity within these tangential portals. However, most commercial inverse planning systems could not handle the “skin flash” appropriately. Due to setup uncertainties and breathing motion, a portion of the breast (target) tissue may move outside the skin line as indicated by the treatment-planning CT images of the patient. The traditional IMRT technique to overcome target motion uncertainty is to expand the PTV and optimize the dose coverage to the entire PTV. However, this strategy may not work because a portion of the PTV will be expanded into the air, which does not have the necessary mass to absorb the dose. Some treatment-planning systems ignore the regions outside the skin contour entirely. Therefore, it may be necessary to add “virtual” tissues in the PTV for the inverse-planning system. Sometimes it may require users to manually open certain IMRT segments to take care of the skin flash effect.

Nevertheless, there has been interest in using IMRT for left-sided breast cancers in order to spare myocardium from the high-dose region of the radiotherapy fields. The Guerrero Urbano and Nutting IMRT review includes a concise summary of early work through about 2002.¹⁹³ No robust data regarding clinical outcomes after IMRT for breast cancer exist; however, a variety of dosimetric studies¹⁹⁴^–¹⁹⁸^,¹⁹⁹^,²⁰⁰ have suggested reductions in lung and myocardium doses when IMRT is compared to conventional radiotherapeutic techniques. Hurkmans et al.²⁰¹ used an NTCP model to estimate the NTCP for cardiac and lung complications due to radiotherapy and found that IMRT did decrease the NTCP for late cardiac toxicity compared to more conventional radiotherapy techniques but had a minimal effect on the NTCP for radiation pneumonitis.

Hong et al.¹⁹⁶ reported a dosimetric study of IMRT in 10 cases of intact breast cancer showing significant reduction of dose to the coronary arteries, ipsilateral lung, and surrounding soft tissues. It simultaneously improved dose homogeneity throughout the target volume. Li et al.¹⁹⁷ described a combined electron and IMRT technique for breast cancer treatment, which led to improvement over the conventional treatment technique using tangential fields with reduced dose to the ipsilateral lung and the heart. Other studies¹⁹⁵^,²⁰⁰ also confirmed that IMRT reduces the high-dose volume in tangential breast irradiation significantly and enables more complete cardiac sparing without compromising PTV coverage in some patients. Furthermore, IMRT creates a possibility to improve field matching in case of multiple field irradiations of the breast and lymph nodes.²⁰⁰^,²⁰²^,²⁰³ In addition, IMRT for tangential breast radiation therapy was found to be an effective and efficient method to achieve uniform dose throughout the breast. Preliminary findings reveal minimal or no acute skin reactions for patients with different breast sizes in 32 patients with early-stage breast cancer.²⁰² Taylor et al.²⁰⁴ reviewed results of RT of breast cancer patients in 2006 and found that use of more modern planning had significantly reduced mean heart doses to 2.3 Gy but that a small part of the heart still received more than 20 Gy in left-sided irradiation.

IMRT of Gynecologic Cancer

In regard to the targeting of pelvic lymphatics with IMRT, Taylor et al.²⁰⁵ mapped the pelvic lymphatics of 20 patients using MRI with the administration of iron oxide particles and found that a modified CTV margin of 7 mm around the iliac vessels resulted in adequate coverage of the pelvic lymphatics.

Ahamad et al.²⁰⁶ analyzed the normal tissue-sparing effects of IMRT in the treatment of the pelvis after hysterectomy in patients with gynecologic cancers and found that although more small bowel, bladder, and rectum could be spared with IMRT compared to conventional radiotherapeutic techniques, these benefits rapidly diminished with even small expansions of the target volumes. D’Souza et al.²⁰⁷ used the same dataset of patients as Ahamad et al.²⁰⁶and found that IMRT may allow higher doses of radiation (54 Gy) to be delivered safely to the node-bearing regions of the pelvis and the vaginal apex compared to conventional techniques that administer 50.4 Gy. Gielda et al.¹⁴⁸reported on a small study of gynecologic cancer patients ineligible for brachytherapy who were treated with tomotherapy in an attempt to reduce toxicity to bowel and femoral heads.

Salema et al.²⁰⁸ reported on 13 patients treated with extended field pelvic and para-aortic radiotherapy using IMRT and found that two patients experienced grade 3 or higher toxicity. Both of these patients received concurrent cisplatin-based chemotherapy.

