Introduction

Radiation therapy (RT) is a well established cornerstone of oncologic management. It is estimated that 40% to 60% of patients with cancer will benefit from RT at some point in their treatment course.1 Reflecting on this high utilization rate is both exciting and compelling. An estimated 1.8 million new cancer cases occurred in 2020 in the United States alone.2 This means that RT was potentially indicated as a modality in approximately 900,000 of those patients. The significant impact of this number places the RT modality as one of the most common single oncologic therapeutic options for patients with cancer. Thus meaningful improvements in RT will affect hundreds of thousands of patients with cancer annually. Studying the optimal use of RT is an exceedingly important part of understanding advancements in cancer therapy as a whole. Validated improvements in oncologic outcomes associated with technological improvements in RT will likewise provide evidence-based improvement for thousands of patients with cancer.

Like many cancer therapies, RT is rapidly evolving. The improvements in RT are the result of multiple technological advances. This reality should be considered in the broader context of improvements in cancer therapies.3 As computational advances occur along with imaging advances, each will have an important impact on the methods by which RT is given. There have been significant limitations to RT that these technological advances seek to overcome. Well designed, prospective, multi-institutional clinical trials will be needed to determine whether the proposed advances provide clinical benefit, and methods to improve RT will need to be continually introduced and evaluated. Radiation oncologists, medical oncologists, radiologists, clinical trialists, and patient advocates need to understand these advances to test them in a robust fashion. This review focuses on the concept of adaptive RT (ART) and, more specifically, magnetic resonance (MR)-guided ART (MRgART), as enabled by the integration of an MR imaging (MRI) scanner within the linear accelerators (linacs) that are used to deliver radiation. Our objective in this review is to illustrate how this novel category of RT differs from historic RT and how it is positioned to potentially improve outcomes associated with RT. Critical questions and potential applications associated with the use of these technologies are addressed.

Evolution of RT Technology Over the Past 30 Years

The past 30 years have seen dramatic technological changes in RT.4-6 Before 1990, RT used relatively simple techniques, in which image guidance was limited to using 2-dimensional (2D), plain film x-rays. In the most simplistic terms, a plain film x-ray was acquired during radiation planning, and the region of the body that contained malignancy was outlined and targeted for treatment. The field shape was typically drawn with straight lines, using bony anatomy that could be seen and referenced on x-rays as a guide. Lines were drawn to create a lead radiation portal, or port, that guided RT into the body. Because this planning process only used a 2D image, it was historically referred to as 2D RT. Although 2D-based RT seems primitive to many radiation oncologists today, it has dramatically influenced current RT practice. It was during the 2D era, from the 1950s through the 1980s, that RT formed its foundation as a cancer therapy.6 That foundation remains very influential in the modern era. Despite often being dismissed as technologically simplistic, the 2D era produced clinical outcome data that continue to influence current day RT. Indeed, many of our current standard-of-care RT doses, including normal organ dose tolerances, were derived largely during the 2D era. For example, despite technological advances over the past 30 years, postoperative RT doses for pancreatic cancer have remained largely unchanged.7, 8 This is despite modern methods to control and deposit RT dose. A movement beyond the 2D-based normal tissue dose limits, total dose and fractionation schedules, and regional anatomic treatment volumes (as defined by surface anatomy and/or 2D imaging) is imperative to accelerate the capabilities of RT into the modern era.9

Three-Dimensional, Intensity-Modulated RT, Volumetric-Modulated Arc Therapy, and Particle Therapy (Protons/Carbon)

With the invention of computed tomography (CT) came the ability to define tumors and organs in 3 dimensions.6 Such technology and capabilities were quickly adopted by radiation oncologists. This introduced a volumetric dimension of data to the historic 2D perspective that allowed radiation oncologists to define entire organs in 3 dimensions. RT beams could be modeled to pass through organs with an understanding of how much radiation dose each beam contributed to the specific organs.6 Developing a 3D computational model of the patient using CT enabled relatively quick and accurate calculations of RT dose distributions throughout these organs. During this same time period, clinical outcomes began to emerge illustrating the relation between the volume of organs treated with RT and subsequent toxicity events.10 Such data formed a new basis for RT plan evaluation and review. Shortly after the introduction of CT-based, 3D-conformal RT came intensity-modulated RT (IMRT).9, 11 The ability to modulate and sculpt the RT dose around normal organs was dramatically improved by IMRT. There have been demonstrations of reduced toxicity when using these novel techniques; however, pure randomized data are limited.12, 13 IMRT has also expanded into more advanced methods, such as volumetric-modulated arc therapy (VMAT), which is an enhanced method of delivering IMRT using arcs rather than static gantry positions. During VMAT delivery, the RT treatment machine rotates around the patient, improving radiation delivery. It has been shown that VMAT is faster and provides better dose distributions than competing techniques.14

