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Conformal Radiotherapy
PRACTICAL RADIATION ONCOLOGY FOR THE SURGICAL ONCOLOGIST
CONFORMAL RADIOTHERAPY What Is It and Why Does It Matter? Robert M. Cardinale, MD, and Brian D. Kavanagh, MD
It can be difficult for other medical specialists to stay abreast of the latest cancer treatment technology available to radiation oncologists because most physicians have not received any formal training in radiation oncology during medical school or residency. Even if they had, much of what might have been taught years ago currently would be outmoded. In the past decade, MR and CT scan-based imaging technology has been integrated fully with radiotherapy planning software and treatment delivery hardware to create the modality known as three-dimensional conformal radiotherapy (CRT). In many ways three-dimensional CRT is the apotheosis of a century's progress in refining clinical strategies and therapeutic techniques in radiation oncology. To understand three-dimensional CRT is to appreciate the key paradigms of modern radiotherapy. The goals of this article are to (1)familiarize the reader with the terminology and methodology of three-dimensional CRT, (2) characterize the importance of three-dimensional CRT in the evolution of radiotherapy, with particular emphasis on its potential to optimize treatment outcomes, (3) demonstrate important components of three-dimensionalCRT through a typical clinical example, and (4) describe selected advanced topics and future directions of three-dimensional CRT. WHAT IS THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY?
Two-dimensional radiation therapy (RT) remains the standard of care for radiation treatment delivery in most radiation oncology departments -
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From the Department of Radiation Oncology, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, Virginia SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9 . NUMBER 3 . JULY 2000
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and has been in use for nearly three decades for treating most tumor types. Two-dimensional RT treatment planning and dose calculations are performed from a single two-dimensional slice (contour) through a given treatment volume. The physician, in turn, must rely on bony landmarks on plain simulation radiographs to identify the tumor and important normal structures to draw blocks and align treatment beams. Often significant assumptions about anatomic orientations must be made. Conventional techniques of treatment based only on two-dimensional representations of tumor volumes often include generous margins of tissue around the tumor, which may result in an excess dose delivered to normal tissues. Three-dimensional CRT allows the user to define narrower field borders and alternative beam orientations because it provides greater anatomic certainty. The box below outlines some of the current problems of twodimensional RT.
Problems with Current (Two-Dimensional) Treatment Planning and Delivery of External Beam Radiation Therapy Lack of realistic appreciation of tumor, lymph nodes, and at-risk tissue volumes Lack of appreciation of real volume of normal tissue or organs irradiated to various doses Deficiencies in the algorithms for computing dose Failure to compute dose throughout the volume of interest Restriction of treatment to coplanar beams Failure to provide estimates of error Unavailability of tools to compare and judge rival plans Inadequate definition of geometric coverage of anatomic structures by external beams Failure to provide tools for specifying and verifying the accuracy of treatment delivery Data from Emami B, Graham M, Michalski J, et al: Three dimensional conformal radiation therapy: Clinical aspects. In Principles and Practice of Radiation Oncology. Philadelphia, Lippincott-Raven, 1997.
The descriptors "three dimensional" and "conformal" each imply important traits distinguishing three-dimensional CRT from conventional radiotherapy. The methodology is three dimensional insofar as imaging technologies such as MR imaging and CT scanning are directly interfaced with radiotherapy treatment planning systems to allow a targeted region to be considered as a three-dimensionalvolume in relation to neighboring normal tissue volumes inside the patient. The word conformal is derived from the Latin conformalis, meaning "of the same shape." The implication for three-dimensional CRT is that the shape of the therapeutic beam(s) of radiation used for a given patient is tailored to produce the condition in which the volume that receives the prescribed dose of radiation conforms closely to the designated target volume. In most cases the solution to
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achieve this goal is determined by a trial-and-errorprocess to orient beams that are then shaped by customized fabricated lead blocks or multileaf collimators to encompass the target volume appropriately. Generally it is necessary to allow for an extra margin around the target volume to account for day-to-day variations in the patient's set-up position (typically 0.5-1 cm) and to incorporate the beam's penumbra, the region near the edge of the beam where the dose falls off from full intensity (approximately 0.5 cm). One of the most useful features of commercially available three-dimensional CRT planning systems is the beam's eye view feature, which provides the clinician with a three-dimensional computer-generated illustration of key structures as they would appear from the vantage point of the source of the beam within the treatment machine.27The beam's eye view application is helpful in providing a first pass, real-time visual evaluation of a potential individual beam of radiation for a given patient by revealing the relative positions of the tumor or designated volume to be targeted and dose-limiting normal tissues (Figs. 1 and 2). It is intuitively appealing to assume that certain features of three-dimensional CRT, such as the powerful computer-generated visual displays that allow much greater freedom in choosing beam arrangements, render it universally superior to conventional radiotherapy. Three-dimensional CRT planning can present the user with a potentially confusing and highly subjective assortment of options, however, and so it becomes particularly important to apply quantitative methodologies in the comparison of alternative beam arrangements. The dose-volume histogram has proved to be a helpful tool in characterizing graphically the tumor and normal tissue radiation dose impact for a given combination of bearns.'j In a typical dosevolume histogram, for a designated volume of tumor or normal tissue, the x-axis represents the total dose received and the y-axis represents the percent of the total volume receiving any given dose (Fig. 3). THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY: WHY DOES IT MATTER? For its potential importance to be fully characterized, three-dimensional CRT should be regarded within the context of the historical progress of clinical radiotherapy during the past century. Since the discovery of radioactivity around the dawn of the twentieth century and the first applications of radiation for medical treatment soon thereafter, major milestones in the development of the field of radiotherapy have included both technologic achievements and breakthroughs in clinical knowledge resulting from empirical observations and prospective studies. An exhaustive list is beyond the scope of this article but a few selected examples are illustrative. Important advances in the capacity for safe and effective administration of ionizing radiation have included the production of machines capable of higher and higher x-ray energy potential, which results in more
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Figure 1. Lateral (A) and anteroposterior (AP) (B) beam's eye view images showing CT anatomic information used for block construction for local field irradiation of a prostate tumor.
illustration continued on opposite page
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Figure 1 (Continued). Digitally reconstructed lateral (C) and AP (D) radiographs showing bony anatomy, isocenter position, and outlined prostate, rectum, and bladder. The digitally reconstructed radiographs (DRRs) are compared with linear accelerator portal images for accuracy verification at the time of treatment.
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Figure 2. Axial view of prostate tumor treatment plan. The isodose lines represent 95, 90, 80, and 35% of the maximum dose delivered to the prostate gland.
Figure 3. Dose volume histogram of prostate case demonstrating differential doses given to prostate gland and rectal tissues.
