Current Status and Future Potential of Advanced Technologies in Radiation Oncology

ABSTRACT: This article is part of a CME activity described in Oncology Vol. 23 No. 3

The entry of new technology into medical practice is complex. New technology in radiation oncology includes advances in imaging (including anatomic and molecular/functional imaging) and radiation therapy planning and delivery involving intensity-modulated radiation therapy (IMRT), stereotactic radiation therapy (SRT), and therapy with particles such as protons and carbon ions. The necessary research and development includes establishing baselines as to the current state of the art, and establishing quality assurance guidelines and procedures that meet the demands of the new technology. It further involves developing consensus as to what data and studies are needed, ranging from single-institution studies to multi-institutional phase II and phase III clinical trials, including measures of cost-effectiveness as appropriate.

On November 30–December 2, 2006, the Radiation Research Program of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) hosted a workshop entitled “Advanced Technologies in Radiation Oncology: Evaluating the Current Status and Future Potential of Proton and Other Heavy Charged- Particle Radiation Therapy, Intensity Modulated Radiation Therapy and Stereotactic Radiation Therapy.” The purpose of this workshop was to discuss current issues related to the advanced technologies, with an eye toward (1) defining the specific toxicities that have limited the success of “conventional” radiation therapy, (2) examining the evidence from phase III studies for improvements attributed to the advanced technologies in the management of several cancers commonly treated with radiation therapy, and (3) determining the opportunities and priorities for further technologic development and clinical trials.

The 2½-day workshop included presentations on general topics such as quality assurance, a framework for device-based clinical trials, and device evaluation from the perspective of the US Food and Drug Administration (FDA). In addition, there were several presentations on the state of the science by anatomic site, followed by three breakout groups: (1) brain, head and neck, pediatrics; (2) trunk (breast, lung, upper abdomen); and (3) pelvis (prostate, uterus, colon/rectum).

The workshop agenda, a list of the workshop participants, and their presentations can be found at the following website (more details may be obtained from the authors): http:// www3.cancer.gov/rrp/workshop/ 2006AdvancedRadiationTech/presentations. html. The participants had been selected by National Institutes of Health (NIH) staff to represent a broad spectrum of expertise from NIH-funded grantees, cooperative cancer clinical trials groups, cancer centers, professional societies, and industry. Each participant declared their conflicts of interest to all the participants at the outset of the workshop. No formal votes were taken, but the leaders of the breakout sessions did summarize the deliberations for NIH staff, who were solely responsible for compiling this report.

General Summary
The new technologies undoubtedly offer a substantial theoretical advantage in radiation dose distributions that, if realized in clinical practice, may help many cancer patients live longer and/or better. The precision of the advanced technologies may allow us to reduce the volume of normal tissue irradiated in the vicinity of the clinical target volume (CTV) or, in other words, decrease the planning target volume so that it approximates the CTV. Therefore, defining the precise size and shape of the CTV as well as the organs at risk becomes critical, as does accounting for changes in the position (motion) and changes in size and shape (deformation) of the CTV and the organs at risk, between and within radiation fractions, in order to avoid inadvertently missing the CTV.

The advanced technologies can also result in a greater volume of healthy tissue receiving some radiation compared with “conventional” techniques of radiation therapy, due to the generation of such radiation by the machines and/or the multiple fields employed.[1,2] Therefore, investigators must also consider long-term toxicity, including the risk of new radiation-induced cancers.

The costs of the new technologies were considered in the discussions in general terms only, including the need for expert personnel, additional time for treatment planning and delivery, and the cost of equipment. Issues of reimbursement and the regulation of how and when new treatments and technologies are approved for clinical use, however, were considered to be beyond the scope of this workshop and the mission of the NCI.

This workshop was not intended to reach any conclusions as to the superiority of one technology over another, nor did the participants feel that was possible in most cases due to a paucity of data. The workshop summarized the state of the science as of the end of 2006 (some references have been updated, however, in the discussion that follows), emphasized the need for developing quality assurance procedures and technologies suitable for clinical trials and clinical practice, and prompted vigorous discussion as to what clinical trials were possible and necessary before the new technologies entered routine medical practice.