Shortly after the introduction of IMRT and VMAT came a more accelerated adoption of particle therapy.15 Particle therapy, essentially the use of accelerated heavy ions, can deliver very steep dose gradients because of the physical properties of its particles. This use of particle therapy also contributed to reductions in normal tissue doses and toxicity in specific indications.15 A schematic timeline of this information is provided in Figure 1.

Historic Evolution of Radiation Technology Over the Past 30 Years: Image-Guidance Radiotherapy (IGRT), 2-Dimensional Radiotherapy (2D-RT), 3D-RT, Intensity-Modulated RT/Volumetric Modulated Arc Therapy (IMRT/VMAT), Particle Therapy, and Adaptive Therapy (ART).

The Use of Image Guidance in RT

Shortly after the introduction of 3D-based RT and, subsequently, IMRT came image-guided RT (IGRT). This relies first on the use of a CT simulation study, in which a patient model is derived from an immobilized patient, and external marks are placed on the patient for localization during daily treatment. This scan is also used for contouring and identifying normal organ positioning. When IGRT is implemented, patients are imaged immediately before each fraction of RT with on-board imaging systems that provide 3D (volumetric) images. The tumor and normal organ segmentations on these images are typically compared with those on the higher quality initial CT simulation images. The patient is then repositioned (adjusted slightly) to align these normal organs with their locations at the time of the CT simulation. In some circumstances, this is repeated at each fraction and thus enables slight adjustments for the location of the tumor along with normal organs. Figure 2 illustrates the concept of plain films versus daily image guidance using a CT scanner in the RT room. Figure 2B specifically demonstrates the use of daily CT to confirm the location of normal organs, such as the stomach. These organs are compared with their position from the original CT simulation image. Those structures are drawn on the CT simulation images, then their original position is superimposed onto each daily image to reflect the original position of these organs.

Illustrations of Radiation Treatment Given (A) Without Daily Computed Tomography (CT)-Based Image Guidance Using Plain Films and (B) Treatment Using CT on Rails.

Currently, most volumetric IGRT is performed with kilovoltage (kV) cone-beam CT (CBCT), megavoltage (MV) CT, and CT on rails. Other non-CT methods can include optical imaging, ultrasound imaging, orthogonal x-ray imaging (kV/kV or MV/kV), or fluoroscopic imaging (for guiding brachytherapy or intrafraction imaging). The concept and advantages of IGRT have been the subject of multiple separate review articles16, 17; however, it is also important to understand current limitations. Although physicians can visualize anatomic organs and tumor volumes using image guidance, responding to anatomic variations, such as relative positional changes or changes in shape or size (such as peristalsis), using only patient positional shifts is suboptimal. This creates the principal limitation of IGRT, which is the absence of the ability to correct for the volume changes and deformations of the tumor and/or normal structures. This results in a discrepancy between the actual RT dose that is delivered to the tumor or normal structures and the treatment plan. Figure 3 highlights such uncertainty and the impetus for ART.

Limitations of Image Guidance Alone—Volume Change/Deformations Can Be Seen But Not Accounted for Dosimetrically: Treatment of the Prostate Gland Associated With Significant Rectal Movement and Gas Causing Distension. CT indicates computed tomography; RT, radiotherapy; MV, megavoltage.

There are also CT-based and MRI-based methods to account for movement of tumors, such as 4D-CT and 4D-MRI. These imaging methods allow for tumor movement to be visualized during the breathing cycle and subsequently accounted for with RT treatment volumes.18, 19 However, it is difficult to account for normal organ movement during the time at which the beam is turned on. Movement of the radiation beam can allow for some tumor tracking; however, the ability to account for normal organ movement is limited to absent.