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deeply penetrating and more sharply defined beams of radiation.13In the first half of the century, Grenz-ray devices that produced x-rays of less than 20 kV potential gave way to contact therapy and superficial therapy units and later to orthovoltage therapy machines that provided potentials in the range of 150 to 500 kV. In the 1950s, radioactive cobalt 60 sources became available to provide gamma rays of 1.17 to 1.33 mV for external beam treatment, and the first attempts at conformal treatments through beam shaping were described as early as 1960.26,28 Currently, linear accelerators that produce x-ray potentials in the ranee of 6 to 25 mV afford even more favorable distributions of radiation do; within patients. When these high-energy beams target deep-seated tumors, there is relatively less dose of radiation deposited in more superficial normal tissues, which allows for higher doses to be delivered to the tumor given the same doses to the surrounding normal tissue. During the 1970s, CT imaging technology became practical for widespread use, and by the 1980s, efforts to link it more closely to radiotherapy planning and administration were ~ n d e n v a v . ' ~ In, ~1994, ~ the oreanizers of a scientific symposium declared that thh development of ctnformal radiotherapy represented the dawn of a "new era in the irradiation of cancer."19 Other articles more thorouehlv address the mvriad clinical investi" gations that have shaped contemporary treatment strategies for different types of cancers. A prevailing common theme that emerges is that in the definitive primary or postoperative radiotherapeutic management of solid tumors, optimal results are achieved when the most carefullv desiened " region of gross tumor and surrounding microscopic extensions of tumor are given the highest radiation doses possible. The ultimate goal of threedimensional CRT is to deliver these hieher tumor doses while still main" taining an acceptably low risk of radiation injury to adjacent normal tissues. The term therapeutic ratio is often applied to represent the overall effect of a schedule of radiotherapy with particular consideration for the chance of local tumor control relative to the risk of treatment-related complications. Three-dimensionalCRT stands as the current phase of progress in the continuing efforts to optimize the therapeutic ratio for selected tumors managed with radiotherapy. The most sophisticated available imaging technology is coupled to the most advanced hardware and software for treatment administration. The region to be targeted with radiotherapy is outlined carefully according to the recognized patterns of failure for that particular tumor, and external beam treatment fields are shaped and arranged to optimize the therapeutic ratio in the given situation. In summary, the overarching goal of three-dimensional CRT is to imDrove on the clinical outcome for a cancer patient in one or both of the following ways: J
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1. Three-dimensional CRT can be used to deliver standard tumor doses with a decrease in the amount of adjacent normal tissue receiving high doses of radiation. The expectation for threedimensional CRT in this setting would be a reduction in normal
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tissue side effects for an eauivalent effect on tumor control in the irradiated region. 2. Three-dimensional CRT can be used to deliver higher than standard tumor doses because normal tissue volumes exposed to potentially injurious dose levels are reduced compared with conventional techniques. The goal in this case is to increase local tumor control rates over those obtained by conventional techniques. This application of three-dimensionalCRT holds promise for improved outcomes for selected tumor sites; however, it must be tested in formal dose-seeking studies that carefully examine tumor control, toxicity, quality of life, and cost. - -
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THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY TREATMENT PLANNING PROCESS
A more complete understanding of three-dimensional CRT requires some familiarity with how it is used in clinical practice and what technologic components are necessary for optimal clinical use. The process of three-dimensional CRT is more complex and time consuming than standard two-dimensional planning. The specific tools of three-dimensional CRT revolve around modern imaging modalities, computer simulation, treatment delivery, and verification procedures. The sequence of steps required to produce a three-dimensional CRT treatment plan may vary somewhat from one institution to another; however, the general principles are the same. The components of a three-dimensional CRT system are as follows: 1. Simulation patient immobilization procedures three-dimensional image acquisition with patient in treatment position identification of treatment isocenter marks on patient for subsequent set-up 2. Three-Dimensional Treatment Planning download imaging (CT) information into planning computer outline, slice-by-slice, tumor volumes and organs on computer choose optimal beam arrangements virtual block design using beam's eye view make digitally reconstructed radiographs (analogous to standard simulation radiographs, used to verify field accuracy by comparing with linear accelerator portal film) three-dimensional dose calculation and display analyze target and critical organ dose volume histograms 3. Three-Dimensional CRT Dose Delivery shape beam with custom cut blocks or multileaf collimator (beam shaper located in gantry of linear accelerator) input beam parameters on linear accelerator verification procedures using portal images compared with digitally reconstructed radiographs dose verification procedures
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Case Example of Three-Dimensional Conformal Radiotherapy: Esophageal Cancer
A 65-year-old woman with progressive dysphagia and weight loss underwent endoscopy, which revealed a 75%circumferentialsquamous cell esophageal tumor that extended from 20 to 25 cm from the incisors. Because of the local extension of tumor, which invaded the trachea, the patient was enrolled on an institutional study that evaluated preoperative radiation therapy combined with concurrent weekly tax01 and carboplatin chemotherapy. Subsequent to this treatment, the patient underwent surgical resection and the pathologic specimen revealed a complete response.
Below are descriptions of some of the important components of the three-dimensional CRT planning process, followed in each section by particulars to the previously mentioned treated patient case. Fluoroscopic Simulation and Orthogonal Radiograph Acquisition
A vital component of three-dimensional CRT is the process of image acquisition. In most departments a traditional fluoroscopic simulation is performed before the simulation CT scan. Initially, patients undergo immobilization procedures, which may involve designing custom-fabricated devices such as casts, foam body molds, thermoplastic head holders/ masks, and bite-blocks. The immobilization devices are constructed so that the patient can be positioned for planning and daily treatment in a reproducible fashion. The patient described previously was first placed prone on the table in the fluoroscopic simulator room. With her arms placed above her head to allow for lateral beam portals, a hardened foam cast was molded to conform to her upper body shape. Under fluoroscopic guidance, the body position was aligned as straight as possible using bony landmarks as a guide. The physician determined the isocenter position in x, y, and z directions using all available imaging information (prior diagnostic CT, endoscopy report, barium studies). The patient was then given diluted barium to swallow; subsequently a set of anteroposterior and lateral radiographs was obtained. The isocenter set-up points were then marked using permanent small tattoos placed on three body positions to define the triangulation laser set-up points for CT simulation and treatment alignment. CT Simulation
CT simulation is usually performed immediately after standard fluoroscopic simulation, but it can be performed in certain instances without a prior simulation procedure using a dedicated CT simulator unit. In that setting a CT simulator is used for both CT image acquisition and isocenter set-up using a three-dimensional computer-driven virtual fluoroscopy
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tool while the patient remains on the CT couch. Special lasers are then used to mark the patient. An important step at this time is to reproduce the simulation set-up position exactly as before using the CT localizing lasers to match the setup points and to make sure the patient is positioned in the same manner within the immobilization device. Small lead BBs and teflon catheters are used to mark the beam isocenter entry points on the patient. The physician marks the superior and inferior extent of the proposed treatment portals, and these points are used to define the length of the CT scan. The simulation CT scan is usually performed with additional margins above and below the areas to be targeted to allow for consideration of radiation beams that lie outside of the transverse plane of the tumor. Typically, CT scans are acquired with 3- to 5-mm-thick slices depending on the resolution required to generate useful three-dimensional images and digitally reconstructed radiographs. The CT volumetric data are then transferred electronically to the treatment planning computer system, where the remaining simulation and dose display procedures are completed. The example patient was scanned from above the clavicles through the diaphragm while immobilized in the treatment position in the CT scanner. The combined simulation process was performed within a 1-hour simulation time slot. Treatment Planning I: Target and Normal Tissue Delineation The next important step in the planning process is for the treating physician to identify and outline the appropriate tumor volumes on each consecutive CT slice on the treatment planning computer. This is normally done with a computer mouse or track ball device. There are usually two main tumor volumes of interest: the gross tumor volume (GTV), which usually represents the gross tumor as seen on CT, and the clinical tumor volume (CTV).8The CTV consists of the GTV plus local or regional volumes that are at risk for containing tumor cells, such as locoregional lymph nodes or other areas that the clinician believes are likely to harbor microscopic tumor deposits. The trained dosimetrist or physicist may help the physician identify and outline the important anatomic structures in the region of interest as well. The delineation of these structures is important to aid in beam orientation and block construction. For the case described, the esophageal tumor (GTV), regional lymph node areas (CTV), and critical anatomic structures (lungs, heart, spinal cord) were delineated with separate colors on each CT slice. Treatment Planning II: Virtual Simulation and Dose Calculation With the physician and treatment planning dosimetrist present at the treatment planning computer, a virtual simulation is performed in a manner that mimics conventional simulation. Studies of preoperative che-