Challenges Posed by the Advanced Technologies

Determining the ‘Correct’ Size and Shape of the Target Volume
The advanced technologies can conform the radiation dose very closely to the CTV and spare the organs at risk. In order to conform the radiation dose closely to the CTV, however, it is crucial to know the precise size and shape of the target volume. That can be a challenge because current imaging tools are often inadequate for determining the “correct” target volume, as evidenced by the fact that concordance among target volumes drawn by different experts on the same patients’ images was low-not only for covering microscopic disease extensions beyond the tumor visible on imaging studies but, in some cases, even for the gross tumor volume.[5-7]

Preventing Excessive Dose Heterogeneity Within the CTV
In a recent study involving 803 patients, whose IMRT treatment plans were done by experienced physicists (each of whom had already planned at least 50 IMRT cases) at five different institutions, it was discovered that in nearly one-half of the patients, the plan delivered to the CTV a maximum dose that was more than 10% higher than prescribed by the physician (it was 40% higher in the worst case). Furthermore, in nearly two-thirds of patients, the plan delivered to the CTV a minimum dose at least 10% lower than prescribed (it was 100% lower, ie, zero, in the worst case).[3] Those authors did not report the outcomes (tumor control or toxicity) relative to the doses, but in our current state of knowledge those “hot” and “cold” spots are rather alarming since we do not yet have the ability to identify “subvolumes” within the clinical target volume that should receive doses substantially higher or lower than prescribed by the physician.

Preventing Errors in Treatment Delivery
In another recent study, investigators at 128 Radiation Therapy Oncology Group (RTOG) member institutions, in order to be credentialed for participation in NCI-sponsored clinical trials employing IMRT, imaged an anthropomorphic phantom, developed an IMRT treatment plan, and then treated that phantom.[4] The goal was to deliver to the CTV a dose within 7% of the planned dose, with 4-mm agreement between the high-dose gradient and the edge of the critical organs at risk to be spared.

Approximately one-third of those institutions failed this test on the first attempt. It was discovered that the dose delivered differed from the planned dose by up to 22%, while the high-dose region was off by up to 1.5 cm. The sources of error were many, including:

• Inaccurate positioning of the phantom
• Inaccurate modeling by the treatment planning system (TPS) algorithm of field sizes formed by the multileaf collimator leaves
• Inaccurate handling by the TPS of inhomogeneity corrections
• Variable handling of cost-function optimization by algorithms that could not be controlled by the user
• Incorrect data input into the TPS
• Indexing errors in the table movement system
• Incorrect monitor unit settings

When so many of the top institutions in the United States had such difficulty in properly irradiating a phantom, with relatively relaxed criteria, that raises concerns about how patients are being treated by IMRT outside of NCI-sponsored clinical trials.

Furthermore, the locations as well as the sizes and shapes of the CTV and the organs at risk can change between (and even during) treatments due to voluntary or involuntary motion of the patient/organs, tumor shrinkage, edema, weight loss, etc. That makes maintaining conformity between the radiation dose distribution and the CTV during treatment difficult, even if conformity were excellent at the onset of treatment.

Ensuring Calculation of the Correct Dose Given Tissue Heterogeneity
Some treatment planning systems have problems calculating doses accurately in the presence of tissue heterogeneity, for instance when treating in or near the lungs. As a result, the radiation dose distribution in vivo may be quite different from what appears on the computer screen.[8] This may be even more challenging in the case of particle therapy.

Resources Available to Investigators

The NCI has supported many efforts, some of which are briefly described below, for coping with the challenges posed by the advanced technologies and protecting patients participating in NCI-funded cooperative group clinical trials that require or allow the use of the advanced technologies. Appropriate credentialing via facility questionnaires, benchmarks, and phantom irradiation are among the prerequisites for participation. In addition, many trials mandate pretreatment or rapid expert review of the target volumes, isodose distributions, and so forth. Furthermore, data on patient outcomes are always collected and analyzed. It bears emphasis, however, that the NCI mandate only covers the small fraction of patients who volunteer to participate in NCI-funded research.

Some workshop participants did express strong opinions about the need for minimum standards for appropriately and safely using the advanced technologies in practice outside the research setting, including training, credentialing, expert review, postmarketing surveillance of outcomes, pay-for-performance, and so forth. However, we must treat those issues as beyond the mission of the NCI and more appropriately addressed by the professional societies, the FDA, and the payors.

Atlases
Common atlases for delineating target volumes and organs at risk are being developed in an effort to increase consistency among investigators who participate in clinical trials involving patients with common cancers (see, for example, http://www. rtog.org/contour.html). It should be emphasized that while the atlases attempt to define the “correct” target volumes and organs at risk, whether or not those volumes are indeed correct will only be known when the outcomes of patients enrolled in those trials are analyzed. In essence, an atlas constitutes a hypothesis, proposed by expert consensus, which must be validated and refined by analyzing outcomes.