Adaptive Radiation Therapy Background

ART represents the next advancing frontier of IGRT. In its most basic definition, ART enables the changing of RT dose delivery to account for changes in either the tumor or normal structures during the course of RT delivery. The concept of ART was first introduced in 199720 and, by 2010, ART was widespread within the radiation oncology literature.21, 22 Its adoption has considerably accelerated recently with expanding technological innovations, including MR guidance.23, 24 There are many different anatomic changes that would require the modification of an RT dose distribution, including motion of normal organs and variations in tumor or organ size, changes in patient external anatomy (such as weight loss or gain), and positioning variations associated with daily alignment. Moreover, ART can also signal the need to modify the total RT dose based on progressive biologic changes in the tumor seen on imaging acquired during the radiation course. As an example, some recent trials have adjusted treatment based on positron emission tomography (PET) response, enabling true biologic personalization of therapy.25 Overall, if changes are seen using the image guidance techniques detailed above, ART can correct the RT dose distribution to accommodate these changes. Under these circumstances, RT dose prescriptions can sometimes be increased based on tumor response or reduced to spare adjacent normal organs. This is a highly complex procedure and considerable technical challenges are associated with its implementation (Fig. 4).

Traditional Radiotherapy (RT) Compared With Adaptive RT (ART). A comparative overview of the workflow associated with adaptive RT compared with traditional non-ART is presented. CT indicates computed tomography; MR, magnetic resonance.

There are several categories in which ART could be applied and may hold an important role. Each of these requires additional investigation and prospective evaluation before it is routinely recommended as a standard of care. It is important to recognize that, despite the existence of ART as a well described technique for at least a decade, the routine implementation and utilization of daily CT-based ART remains relatively limited.26 There are several reasons for this limited utilization. First is the tremendously labor-intensive and time-consuming nature of the adaptive process. Radiation oncologists often must be present for extended periods of time at each treatment to identify, modify, and approve new radiation plans. There is very limited reimbursement currently for the effort of involved personnel required to perform this adaptation. Second, the technical capability to perform adaptation is demanding. Imaging and adaptation technologies must be sophisticated enough such that they can be used to robustly detect and correct for the changes in tumor and normal organs. Such systems are not routinely available but are currently the subject of active research and development at high-volume academic centers and on a selective, case-by-case basis.27-31 Currently, this makes the widespread implementation of CT-based ART in a community practice limited. There are novel systems being introduced, such as the Varian Ethos system, that may affect this accessibility in the coming years.32 Another important consideration is the time associated with ART, which is a considerable limitation that should be considered. This can require a radiation oncologist to spend considerable time at the treatment machine re-contouring daily. Despite these limitations and relatively rare usage, the potential benefits of ART are significant. Moreover, MR guidance is introducing a highly feasible manner in which ART can be performed (Figs. 5 and 6).

Detailed Overview of Workflow, Additional Steps, and Potential Dose Improvements Associated With Adaptive Radiotherapy (ART) Either Online or Offline. IGRT indicates image-guided radiotherapy; RT, radiotherapy.

Detailed Example of Dose Distribution Differences Seen With Adaptive Therapy Using Magnetic Resonance Guidance. CT indicates computed tomography.

MR-Guided Adaptive RT

A central limitation of ART is the ability to routinely perform it with the state-of-the-art and most widely disseminated, 3D, on-table imaging modality, CBCT. The images that CBCT can generate on a daily basis often do not provide sufficient soft tissue contrast to accurately identify the required precise boundaries between normal organs and tumors. These images also suffer from organ motion-induced artifacts that further degrade image quality. CT on rails, a system that is essentially a diagnostic CT collocated with the RT delivery device, can offer a higher contrast image of the tumor and normal organs than CBCT provides. However, these systems are uncommon, and their use is relatively cumbersome and time-consuming. On-board MRI provides the superior soft tissue contrast of MRI, allowing ART to be performed with a much greater degree of confidence. An example of such imaging differences is presented in Figure 7 for a tumor that moves because of respiration. This is an example of a patient undergoing treatment with RT for a pancreatic tumor using CBCT guidance compared with a similar patient undergoing treatment using MRI guidance. The clarity of these daily MR images offers a more realistic and feasible method to perform ART using available images.