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moradiotherapy for esophageal cancer have indicated a substantially escalated risk of perioperative mortality when large amounts of normal thoracic tissues are treated with high doses.9Consequently, it is important to design fields that are tailored carefully to minimize excess irradiation of adjacent lung parenchyma and heart tissue. The three-dimensional treatment planning system can display the anatomic patient information in several spatial views simultaneously, including any axial, coronal, sagittal two-dimensional or three-dimensional views.12The GTV and CTV are displayed in these projections as well as any or all of the outlined anatomic structures of interest. These volume renderings allow the clinician to appreciate the relative position of the tumor volumes in relation to normal structures to a much greater degree than with a traditional plain film radiograph. Once the user has decided on beam orientations, the computer records the specific gantry, couch, and collimator instructions that will be used for actual treatment. Beam apertures for cerrobend blocks or multileaf collimators can be shaped on the computer using beam's eye view display.23The aperture is usually made larger than the specified target to account for positional uncertainties and scatter of radiation effects. The treatment planning computer generates digitally reconstructed radiographs of each incident beam. The digitally reconstructed radiograph displays bony anatomy that is used for field verification with treatment machine port films. Dose distributions are calculated in three dimensions using dose algorithms that account for tissue inhomogeneities (air or bone).rhe various dose levels are projected on the CT image in any desired plane or three-dimensional rendition (isodose curves). Beam modifiers such as wedges and tissue compensators may be added to shape further the radiation isodose curves to conform maximally to the target. Often, several modifications to beam weight, beam orientation, and wedge angle are performed to optimize the treatment plan. Dose volume histograms (DVHs) also may be used to select the best plan. Figures 4 to 7 show beam's eye view displays, digitally reconstructed radiographs, and isodose curves for the boost portion of the patients' treatment. After adequate microscopic doses are delivered to a larger field arrangement, the boost or conedown fields were generated as shown. For the examule case, beam orientations were chosen that attem~tedto avoid spinal coid, heart, and lung tissue. The entire plan of radiLtion must be considered initially so as not to "burn any bridges" that may be needed later (e.g., spinal cord dose). The composite treatment was delivered through seven different beam orientations given over the treatment course with three separate plans each using different beam orientations. Each subsequent plan treated a smaller overall volume, as is typical for many treatment sites. The larger field was treated to 36 Gy and the reduced fields received an additional 14.4 Gy for a cumulative target dose of 50.4 Gy given in once daily 1.8 Gy fractions. The final boost dose of radiation was delivered through an anteroposterior, right posterior oblique, and left posterior oblique field arrangement. Because the spinal cord already had been irradiated in the initial fields, it was important that the oblique beams be "off-cord so that the cumulative total dose to the spinal cord did not exceed tolerable limits.
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Figure 4. Esophageal carcinoma. DRR of oblique (A) and AP (B)beam used for boost portion of treatment. Note the differential and off cord blocking used.
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Figure 5. Esophageal carcinoma. Axial view showing beam orientations without blocking. Note the divergence of the treatment beams and beam modifiers (wedges). Wedges are used to attenuate the beam differentially to increase dose conformity.
SPECIAL APPLICATIONS AND FUTURE DEVELOPMENTS OF THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY
The continuing evolution of three-dimensional CRT technology has led to investigations of more sophisticated applications of the fundamental tools of three-dimensional CRT in an attempt to expand further the potential clinical benefits of radiotherapy. Among the most promising and innovative endeavors are the developments of intensity-modulated radiotherapy (IMRT),body stereotactic radiosurgery, and genetic radiotherapy. Intensity-Modulated Radiotherapy
Intensity-modulated radiotherapy (IMRT) is a refinement of threedimensional CRT methodology currently in the pioneering stages. IMRT is a dose delivery method whereby the intensity of individual rays within the cross-sectional profile of a larger external beam is adjusted selectively to generate the desired pattern of dose distribution. This technique in-
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Figure 6. Dose volume histogram of esophageal case boost plan for tumor, spinal cord, and heart.
Figure 7. Cut-away three-dimensional view shows prescription isodose volume encompassing tumor and avoiding spinal cord and a significant volume of heart tissue.
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creases the conformity for treatments of complex targets over current state-of-the-art standard three-dimensional CRT. Essential for IMRT are a means to modify the flux of photons across the profile of a radiation beam and an algorithm for inverse dose planning. The former goal may be accom~lished with the use of a dvnamic multileaf collimator. a device that I contains computer-controlled motors that slide strips, or leaves, of lead blocking material across the beam, stopping at various positions for predetermined lengths of time. The net result is that each small section within the beam receives greater or lesser intensity of radiation according to the desired dose objectives. Figure 8 contains an example of a laterally directed, intensity-modulated beam that was used to treat a pelvic tumor and lymph nodes. The other critical component of IMRT, inverse dose planning, requires the implementation of a computer program designed to derive an optimized solution to a score function based on the clinical obiectives in the case. Details of the methodology are beyond the scope of {his article but are available e l s e ~ h e r e . ~Basically, , ~ ~ , ~ ~the , ~ inverse ~ dose planning algorithm seeks an optimum solution through an iterative process of ray intensity adjustments for a given configuration of number and orientation of beams. The inverse dose planning required for IMRT occasions additional opportunities for alternative concepts for radiation dose prescription. For any given clinical situation, radiotherapy dose prescriptions are typically limited by the total dose that can be administered safely to normal tissues in the field. Established guidelines predict an acceptably low risk of severe normal tissue complications for particular doses to individual tissue types or organ^.^ It has become widely recognized, however, that the functional response of organs and tumors to radiation dose is a complex process complicated by numerous factors. Among the important considerations are the percent of total organ volume irradiated and the dose per fraction of radiation use. Because it is only with the advent of the treatment plannine tools of three-dimensional CRT that com~leteinformation about the thrge-dimensional distribution of dose within patient has been available, there is still a need to analyze further the relative contributions of these and other factors. As data accumulate from careful prospective studies, it likely will become possible to make more accurate predictions of normal tissue complication probabilities based on a more complete knowledge of expected tissue effects. IMRT planning then could be driven by biologic indices that would vredict the normal tissue comvlication vrobabilities associated with given beam intensity profiles. It is possible that by means of IMRT or a similar beam modification technique, the total dose within the tumor might be escalated selectively without an incremental increase in expected effects on adjacent normal tissues. IMRT has been reported in the treatment of patients with prostate ~ancer,'~ and other indications are being e ~ p l o r e d . ~An , ~ ,example '~ of a patient treated at our institution with IMRT on a protocol designed to spare salivary function for head and neck tumors is shown in Figure 9. I
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Figure 8. Three-dimensional profile of a standard radiotherapy blocked field (A) compared with an IMRT lateral treatment beam (6).IMRT treatment is delivered using a dynamic multileaf collimator which moves individual l-cm leaves across the field during beam-on time to create the desired final profiles.
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Figure 9. Complex three-dimensional CRT (A) and IMRT (B) plans of a head and necktumor including local lymph node regions. The IMRT plan allows for significant sparing of parotid function and treats less normal tissue to high doses as compared with the three-dimensional CRT plan. The IMRT plan is easier to deliver, is fully automated, and requires no blocks.