Portelance et al.²⁰⁹ reported dosimetric comparison between 3DCRT and IMRT for 10 patients with cervical cancer. They demonstrated that, with similar target coverage, normal tissue sparing was superior with IMRT. Mundt et al.²¹⁰ reported the clinical experience of 40 patients with gynecologic malignancy who underwent IMRT to the pelvis. Compared with 35 historic control patients who were treated with conventional techniques, patients treated with IMRT experienced fewer acute gastrointestinal (GI) symptoms than those treated with conventional whole-pelvic radiotherapy. The ability of IMRT to deliver local control while reducing grade ≥2 bowel toxicity was shown in a recent report by Portelance et al.²¹¹ from the multi-institutional RTOG 0418 cervical cancer trial. Ring et al.²¹² did a study on 36 patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB2 to IIIB cervical cancer. They were treated with extended-field RT with concurrent cisplatin to target suspicious pelvic or para-aortic lymph nodes or excessive local pelvic tumor burden. At 32 months, 24 patients were disease free and an additional eight were still alive but with disease.

IMRT of Gastrointestinal Cancer

Pancreatic cancer remains a disease with a poor prognosis. In 1995 Lillemoe²¹³ reviewed then-current disease management. By this time mortality from surgical resection had been reduced to 2% or 3%, but the weighted-average 5-year overall survival was still only about 22%. In 2011, Showalter et al.²¹⁴ reanalyzed the data from RTOG 9704 on the results of surgical resection and adjuvant chemoradiation. Interpolating their Figure 2, one can estimate 5-year overall survival as about 28% for node negative and 19% for one to three positive nodes—not significantly different in 15 years.

Crane et al.²¹⁵ attempted a dose-escalation study with RT and gemcitabine in unresectable pancreatic cancer patients but had to discontinue due to dose-limiting toxicity.

Ben-Josef et al.²¹⁶ reported on 15 patients with pancreatic cancer treated with concurrent capecitabine and IMRT (45 to 55 Gy) and reported that only one patient had grade 3 GI toxicity, specifically GI ulceration, which responded to medical management.

Brown et al.²¹⁷ performed a dosimetric analysis of 15 patients with pancreatic cancer and compared 3DCRT, IMRT with sequential boost, and IMRT with integrated boost and found that IMRT with integrated boost allowed dose escalation up to 64.8 Gy to the primary tumor. More recently, Yovino et al.²¹⁸ reported that IMRT produced a statistically significant reduction in upper and lower GI toxicity compared to 3DCRT in chemoradiation treatment following RTOG 9704 guidelines.

IMRT for gastrointestinal cancers (including pancreas) was recently reviewed by Bockbrader and Kim²¹⁹ from the radiobiologic and dosimetric as well as clinical outcomes viewpoint. Meyer et al.²²⁰ gave the rationale for IMRT with PET/CT in anorectal cancers as to reduce radiation-associated morbidity. They also present some clinical data.

Guerrero Urbano et al.²²¹ performed a dosimetric evaluation in five patients with locally advanced rectal cancer and found that IMRT with simultaneous integrated boost theoretically reduced the radiation dose to the small bowel compared to 3D conformal techniques. Milano et al.²²² reported on 17 patients with squamous cell carcinomas of the anal canal treated with IMRT with whole-pelvic radiation does of 45 Gy followed by boost to the anal canal. Thirteen patients received concurrent 5-fluorouracil and mitomycin-C chemotherapy. Treatment was well tolerated with no grade 3 or higher nonhematologic toxicity and no required treatment breaks from skin or GI toxicity. However, one patient receiving mitomycin-C chemotherapy did experience grade 4 hematologic toxicity. Three patients who did not achieve a complete response required abdominoperineal resection and colostomy. With a mean follow-up of 20.3 months, there were no other local failures.

Milano et al.²²³ also reported on seven patients with gastric cancer treated with IMRT to a dose of 50.4 Gy. No patient experienced grade 3 toxicity. The treated IMRT plans were compared to conventional anteroposterior/posteroanterior and three-field plans, and the IMRT plans were found to provide better coverage of the target volumes compared to conventional techniques, with better sparing of the liver and kidneys.

IMRT of Lung Cancer

Because of concerns regarding respiratory motion in radiotherapy of lung cancer, the use of IMRT in lung cancer requires some method to account for tumor and organ motion during treatment planning and delivery; these techniques include both respiratory gating¹²⁰ and four-dimensional CT planning.²²⁴ Starkschall et al.²²⁵ recently reported direct 4D CT measurements of interfraction GTV movement during free breathing and concluded that breath-hold gating provides reproducible tumor localization. With cone beam CT or orthovoltage x-ray, the appropriate margins are 0.3 cm for implanted fiducials and 0.8 cm for bony landmarks.