Example of Cone-Beam Computed Tomography (CT), Which Is Typical for Daily Image Guidance on Linear Accelerators, Compared With Daily Magnetic Resonance Imaging.

Some of the most common current uses for MR-guided RT include prostate tumors, oligometastatic disease, pancreatic tumors, central lung tumors, brain tumors, and rectal tumors.33 It is important to consider that the precise utilization of this technology is rapidly evolving and, as the technological capabilities develop, the utilization may change.

Randomized Trials Evaluating Adaptive RT

Despite the timeline and availability of ART, the currently published randomized clinical trials evaluating ART compared with non-ART are very limited. Only a small handful of trials have been performed attempting to prospectively quantify the benefits of this technology. Fortunately, this area is growing, and additional data should be available in the coming years. There are previous retrospective studies demonstrating that ART can improve target coverage and also reduce the doses of RT delivered to organs at risk in a variety of tumor sites, including head and neck, lung, breast, abdomen, and pelvis.34-36 Multiple historic trials have evaluated the feasibility of performing ART, and multiple reviews have been published on the topic.26 A few examples for consideration include the following: An early prospective trial conducted by Vargas et al demonstrated that ART could be performed in patients with prostate cancer and that higher doses of RT could be delivered to the prostate without higher rates of toxicity if normal organs are identified and accounted for in the process of RT delivery.35 In other tumor sites, such as lung, ART has also been attempted; however, clear clinical benefits of such adaptation are limited.37 There have been a few recent examples of biologic imaging during a course of treatment that have shown promise using fluorodeoxyglucose-PET (ClinicalTrials.gov identifier NCT01333033).38 There are also ongoing trials for which long-term outcomes are pending, such as NRG Oncology/Radiation Therapy Oncology Group trial 1106 (NRG/RTOG 1106) and the ARTFORCE Trial (ClinicalTrials.gov identifier NCT01504815).39-41 Specifically, RTOG 1106 adapted the radiation dose during treatment based on PET. The results of the study have been presented in abstract form and showed no significant differences in grade 3 or worse toxicity of the lung, esophagus, or heart. In addition, there was no difference in overall survival (OS), progression-free survival, or lung cancer-specific survival between treatment arms (adaptive vs nonadaptive). ART did improve in-field local-regional tumor control by 11% and in-field primary tumor control by 17% during the trial. The full publication of this experience is anticipated. Considerable additional effort is needed in the form of prospective trials to demonstrate the value of performing ART. This is primarily because the effort associated with the process is exceedingly time-consuming with the current technology. Before sufficient support of that time and effort can be provided or more robust technologies become available, there should be commensurate compensation for the considerable additional time and effort associated with this work.42-51 Table 1 summarizes select prospective trials that have recently examined different adaptive strategies.35, 37, 38, 41

TABLE 1. Recent Prospective Trials Examining Different Adaptive Strategies REFERENCE NO. OF PATIENTS DESIGN/RANDOMIZATION/QUESTION ADDRESSED CONCLUSIONS Vargas 200535 331 High doses were safely delivered in selected patients by ART Highest dose was selected on the basis of normal tissue tolerance constraints Rectal toxicity rates reflect dose-volume cutoff points Rectal toxicity rates in different dose levels and treatment groups to ascertain whether equivalent toxicity rates could be achieved Spoelstra 200937 24 Patients with lung cancer eligible for chemoradiotherapy and gated delivery underwent 4D-CT after 15 fractions The role of ART is limited when respiratory-gated RT is used to reduce the toxicity related to concomitant chemoradiotherapy Scan was coregistered with the initial planning 4D-CT, and a new planning target volume was generated based on the tumor visualized after 15 fractions Goodman 202138 225 Phase 2 trial, esophageal cancer/GEJ Adaptive treatment was promising using PET imaging as a biomarker to individualize therapy for patients with esophageal and GEJ adenocarcinoma Change in maximum standardized uptake value (SUV) from baseline was assessed This approached improved pCR rates specifically in PET nonresponders PET nonresponders (<35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions); PET responders (≥35% decrease in SUV) continued on the same chemotherapy during chemoradiation Kong 202141 138 PET-guided adaptive radiation boost increased in field tumor control by 11% 127 Patients were enrolled (43 in the standard arm and 84 in the adaptive arm) No difference was seen in overall survival, progression-free survival, or lung cancer-specific survival between treatment arms ART boost based on FDG-PET/CT scan during RT, and resimulation with CT scan was applied Abbreviations; 4D, 4-dimensional; ART, adaptive radiotherapy; CT, computed tomography; FDG-PET, fluorodeoxyglucose-positron emission tomography; GEJ, gastroesophageal junction; Gy, grays; pCR, partial complete remission; PET, positron emission tomography; RT, radiotherapy. Hypothesized Advantages of MR-Guided ART