Body Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS),a term introduced by Leksell in 1951, refers to a single high-dose radiation treatment delivered under stereotactic conditions to well-defined intracranial targets. SRS is a special case of three-dimensional CRT that was conceived to be more analogous to conventional surgery than to conventional radiotherapy because of its ablative intent of targeted tissues. SRS has become widely available over the past decade. Encouraging clinical outcomes have been achieved for intracranial arteriovenous malformations, acoustic neuromas, brain metastases, and, more recently, functional disorders. Because of these promising results and the availability of threedimensional CRT computers and stereotactic body frames, investigators recently have begun treating isolated tumors outside the cranium with radiosurgery-like doses given in one or several outpatient treatment sessions. This new area of body radiosurgery (BodySRS) relies on noninvasive, accurate immobilization and relocalization systems. Unlike cranial SRS, in which the external frame is fixed into the skull bone for extreme accuracy, body targets require an extra margin of tissue to be included in the prescription region because of positional uncertainties and organ motion. Initial promising results of BodySRS have been reported by Blomgren et a12 from Karolinska Hospital.15 They have performed BodySRS on 50 patients with isolated primary and metastatic tumors, delivering a mean dose of 28 Gy over one to five treatment sessions. It is important to realize that the true biologically equivalent dose to the tumor is much higher than 28 Gy given in standard fraction sizes (2 Gy). With a mean follow
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up of 11months, 29% of tumors showed growth arrest, 39%were reduced in size, and 32% disappeared. The local failure rate was 5%. A typical BodySRS plan of a patient treated at our medical center is shown in Figure 10. Further modifications of BodySRS include IMRT treatment delivery and the use of treatment gating, which coordinates beam output from the linear accelerator regulated with the breathing cycle of the patient. Gating should allow for a reduction in the margin of normal tissue targeted, especially for lung and liver tumors.14 Genetic Radiotherapy
Another role for three-dimensional CRT might be in the area of genetic radiotherapy, a speculativebut tantalizing clever proposed marriage between clinical radiotherapy and gene therapy.' The basic idea for genetic
Figure 10. Body radiosurgery plan for a patient with a solitary liver metastasis who refused surgical intervention. The patient received protocol therapy of 12 Gy each on 3 separate treatment days. The outpatient treatment was well tolerated, and required no sedation. A 5month post-treatment liver CT scan demonstrated a complete response.
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radiotherapy is that certain radiation-inducible genes, introduced into a patient via a viral vector or other appropriate means, might be promoted selectively (by targeted radiation) to achieve functional alterations in protein synthesis or other important cellular functions in a particular region within the body.17 The most direct potential oncologic applications of genetic radiotherapy involve genetic modulation of features of tumor cells known to affect radiosensitivity. For example, it has been demonstrated that certain squamous carcinoma cells defend themselves against the cytotoxicity of fractionated irradiation by means of a proliferative response triggered by activation of the cell membrane-bound epidermal growth factor recept~r.'~,~* A large-scale National Institutes of Health-funded research project is currently underway to develop an effective means of introducing genes that code for the production of a nonfunctional epidermal growth factor receptor. The goal is to abrogate the tumor cells' radiation-induced signals to replicate, thus enhancing the tumoricidal efficacy of radiotherapy. Proposed nononcologic applications have included introduction of radiationinducible genes to control cholesterol metabolism or other factors related to cardiovascular disease. In either scenario it is important to minimize the occurrence of unintended consequences caused by genetic modulation within tissue surrounding the targeted volume. The careful application of three-dimensional CRT is critically important to guarantee activation of radiation-inducible genes in the entire target volume while limiting activation in surrounding uninvolved tissue as much as possible. References 1. Advani SJ, Chmura SJ, Weichselbaum RR: Radiogenetic therapy: On the interaction of viral therapy and ionizing radiation for improving local control of tumors. Semin Oncol 24:633, 1997 2. Blomgren H, Lax I, Goranson H, et al: Radiosurgery for tumors in the body: Clinical experience using a new method. Journal of Radiosurgery 1:63,1998 3. Bortfeld T, Burkelbach J, Boesecke R, et al: Methods of image reconstmction from projections applied to conformation radiotherapy. Phys Med Biol35:1423,1990 4. Cardinale RM, Benedict SH, Wu Q, et al: A comparison of three stereotactictechniques: Arcs vs. noncoplanar fixed fields vs. intensity modulation. Int J Radiat Oncol Biol Phys 42:431, 1998 5. Cardinale RM, Wu Q, Benedict S, et al: Potential benefit of intensity modulated stereotactic radiosurgery using micro-multileaf collimation of static noncoplanar beams [abstract 22641. In Programs and Abstracts of the 40th Annual Meeting of ASTRO, Phoenix, 1998, p 359 6. Drzvmala RE, Mohan R, Brewster L, et al: Dose-volume histograms. Int J Radiat Oncol ~ i o f p h y 21:71,1991 s 7. Emami B, Lvman T, Brown M, et al: Tolerance of normal tissues to therapeutic irradiation. Int J ~ a d i a < ~ n c o i ' ~Phys i o l 21:109, 1991 8. ICRU Report 50: Prescribing, Recording and Reporting Photon Beam Therapy. Bethesda, MD, International Commission on Radiation Units and Measurements, 1993 9. Kavanagh BD, Anscher M, Leopold K: Patterns of failure following combined modality therapy for esophageal cancer: 1984-1990. Int J Radiat Oncol Biol Phys 24:633,1992 10. Kavanagh BD, Wu Q, Segreti EM, et al: The application of intensity-modulated radiotherapy in the management of uterine cervix cancer [abstract 22841. In Programs and Abstracts of the 40th Annual Meeting of ASTRO, Phoenix, 1998, p 369
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11. Kavanagh BD, Lin PS, Chen P, et al: Radiation induced enhanced proliferation of human squamous cells in vivo: A release from inhibition by epidermal growth factor. Clin Cancer Res 1:1557,1995 12. Kessler ML, McShan DL, Fraass BA: Displays for three-dimensional treatment planning. Semin Radiat Oncol2:226-234,1992 13. Khan F: The Physics of Radiation Therapy. Baltimore, Williams and Wilkins, 1994 14. Kubo H: Respiration gated radiotherapy treatment: A technical study. Phys Med Biol 41:83,1996 15. Lax I, Blomgren H, Naslund I, et al: Stereotactic radiotherapy of malignancies of the abdomen. Acta Oncol6:677, 1994 16. Ling CC, Burman C, Chui CS, et al: Conformal radiation treatment of prostate cancer using inversely-planned intensity-modulated photon beams produced with dynamic multileaf collimation. Int J Radiat Oncol Biol35:721, 1996 17. Maureri HJ, Hanna NN, Wayne JD, et al: Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 56:4311,1996 18. McShan DL, Silverman A, Lanza DM, et al: A computerized three-dimensional treatment planning system utilizing interactive colour graphics. Br J Radiol 52478,1979 19. Meyer JL, Purdy JA: 3-D Conformal Radiotherapy: A New Era in the Irradiation of Cancer. Basel, Karger, 1996 20. Mohan R, Barest G, Brewster L, et al: A comprehensive three-dimensional radiation treatment planning system. Int J Radiat Oncol Biol Phys 15:481,1988 21. Mohan R, Wang X, Jackson A, et al: The potential and limitations of the inverse radiotherapy technique. Radiother Oncol32:232,1994 22. Mohan R, Wu Q, Wang X, et al: Intensity modulation optimization, lateral transport of radiation and margins. Med Phys 23:2011,1996 23. Mohan R: Field shaping for three-dimensional conformal radiation therapy and multileaf collimation. Semin Radiat Oncol5:86-99,1995 24. Schmidt-Ullrich RK, Mikkelson RB, Dent P, et al: Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15:1191,1997 25. Spirou SV, Chui CS: Generation of arbitrary fluence profiles by dynamic jaws or multileaf collimators. Med Phys 21:1031,1994 26. Takahashi S, Kitabatake T, Morita K, et al: Conformation radiotherapy applied to cancer of uterus. Nippon Acta Radiol 20:2746,1961 27. Vijaykumar S, Myrianthopoulos LC, Rosengerg I, et al: Optimization of radical radiotherapy with beam's eye view techniques for non-small cell lung cancer. Int J Radiat Oncol Biol Phys 21:779, 1991 28. Wright KA, Primos BS, Trump JG, et al: Field shaping and selective protection in megavolt radiation therapy. Radiology 72:101,1959
Address reprint requests to Robert M . Cardinale, MD Department of Radiation Oncology Medical College of Virginia Hospitals P.O. Box 980058 401 College Street Richmond, VA 23298-0058
CONFORMAL RADIOTHERAPY What Is It and Why Does It Matter? Robert M. Cardinale, MD, and Brian D. Kavanagh, MD
It can be difficult for other medical specialists to stay abreast of the latest cancer treatment technology available to radiation oncologists because most physicians have not received any formal training in radiation oncology during medical school or residency. Even if they had, much of what might have been taught years ago currently would be outmoded. In the past decade, MR and CT scan-based imaging technology has been integrated fully with radiotherapy planning software and treatment delivery hardware to create the modality known as three-dimensional conformal radiotherapy (CRT). In many ways three-dimensional CRT is the apotheosis of a century's progress in refining clinical strategies and therapeutic techniques in radiation oncology. To understand three-dimensional CRT is to appreciate the key paradigms of modern radiotherapy. The goals of this article are to (1)familiarize the reader with the terminology and methodology of three-dimensional CRT, (2) characterize the importance of three-dimensional CRT in the evolution of radiotherapy, with particular emphasis on its potential to optimize treatment outcomes, (3) demonstrate important components of three-dimensionalCRT through a typical clinical example, and (4) describe selected advanced topics and future directions of three-dimensional CRT. WHAT IS THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY?