The poor local control rates of conventional radiotherapy doses in the treatment of lung cancer²²⁶ have led to much interest in using IMRT to allow for dose escalation to improve local control. Holloway et al.²²⁷ reported the initial results of five patients with unresectable stage II and III non–small-cell carcinoma treated on a phase I dose-escalation trial using induction chemotherapy followed by IMRT to a dose of 84 Gy using 2.4 Gy daily fractions. PET CT was used to define target volumes. One patient developed lethal radiation pneumonitis and the trial was halted. Murshed et al.²²⁸ performed a dosimetric analysis of 41 patients initially treated with 3DCRT to a dose of 63 Gy. IMRT plans were then generated using these patients’ initial planning CT scans, and IMRT was found to decrease the volume of lung irradiated to both 10 and 20 Gy. Target coverage was improved with IMRT, and the volumes of heart and esophagus irradiated were also reduced. Figures 10.19 and 10.20 illustrate MLC portals and IMRT treatment plans for lung cancer.

Grills et al.²²⁹ performed a dosimetric comparison of four radiotherapy techniques in 18 patients with stage I–IIB lung cancer. The study compared IMRT, optimized multiple-beam 3DCRT, two- to three-beam 3DCRT, and traditional wide-field radiotherapy with elective nodal irradiation. This study found that IMRT and optimized 3DCRT resulted in similar doses of radiotherapy to normal tissues in node-negative patients; however, in node-positive patients, IMRT resulted in a 15% decrease in the volume of lung treated to 20 Gy (V_{20 GY}) and a 30% decrease in the NTCP for radiation pneumonitis. In 2010, Liao et al.²³⁰ reported the outcomes of 409 non–small-cell lung carcinoma patients treated at MD Anderson. Three hundred and eighteen patients received CT/3DCRT and 91 received 4D CT/IMRT to a median dose of 63 Gy. The mean lung dose was slightly higher for the IMRT group (24.9 Gy compared to 22.1), but the mean and 95% confidence interval range was lower for IMRT (34.4% ± 1.2% vs. 37.0% ± 1.1%). When corrected for factors such as smoking status, histology, and nodal status, the hazard ratio for IMRT to 3DCRT was significantly less than one, as was that for toxicity (grade 3 pneumonitis), while distant metastases were similar. Thus, IMRT gave similar or better results in terms of survival and local control while reducing treatment toxicity. Vogelius et al.²³¹^,²³² pose a cautionary warning—their dosimetric modeling showed that when RT is used in combination with chemotherapy, the larger volume exposed to lower radiation doses in IMRT could pose problems with pneumonitis as compared to 3DCRT or proton therapy. They propose inclusion of chemotherapy in radiation planning as an equivalent radiation dose in the tissue volume.

FIGURE 10.19. Illustration of anterior-posterior (A) and oblique (B) multileaf collimator configuration.

FIGURE 10.20. Intensity-modulated radiation therapy (IMRT) plan for locally advanced non–small-cell lung cancer. Inner red line is the gross tumor volume (GTV); clinical tumor volume (CTV) is shown as a light blue aqua contour, which includes nodal regions to left of the GTV. The outermost yellow contour is the 60 Gy isodose line.

IMRT Experience with Other Cancer Sites

In addition to strong data supporting the use of IMRT in head and neck and prostate cancer, there are a number of preliminary studies reporting the feasibility and outcomes of IMRT in other cancers; many of these reports are theoretical dosimetric studies. Theoretically improved dosimetry alone probably does not serve as sufficient justification for the routine use of IMRT in these cases, and in the absence of robust clinical data regarding actual treatment outcomes, IMRT in these settings should be considered investigational.

In closing, IMRT clearly results in improved radiation dose distributions in a variety of cancers. In some cases, the superior dosimetry of IMRT has resulted in improved clinical outcomes for patients; however, the scientific evidence documenting these clinical improvements lags far behind the data documenting improved dosimetry. Many patients present with disease for which the likelihood of cure is remote, but for whom reduction of tumor burden with fewer debilitating toxicities will be an attractive option. Reduction in treatment morbidity is an immediately realizable benefit of IMRT. Improvement of survival will require better ability to image the biologic activity of malignancies, and this is an area of very active research. It is incumbent on radiation oncologists to continue to document improved clinical outcomes with IMRT in the peer-reviewed literature if we wish to justify the use of this expensive technology to our communities in an era of skyrocketing medical costs.

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