The image quality and soft tissue contrast limitations highlighted above with non-MRI–based imaging have led many groups to consider incorporating MRI into the process of treatment planning and RT delivery. There are important novel aspects to consider about this process. The first is understanding how MR guidance differs from MR registration. For over a decade, MRI has been used as an additive to CT-based RT planning to help define soft tissues; this is described as MR simulation.52 However, the concept and process of adaptive MR guidance differs from this historic process of registering an MRI to a CT, which is outlined in Figure 8. Clinical implementation of MR simulation has been expanding over the past 8 years.

(A) Computed Tomography (Ct) to Magnetic Resonance (MR) Registration Is Compared With Daily MR Acquisition for the Purpose of MR Guidance. (B) MR-Guided Radiotherapy (RT) Acquires an MR Image Each Day. This enables clear visualization of targets as they change daily. MRI indicates magnetic resonance imaging; Sim, simulation; SV, seminal vesicle.

There are several advantages to using MRI as part of the daily image guidance to align and treat a patient using RT. It is well known from diagnostic radiology that MR offers superior soft tissue contrast. This improved soft tissue visualization is particularly helpful during the process of RT delivery in distinguishing tumors from the adjacent normal organs. It is critical to understand that soft tissues move during the radiation treatment because of physiologic anatomic changes, such as bowel peristalsis, respiration, or changes in tumor size.53-55 Therefore, improved visualization of these moving soft tissues enables radiation oncologists to precisely understand changes in dose distribution to these structures over the course of treatment. This improved soft tissue visualization also allows for the routine use of adaptation based on changes in daily anatomy. In addition to daily visualization of the soft tissues, MR guidance offers the ability to actively monitor and visualize these organs in real time while the beam is turned on. This allows radiation oncologists to see any unexpected movements while the treatment is being delivered that could result in higher or lower than anticipated doses delivered to these organs. Both of the commercially available MR-guided RT systems include adaptive capabilities to account for changes in normal organs and tumors that are seen on a daily basis. One important consideration is that MR systems often can account for tumor movement during treatment with gating. Gating refers to turning a beam on or off, depending on the position of a tumor. Normal organs, however, can move differently than a primary tumor—second to second during treatment—and this is not accounted for with gating or even with daily adaptation. The impact of this movement is not fully understood but is often visualized (as seen in Fig. 9).

Illustration of Bowel Movement Intrafraction on Close Proximity to High-Dose Radiotherapy (RT) Into an Otherwise Voided Space. CT indicates computed tomography; MRI, magnetic resonance imaging; sim, simulation.

Overview of Currently Available MR-Guidance Technology

Currently, 2 commercially available technologies combine an MRI device with a radiation delivery machine. Each of these technologies has important distinguishing features but overall they represent a common goal, which is the integration of improved soft tissue imaging capabilities (using MR) with a radiation machine to deliver RT. These devices are manufactured by 2 different companies: ViewRay Technologies Inc and Elekta AB. There are also 2 devices that are in development, one is by an Australian-based development group56 and the second is the Aurora-RT system (MagnetTx Oncology Solutions).57 The commercially available devices are gaining rapid and widespread adoption, with >26 Elekta systems clinically operational (>90 sold) and >41 ViewRay systems installed and in use globally (personal email communication from both companies). Key differences between devices are presented in Table 1. The ViewRay MRI-cobalt device has been cleared by the US Food and Drug Administration (FDA) since May 2012, and the ViewRay MRIdian linac has been FDA cleared since February 2017, with most of the installed cobalt systems subsequently being upgraded to the linac version. The Elekta Unity system received FDA clearance in December 2018. To date, ViewRay has produced 2 different systems consisting of their first device, a split 0.35-Tesla MR scanner with a ring gantry and 3 multileaf, collimator-equipped cobalt-60 heads. The cobalt-based device is no longer in production, although a few are still in clinical operation worldwide. The subsequent MRIdian linac is capable of 6-MV photon production combined, again, with a 0.35-T MR scanner.58 The Elekta Unity system is a 1.5-T MR scanner produced by Philips that is combined with a 7-MV linac produced by Elekta.59, 60 Details regarding each of these systems are summarized in Table 2.56, 58, 61-63