Two-dimensional radiation therapy (RT) remains the standard of care for radiation treatment delivery in most radiation oncology departments -
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From the Department of Radiation Oncology, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, Virginia SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 9 . NUMBER 3 . JULY 2000
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and has been in use for nearly three decades for treating most tumor types. Two-dimensional RT treatment planning and dose calculations are performed from a single two-dimensional slice (contour) through a given treatment volume. The physician, in turn, must rely on bony landmarks on plain simulation radiographs to identify the tumor and important normal structures to draw blocks and align treatment beams. Often significant assumptions about anatomic orientations must be made. Conventional techniques of treatment based only on two-dimensional representations of tumor volumes often include generous margins of tissue around the tumor, which may result in an excess dose delivered to normal tissues. Three-dimensional CRT allows the user to define narrower field borders and alternative beam orientations because it provides greater anatomic certainty. The box below outlines some of the current problems of twodimensional RT.
Problems with Current (Two-Dimensional) Treatment Planning and Delivery of External Beam Radiation Therapy Lack of realistic appreciation of tumor, lymph nodes, and at-risk tissue volumes Lack of appreciation of real volume of normal tissue or organs irradiated to various doses Deficiencies in the algorithms for computing dose Failure to compute dose throughout the volume of interest Restriction of treatment to coplanar beams Failure to provide estimates of error Unavailability of tools to compare and judge rival plans Inadequate definition of geometric coverage of anatomic structures by external beams Failure to provide tools for specifying and verifying the accuracy of treatment delivery Data from Emami B, Graham M, Michalski J, et al: Three dimensional conformal radiation therapy: Clinical aspects. In Principles and Practice of Radiation Oncology. Philadelphia, Lippincott-Raven, 1997.
The descriptors "three dimensional" and "conformal" each imply important traits distinguishing three-dimensional CRT from conventional radiotherapy. The methodology is three dimensional insofar as imaging technologies such as MR imaging and CT scanning are directly interfaced with radiotherapy treatment planning systems to allow a targeted region to be considered as a three-dimensionalvolume in relation to neighboring normal tissue volumes inside the patient. The word conformal is derived from the Latin conformalis, meaning "of the same shape." The implication for three-dimensional CRT is that the shape of the therapeutic beam(s) of radiation used for a given patient is tailored to produce the condition in which the volume that receives the prescribed dose of radiation conforms closely to the designated target volume. In most cases the solution to
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achieve this goal is determined by a trial-and-errorprocess to orient beams that are then shaped by customized fabricated lead blocks or multileaf collimators to encompass the target volume appropriately. Generally it is necessary to allow for an extra margin around the target volume to account for day-to-day variations in the patient's set-up position (typically 0.5-1 cm) and to incorporate the beam's penumbra, the region near the edge of the beam where the dose falls off from full intensity (approximately 0.5 cm). One of the most useful features of commercially available three-dimensional CRT planning systems is the beam's eye view feature, which provides the clinician with a three-dimensional computer-generated illustration of key structures as they would appear from the vantage point of the source of the beam within the treatment machine.27The beam's eye view application is helpful in providing a first pass, real-time visual evaluation of a potential individual beam of radiation for a given patient by revealing the relative positions of the tumor or designated volume to be targeted and dose-limiting normal tissues (Figs. 1 and 2). It is intuitively appealing to assume that certain features of three-dimensional CRT, such as the powerful computer-generated visual displays that allow much greater freedom in choosing beam arrangements, render it universally superior to conventional radiotherapy. Three-dimensional CRT planning can present the user with a potentially confusing and highly subjective assortment of options, however, and so it becomes particularly important to apply quantitative methodologies in the comparison of alternative beam arrangements. The dose-volume histogram has proved to be a helpful tool in characterizing graphically the tumor and normal tissue radiation dose impact for a given combination of bearns.'j In a typical dosevolume histogram, for a designated volume of tumor or normal tissue, the x-axis represents the total dose received and the y-axis represents the percent of the total volume receiving any given dose (Fig. 3). THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY: WHY DOES IT MATTER? For its potential importance to be fully characterized, three-dimensional CRT should be regarded within the context of the historical progress of clinical radiotherapy during the past century. Since the discovery of radioactivity around the dawn of the twentieth century and the first applications of radiation for medical treatment soon thereafter, major milestones in the development of the field of radiotherapy have included both technologic achievements and breakthroughs in clinical knowledge resulting from empirical observations and prospective studies. An exhaustive list is beyond the scope of this article but a few selected examples are illustrative. Important advances in the capacity for safe and effective administration of ionizing radiation have included the production of machines capable of higher and higher x-ray energy potential, which results in more
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Figure 1. Lateral (A) and anteroposterior (AP) (B) beam's eye view images showing CT anatomic information used for block construction for local field irradiation of a prostate tumor.
illustration continued on opposite page
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Figure 1 (Continued). Digitally reconstructed lateral (C) and AP (D) radiographs showing bony anatomy, isocenter position, and outlined prostate, rectum, and bladder. The digitally reconstructed radiographs (DRRs) are compared with linear accelerator portal images for accuracy verification at the time of treatment.
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Figure 2. Axial view of prostate tumor treatment plan. The isodose lines represent 95, 90, 80, and 35% of the maximum dose delivered to the prostate gland.
Figure 3. Dose volume histogram of prostate case demonstrating differential doses given to prostate gland and rectal tissues.
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deeply penetrating and more sharply defined beams of radiation.13In the first half of the century, Grenz-ray devices that produced x-rays of less than 20 kV potential gave way to contact therapy and superficial therapy units and later to orthovoltage therapy machines that provided potentials in the range of 150 to 500 kV. In the 1950s, radioactive cobalt 60 sources became available to provide gamma rays of 1.17 to 1.33 mV for external beam treatment, and the first attempts at conformal treatments through beam shaping were described as early as 1960.26,28 Currently, linear accelerators that produce x-ray potentials in the ranee of 6 to 25 mV afford even more favorable distributions of radiation do; within patients. When these high-energy beams target deep-seated tumors, there is relatively less dose of radiation deposited in more superficial normal tissues, which allows for higher doses to be delivered to the tumor given the same doses to the surrounding normal tissue. During the 1970s, CT imaging technology became practical for widespread use, and by the 1980s, efforts to link it more closely to radiotherapy planning and administration were ~ n d e n v a v . ' ~ In, ~1994, ~ the oreanizers of a scientific symposium declared that thh development of ctnformal radiotherapy represented the dawn of a "new era in the irradiation of cancer."19 Other articles more thorouehlv address the mvriad clinical investi" gations that have shaped contemporary treatment strategies for different types of cancers. A prevailing common theme that emerges is that in the definitive primary or postoperative radiotherapeutic management of solid tumors, optimal results are achieved when the most carefullv desiened " region of gross tumor and surrounding microscopic extensions of tumor are given the highest radiation doses possible. The ultimate goal of threedimensional CRT is to deliver these hieher tumor doses while still main" taining an acceptably low risk of radiation injury to adjacent normal tissues. The term therapeutic ratio is often applied to represent the overall effect of a schedule of radiotherapy with particular consideration for the chance of local tumor control relative to the risk of treatment-related complications. Three-dimensionalCRT stands as the current phase of progress in the continuing efforts to optimize the therapeutic ratio for selected tumors managed with radiotherapy. The most sophisticated available imaging technology is coupled to the most advanced hardware and software for treatment administration. The region to be targeted with radiotherapy is outlined carefully according to the recognized patterns of failure for that particular tumor, and external beam treatment fields are shaped and arranged to optimize the therapeutic ratio in the given situation. In summary, the overarching goal of three-dimensional CRT is to imDrove on the clinical outcome for a cancer patient in one or both of the following ways: J
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1. Three-dimensional CRT can be used to deliver standard tumor doses with a decrease in the amount of adjacent normal tissue receiving high doses of radiation. The expectation for threedimensional CRT in this setting would be a reduction in normal
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tissue side effects for an eauivalent effect on tumor control in the irradiated region. 2. Three-dimensional CRT can be used to deliver higher than standard tumor doses because normal tissue volumes exposed to potentially injurious dose levels are reduced compared with conventional techniques. The goal in this case is to increase local tumor control rates over those obtained by conventional techniques. This application of three-dimensionalCRT holds promise for improved outcomes for selected tumor sites; however, it must be tested in formal dose-seeking studies that carefully examine tumor control, toxicity, quality of life, and cost. - -
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THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY TREATMENT PLANNING PROCESS
A more complete understanding of three-dimensional CRT requires some familiarity with how it is used in clinical practice and what technologic components are necessary for optimal clinical use. The process of three-dimensional CRT is more complex and time consuming than standard two-dimensional planning. The specific tools of three-dimensional CRT revolve around modern imaging modalities, computer simulation, treatment delivery, and verification procedures. The sequence of steps required to produce a three-dimensional CRT treatment plan may vary somewhat from one institution to another; however, the general principles are the same. The components of a three-dimensional CRT system are as follows: 1. Simulation patient immobilization procedures three-dimensional image acquisition with patient in treatment position identification of treatment isocenter marks on patient for subsequent set-up 2. Three-Dimensional Treatment Planning download imaging (CT) information into planning computer outline, slice-by-slice, tumor volumes and organs on computer choose optimal beam arrangements virtual block design using beam's eye view make digitally reconstructed radiographs (analogous to standard simulation radiographs, used to verify field accuracy by comparing with linear accelerator portal film) three-dimensional dose calculation and display analyze target and critical organ dose volume histograms 3. Three-Dimensional CRT Dose Delivery shape beam with custom cut blocks or multileaf collimator (beam shaper located in gantry of linear accelerator) input beam parameters on linear accelerator verification procedures using portal images compared with digitally reconstructed radiographs dose verification procedures
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Case Example of Three-Dimensional Conformal Radiotherapy: Esophageal Cancer
A 65-year-old woman with progressive dysphagia and weight loss underwent endoscopy, which revealed a 75%circumferentialsquamous cell esophageal tumor that extended from 20 to 25 cm from the incisors. Because of the local extension of tumor, which invaded the trachea, the patient was enrolled on an institutional study that evaluated preoperative radiation therapy combined with concurrent weekly tax01 and carboplatin chemotherapy. Subsequent to this treatment, the patient underwent surgical resection and the pathologic specimen revealed a complete response.
Below are descriptions of some of the important components of the three-dimensional CRT planning process, followed in each section by particulars to the previously mentioned treated patient case. Fluoroscopic Simulation and Orthogonal Radiograph Acquisition
A vital component of three-dimensional CRT is the process of image acquisition. In most departments a traditional fluoroscopic simulation is performed before the simulation CT scan. Initially, patients undergo immobilization procedures, which may involve designing custom-fabricated devices such as casts, foam body molds, thermoplastic head holders/ masks, and bite-blocks. The immobilization devices are constructed so that the patient can be positioned for planning and daily treatment in a reproducible fashion. The patient described previously was first placed prone on the table in the fluoroscopic simulator room. With her arms placed above her head to allow for lateral beam portals, a hardened foam cast was molded to conform to her upper body shape. Under fluoroscopic guidance, the body position was aligned as straight as possible using bony landmarks as a guide. The physician determined the isocenter position in x, y, and z directions using all available imaging information (prior diagnostic CT, endoscopy report, barium studies). The patient was then given diluted barium to swallow; subsequently a set of anteroposterior and lateral radiographs was obtained. The isocenter set-up points were then marked using permanent small tattoos placed on three body positions to define the triangulation laser set-up points for CT simulation and treatment alignment. CT Simulation
CT simulation is usually performed immediately after standard fluoroscopic simulation, but it can be performed in certain instances without a prior simulation procedure using a dedicated CT simulator unit. In that setting a CT simulator is used for both CT image acquisition and isocenter set-up using a three-dimensional computer-driven virtual fluoroscopy
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tool while the patient remains on the CT couch. Special lasers are then used to mark the patient. An important step at this time is to reproduce the simulation set-up position exactly as before using the CT localizing lasers to match the setup points and to make sure the patient is positioned in the same manner within the immobilization device. Small lead BBs and teflon catheters are used to mark the beam isocenter entry points on the patient. The physician marks the superior and inferior extent of the proposed treatment portals, and these points are used to define the length of the CT scan. The simulation CT scan is usually performed with additional margins above and below the areas to be targeted to allow for consideration of radiation beams that lie outside of the transverse plane of the tumor. Typically, CT scans are acquired with 3- to 5-mm-thick slices depending on the resolution required to generate useful three-dimensional images and digitally reconstructed radiographs. The CT volumetric data are then transferred electronically to the treatment planning computer system, where the remaining simulation and dose display procedures are completed. The example patient was scanned from above the clavicles through the diaphragm while immobilized in the treatment position in the CT scanner. The combined simulation process was performed within a 1-hour simulation time slot. Treatment Planning I: Target and Normal Tissue Delineation The next important step in the planning process is for the treating physician to identify and outline the appropriate tumor volumes on each consecutive CT slice on the treatment planning computer. This is normally done with a computer mouse or track ball device. There are usually two main tumor volumes of interest: the gross tumor volume (GTV), which usually represents the gross tumor as seen on CT, and the clinical tumor volume (CTV).8The CTV consists of the GTV plus local or regional volumes that are at risk for containing tumor cells, such as locoregional lymph nodes or other areas that the clinician believes are likely to harbor microscopic tumor deposits. The trained dosimetrist or physicist may help the physician identify and outline the important anatomic structures in the region of interest as well. The delineation of these structures is important to aid in beam orientation and block construction. For the case described, the esophageal tumor (GTV), regional lymph node areas (CTV), and critical anatomic structures (lungs, heart, spinal cord) were delineated with separate colors on each CT slice. Treatment Planning II: Virtual Simulation and Dose Calculation With the physician and treatment planning dosimetrist present at the treatment planning computer, a virtual simulation is performed in a manner that mimics conventional simulation. Studies of preoperative che-