TABLE 2. Currently Approved Devices and Features COMMERCIAL NAME (REFERENCE) MANUFACTURE MRI FIELD STRENGTH BORE DIAMETER BEAM STRENGTH NO. OF DEVICES OPERATIONAL GLOBALLY Commercially available ViewRay (Mutic & Dempsey 201458) ViewRay Technologies Inc (Oakwood, Ohio) 0.35 Tesla 70 cm 41 Co-60 source 6 MV Elekta Unity (Raaymakers 2009,61 201762) Elekta AB (Stockholm, Sweden) 1.5 Tesla 70 cm 7 MV 26 In development Australian MRI linac system (Keall 201456) Australian MRI-linac program 1 Tesla 82 cm 6 MV NA Aurora-RT System (Fallone 201463) MagnetTx (Edmonton, Alberta, Canada) 0.5 Tesla 60 cm 6 MV NA Abbreviations: Co-60, cobalt-60; linac, linear accelerator; MRI, magnetic resonance imaging; MV, megavolts; NA, not applicable; RT, radiotherapy. Hypothesized Improvements in the Therapeutic Index Using MR Guidance

There are several categories of hypothesized improvements that are most commonly discussed in association with adaptive MR guidance. These consist of better visualization, routine access to and use of anatomic adaptation, motion management, and incorporation of biologic image guidance. Each of these topics is discussed in greater detail in the sections below.

Better visualization and routine access to ART

There are multiple aspects of RT that could be improved by the routine use of ART and, specifically, MR guidance. MR guidance presents an excellent opportunity to introduce ART into clinical practice for radiation oncology. The ability to see and adapt to changing normal anatomy is theoretically helpful for a variety of reasons. One of the greatest limitations to RT accomplishing a durable cure for patients is the proximity of the tumor to normal dose-limiting structures. This proximity results in the inability of RT to accomplish durable, long-term control. For example, control of solid tumors, such as pancreatic adenocarcinoma (PAC), with RT have historically been very limited secondary to the proximity of the small bowel, stomach, and colon. These structures have dramatically limited the doses of RT that could be used. An excellent contrary example of this circumstance is seen in early stage nonsmall cell lung cancer. Patients treated with ablative (very high) doses of RT for early stage nonsmall cell lung cancer routinely accomplish minimally invasive cure rates equivalent to those accomplished with surgical resection.64 A similar example is seen in patients with prostate cancer. When these patients are treated with high doses of RT, they routinely accomplish cure rates identical to those of surgical resection.65 Understandably, radiation oncologists are reluctant to deliver high doses to pancreatic tumors because of the significant risk of bowel toxicity. Theoretically, adaptive MR guidance can help to overcome this limitation. The narrow therapeutic index (detriments to benefit with increased toxicity) for many tumor types, such as pancreatic tumors, head and neck cancer, primary liver cancer, and rectal cancer, presents limitations for the success of current RT treatment modalities. Tumors require specific doses of RT to be fully eradicated; however, those doses to the tumor often cannot be achieved secondary to excessive toxicity to the adjacent dose-limiting organs. The potential to routinely apply an adaptive dose of radiation accounting for normal structures is very appealing.

Beam-on motion monitoring

Because MRI does not use ionizing radiation, MR guidance can monitor tumors as the beam is delivering RT using fast cine imaging. Repeated imaging has historically been avoided using CT-based image guidance because of the increased radiation risks, and there is no real-time analog to CBCT. Such monitoring can enable visualization when a critical normal organ moves in close proximity to a tumor. With effective motion management technology, this motio