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moradiotherapy for esophageal cancer have indicated a substantially escalated risk of perioperative mortality when large amounts of normal thoracic tissues are treated with high doses.9Consequently, it is important to design fields that are tailored carefully to minimize excess irradiation of adjacent lung parenchyma and heart tissue. The three-dimensional treatment planning system can display the anatomic patient information in several spatial views simultaneously, including any axial, coronal, sagittal two-dimensional or three-dimensional views.12The GTV and CTV are displayed in these projections as well as any or all of the outlined anatomic structures of interest. These volume renderings allow the clinician to appreciate the relative position of the tumor volumes in relation to normal structures to a much greater degree than with a traditional plain film radiograph. Once the user has decided on beam orientations, the computer records the specific gantry, couch, and collimator instructions that will be used for actual treatment. Beam apertures for cerrobend blocks or multileaf collimators can be shaped on the computer using beam's eye view display.23The aperture is usually made larger than the specified target to account for positional uncertainties and scatter of radiation effects. The treatment planning computer generates digitally reconstructed radiographs of each incident beam. The digitally reconstructed radiograph displays bony anatomy that is used for field verification with treatment machine port films. Dose distributions are calculated in three dimensions using dose algorithms that account for tissue inhomogeneities (air or bone).rhe various dose levels are projected on the CT image in any desired plane or three-dimensional rendition (isodose curves). Beam modifiers such as wedges and tissue compensators may be added to shape further the radiation isodose curves to conform maximally to the target. Often, several modifications to beam weight, beam orientation, and wedge angle are performed to optimize the treatment plan. Dose volume histograms (DVHs) also may be used to select the best plan. Figures 4 to 7 show beam's eye view displays, digitally reconstructed radiographs, and isodose curves for the boost portion of the patients' treatment. After adequate microscopic doses are delivered to a larger field arrangement, the boost or conedown fields were generated as shown. For the examule case, beam orientations were chosen that attem~tedto avoid spinal coid, heart, and lung tissue. The entire plan of radiLtion must be considered initially so as not to "burn any bridges" that may be needed later (e.g., spinal cord dose). The composite treatment was delivered through seven different beam orientations given over the treatment course with three separate plans each using different beam orientations. Each subsequent plan treated a smaller overall volume, as is typical for many treatment sites. The larger field was treated to 36 Gy and the reduced fields received an additional 14.4 Gy for a cumulative target dose of 50.4 Gy given in once daily 1.8 Gy fractions. The final boost dose of radiation was delivered through an anteroposterior, right posterior oblique, and left posterior oblique field arrangement. Because the spinal cord already had been irradiated in the initial fields, it was important that the oblique beams be "off-cord so that the cumulative total dose to the spinal cord did not exceed tolerable limits.
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Figure 4. Esophageal carcinoma. DRR of oblique (A) and AP (B)beam used for boost portion of treatment. Note the differential and off cord blocking used.
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Figure 5. Esophageal carcinoma. Axial view showing beam orientations without blocking. Note the divergence of the treatment beams and beam modifiers (wedges). Wedges are used to attenuate the beam differentially to increase dose conformity.
SPECIAL APPLICATIONS AND FUTURE DEVELOPMENTS OF THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY
The continuing evolution of three-dimensional CRT technology has led to investigations of more sophisticated applications of the fundamental tools of three-dimensional CRT in an attempt to expand further the potential clinical benefits of radiotherapy. Among the most promising and innovative endeavors are the developments of intensity-modulated radiotherapy (IMRT),body stereotactic radiosurgery, and genetic radiotherapy. Intensity-Modulated Radiotherapy
Intensity-modulated radiotherapy (IMRT) is a refinement of threedimensional CRT methodology currently in the pioneering stages. IMRT is a dose delivery method whereby the intensity of individual rays within the cross-sectional profile of a larger external beam is adjusted selectively to generate the desired pattern of dose distribution. This technique in-
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Figure 6. Dose volume histogram of esophageal case boost plan for tumor, spinal cord, and heart.
Figure 7. Cut-away three-dimensional view shows prescription isodose volume encompassing tumor and avoiding spinal cord and a significant volume of heart tissue.
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creases the conformity for treatments of complex targets over current state-of-the-art standard three-dimensional CRT. Essential for IMRT are a means to modify the flux of photons across the profile of a radiation beam and an algorithm for inverse dose planning. The former goal may be accom~lished with the use of a dvnamic multileaf collimator. a device that I contains computer-controlled motors that slide strips, or leaves, of lead blocking material across the beam, stopping at various positions for predetermined lengths of time. The net result is that each small section within the beam receives greater or lesser intensity of radiation according to the desired dose objectives. Figure 8 contains an example of a laterally directed, intensity-modulated beam that was used to treat a pelvic tumor and lymph nodes. The other critical component of IMRT, inverse dose planning, requires the implementation of a computer program designed to derive an optimized solution to a score function based on the clinical obiectives in the case. Details of the methodology are beyond the scope of {his article but are available e l s e ~ h e r e . ~Basically, , ~ ~ , ~ ~the , ~ inverse ~ dose planning algorithm seeks an optimum solution through an iterative process of ray intensity adjustments for a given configuration of number and orientation of beams. The inverse dose planning required for IMRT occasions additional opportunities for alternative concepts for radiation dose prescription. For any given clinical situation, radiotherapy dose prescriptions are typically limited by the total dose that can be administered safely to normal tissues in the field. Established guidelines predict an acceptably low risk of severe normal tissue complications for particular doses to individual tissue types or organ^.^ It has become widely recognized, however, that the functional response of organs and tumors to radiation dose is a complex process complicated by numerous factors. Among the important considerations are the percent of total organ volume irradiated and the dose per fraction of radiation use. Because it is only with the advent of the treatment plannine tools of three-dimensional CRT that com~leteinformation about the thrge-dimensional distribution of dose within patient has been available, there is still a need to analyze further the relative contributions of these and other factors. As data accumulate from careful prospective studies, it likely will become possible to make more accurate predictions of normal tissue complication probabilities based on a more complete knowledge of expected tissue effects. IMRT planning then could be driven by biologic indices that would vredict the normal tissue comvlication vrobabilities associated with given beam intensity profiles. It is possible that by means of IMRT or a similar beam modification technique, the total dose within the tumor might be escalated selectively without an incremental increase in expected effects on adjacent normal tissues. IMRT has been reported in the treatment of patients with prostate ~ancer,'~ and other indications are being e ~ p l o r e d . ~An , ~ ,example '~ of a patient treated at our institution with IMRT on a protocol designed to spare salivary function for head and neck tumors is shown in Figure 9. I
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Figure 8. Three-dimensional profile of a standard radiotherapy blocked field (A) compared with an IMRT lateral treatment beam (6).IMRT treatment is delivered using a dynamic multileaf collimator which moves individual l-cm leaves across the field during beam-on time to create the desired final profiles.
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Figure 9. Complex three-dimensional CRT (A) and IMRT (B) plans of a head and necktumor including local lymph node regions. The IMRT plan allows for significant sparing of parotid function and treats less normal tissue to high doses as compared with the three-dimensional CRT plan. The IMRT plan is easier to deliver, is fully automated, and requires no blocks.
Body Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS),a term introduced by Leksell in 1951, refers to a single high-dose radiation treatment delivered under stereotactic conditions to well-defined intracranial targets. SRS is a special case of three-dimensional CRT that was conceived to be more analogous to conventional surgery than to conventional radiotherapy because of its ablative intent of targeted tissues. SRS has become widely available over the past decade. Encouraging clinical outcomes have been achieved for intracranial arteriovenous malformations, acoustic neuromas, brain metastases, and, more recently, functional disorders. Because of these promising results and the availability of threedimensional CRT computers and stereotactic body frames, investigators recently have begun treating isolated tumors outside the cranium with radiosurgery-like doses given in one or several outpatient treatment sessions. This new area of body radiosurgery (BodySRS) relies on noninvasive, accurate immobilization and relocalization systems. Unlike cranial SRS, in which the external frame is fixed into the skull bone for extreme accuracy, body targets require an extra margin of tissue to be included in the prescription region because of positional uncertainties and organ motion. Initial promising results of BodySRS have been reported by Blomgren et a12 from Karolinska Hospital.15 They have performed BodySRS on 50 patients with isolated primary and metastatic tumors, delivering a mean dose of 28 Gy over one to five treatment sessions. It is important to realize that the true biologically equivalent dose to the tumor is much higher than 28 Gy given in standard fraction sizes (2 Gy). With a mean follow
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up of 11months, 29% of tumors showed growth arrest, 39%were reduced in size, and 32% disappeared. The local failure rate was 5%. A typical BodySRS plan of a patient treated at our medical center is shown in Figure 10. Further modifications of BodySRS include IMRT treatment delivery and the use of treatment gating, which coordinates beam output from the linear accelerator regulated with the breathing cycle of the patient. Gating should allow for a reduction in the margin of normal tissue targeted, especially for lung and liver tumors.14 Genetic Radiotherapy
Another role for three-dimensional CRT might be in the area of genetic radiotherapy, a speculativebut tantalizing clever proposed marriage between clinical radiotherapy and gene therapy.' The basic idea for genetic
Figure 10. Body radiosurgery plan for a patient with a solitary liver metastasis who refused surgical intervention. The patient received protocol therapy of 12 Gy each on 3 separate treatment days. The outpatient treatment was well tolerated, and required no sedation. A 5month post-treatment liver CT scan demonstrated a complete response.
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radiotherapy is that certain radiation-inducible genes, introduced into a patient via a viral vector or other appropriate means, might be promoted selectively (by targeted radiation) to achieve functional alterations in protein synthesis or other important cellular functions in a particular region within the body.17 The most direct potential oncologic applications of genetic radiotherapy involve genetic modulation of features of tumor cells known to affect radiosensitivity. For example, it has been demonstrated that certain squamous carcinoma cells defend themselves against the cytotoxicity of fractionated irradiation by means of a proliferative response triggered by activation of the cell membrane-bound epidermal growth factor recept~r.'~,~* A large-scale National Institutes of Health-funded research project is currently underway to develop an effective means of introducing genes that code for the production of a nonfunctional epidermal growth factor receptor. The goal is to abrogate the tumor cells' radiation-induced signals to replicate, thus enhancing the tumoricidal efficacy of radiotherapy. Proposed nononcologic applications have included introduction of radiationinducible genes to control cholesterol metabolism or other factors related to cardiovascular disease. In either scenario it is important to minimize the occurrence of unintended consequences caused by genetic modulation within tissue surrounding the targeted volume. The careful application of three-dimensional CRT is critically important to guarantee activation of radiation-inducible genes in the entire target volume while limiting activation in surrounding uninvolved tissue as much as possible. References 1. Advani SJ, Chmura SJ, Weichselbaum RR: Radiogenetic therapy: On the interaction of viral therapy and ionizing radiation for improving local control of tumors. Semin Oncol 24:633, 1997 2. Blomgren H, Lax I, Goranson H, et al: Radiosurgery for tumors in the body: Clinical experience using a new method. Journal of Radiosurgery 1:63,1998 3. Bortfeld T, Burkelbach J, Boesecke R, et al: Methods of image reconstmction from projections applied to conformation radiotherapy. Phys Med Biol35:1423,1990 4. Cardinale RM, Benedict SH, Wu Q, et al: A comparison of three stereotactictechniques: Arcs vs. noncoplanar fixed fields vs. intensity modulation. Int J Radiat Oncol Biol Phys 42:431, 1998 5. Cardinale RM, Wu Q, Benedict S, et al: Potential benefit of intensity modulated stereotactic radiosurgery using micro-multileaf collimation of static noncoplanar beams [abstract 22641. In Programs and Abstracts of the 40th Annual Meeting of ASTRO, Phoenix, 1998, p 359 6. Drzvmala RE, Mohan R, Brewster L, et al: Dose-volume histograms. Int J Radiat Oncol ~ i o f p h y 21:71,1991 s 7. Emami B, Lvman T, Brown M, et al: Tolerance of normal tissues to therapeutic irradiation. Int J ~ a d i a < ~ n c o i ' ~Phys i o l 21:109, 1991 8. ICRU Report 50: Prescribing, Recording and Reporting Photon Beam Therapy. Bethesda, MD, International Commission on Radiation Units and Measurements, 1993 9. Kavanagh BD, Anscher M, Leopold K: Patterns of failure following combined modality therapy for esophageal cancer: 1984-1990. Int J Radiat Oncol Biol Phys 24:633,1992 10. Kavanagh BD, Wu Q, Segreti EM, et al: The application of intensity-modulated radiotherapy in the management of uterine cervix cancer [abstract 22841. In Programs and Abstracts of the 40th Annual Meeting of ASTRO, Phoenix, 1998, p 369
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11. Kavanagh BD, Lin PS, Chen P, et al: Radiation induced enhanced proliferation of human squamous cells in vivo: A release from inhibition by epidermal growth factor. Clin Cancer Res 1:1557,1995 12. Kessler ML, McShan DL, Fraass BA: Displays for three-dimensional treatment planning. Semin Radiat Oncol2:226-234,1992 13. Khan F: The Physics of Radiation Therapy. Baltimore, Williams and Wilkins, 1994 14. Kubo H: Respiration gated radiotherapy treatment: A technical study. Phys Med Biol 41:83,1996 15. Lax I, Blomgren H, Naslund I, et al: Stereotactic radiotherapy of malignancies of the abdomen. Acta Oncol6:677, 1994 16. Ling CC, Burman C, Chui CS, et al: Conformal radiation treatment of prostate cancer using inversely-planned intensity-modulated photon beams produced with dynamic multileaf collimation. Int J Radiat Oncol Biol35:721, 1996 17. Maureri HJ, Hanna NN, Wayne JD, et al: Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 56:4311,1996 18. McShan DL, Silverman A, Lanza DM, et al: A computerized three-dimensional treatment planning system utilizing interactive colour graphics. Br J Radiol 52478,1979 19. Meyer JL, Purdy JA: 3-D Conformal Radiotherapy: A New Era in the Irradiation of Cancer. Basel, Karger, 1996 20. Mohan R, Barest G, Brewster L, et al: A comprehensive three-dimensional radiation treatment planning system. Int J Radiat Oncol Biol Phys 15:481,1988 21. Mohan R, Wang X, Jackson A, et al: The potential and limitations of the inverse radiotherapy technique. Radiother Oncol32:232,1994 22. Mohan R, Wu Q, Wang X, et al: Intensity modulation optimization, lateral transport of radiation and margins. Med Phys 23:2011,1996 23. Mohan R: Field shaping for three-dimensional conformal radiation therapy and multileaf collimation. Semin Radiat Oncol5:86-99,1995 24. Schmidt-Ullrich RK, Mikkelson RB, Dent P, et al: Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15:1191,1997 25. Spirou SV, Chui CS: Generation of arbitrary fluence profiles by dynamic jaws or multileaf collimators. Med Phys 21:1031,1994 26. Takahashi S, Kitabatake T, Morita K, et al: Conformation radiotherapy applied to cancer of uterus. Nippon Acta Radiol 20:2746,1961 27. Vijaykumar S, Myrianthopoulos LC, Rosengerg I, et al: Optimization of radical radiotherapy with beam's eye view techniques for non-small cell lung cancer. Int J Radiat Oncol Biol Phys 21:779, 1991 28. Wright KA, Primos BS, Trump JG, et al: Field shaping and selective protection in megavolt radiation therapy. Radiology 72:101,1959
Address reprint requests to Robert M . Cardinale, MD Department of Radiation Oncology Medical College of Virginia Hospitals P.O. Box 980058 401 College Street Richmond, VA 23298-0058