IMRT Guidelines
In 2004, the NCI first established guidelines for the writing of and participation in NCI-supported cooperative group protocols that employ IMRT. Those guidelines were updated in 2006, and are available at http://atc. wustl.edu/home/NCI/NCI_IMRT_ Guidelines.html. Each institution participating in such an NCI-supported protocol must be credentialed by the group (eg, RTOG, Children’s Oncology Group [COG]) in charge of the protocol.

Proton Radiation Therapy Guidelines
In 2007, the NCI established guidelines for the writing of and participation in protocols that employed protons. Those guidelines are available at http://www.qarc.org/benchmarks/ ProtonGuidelines_June2007.pdf. Each institution participating in such an NCI-supported protocol must be credentialed by the group (eg, RTOG, COG) in charge of the protocol.

Advanced Technology Consortium
The Advanced Technology Consortium (ATC), whose website can be found at http://atc.wustl.edu/, supports the development and execution of, and digital data exchange for, a growing number of clinical trials (both NCI-funded and others) that utilize the advanced technologies. The consortium has devised a methodology for decreasing interinstitutional variations in the key step of submitting information used for verifying the use of registration (fusion) software for combining different kinds of images. It is currently working on a solution to the problem that some treatment planning systems have when calculating doses in the presence of tissue heterogeneities. It is also designing phantoms to simulate target motion due to respiration.[9]

The ATC seeks to create an environment in which clinical investigators can receive, share, and analyze volumetric, multimodality treatment planning and verification digital data, thereby improving the quality of clinical trials involving advanced technology radiation therapy. The quality assurance requirements change as the technology evolves, and also from protocol to protocol depending upon the question(s) being addressed. The ATC develops uniform processes and an infrastructure to assist the cooperative groups in assuring quality, but the actual responsibility for quality assurance belongs to the investigators and cooperative group(s) conducting the trial.

Patient-Reported Outcomes Measurement Information System
Much of the impact of the advanced technologies in radiation oncology, at least in the short-term, will likely be to decrease toxicity by decreasing the volume of nonmalignant tissues subjected to high doses of radiation while treating common cancers. In other words, these technologies may help patients live better (with a better quality of life) rather than longer. Measuring the quality of life can be challenging, however, and many researchers in radiation oncology are not well versed in that methodology.

The goal of the NIH-supported Patient-Reported Outcomes Measurement Information System (PROMIS) is to enhance and standardize the assessment of patient-reported healthrelated quality of life (HRQOL). Started in 2004, the PROMIS Network has utilized a sophisticated and rigorous multimethod approach to develop item banks measuring physical function, pain, fatigue, depression, anxiety, anger, and social well-being. Researchers can access PROMIS item banks through the PROMIS website (www.NIHpromis.org) to select either static or individually tailored adaptive measures of HRQOL. Either approach yields brief, precise, and valid measures of a patient’s health status.

In a special supplement funded by the NCI, the PROMIS network has extended the item banks to capture data on sexual functioning, cognitive function, sleep/wake function, and illness impact in cancer populations. This supplemental project will evaluate how well the PROMIS item banks perform, both in the treatment and the survivorship phases of care.

Why Clinical Trials Are Needed

Hypotheses regarding improved patient outcomes that are based on physical dose distributions and computer-generated treatment plans require appropriate clinical studies to validate those hypotheses. Admittedly very limited proof of principle currently exists, but the absence of proof is not proof of absence of benefit from the advanced technologies, because time is required for generating credible clinical trial data-both short- and long-term-on survival and patient-reported outcomes. Nonetheless, important and informative data on acute toxicities can be gathered fairly quickly.

Quality assurance procedures that can meet the demands of the advanced technologies must be established and implemented in conjunction with undertaking formal comparative studies. For instance, atlases for delineating target volumes and organs at risk, as well as common tools for standardization of image registration (fusion) software, have been developed as already described. Methods for dealing with the deformation of the target volumes and organs at risk, procedures for preventing errors in treatment delivery due to movement during and between fractions of radiation, and procedures for ensuring calculation of the correct dose in the presence of tissue heterogeneity must be standardized.

The advanced technologies offer exciting and potentially substantial advantages in radiation dose distributions, but given the current state of our knowledge, it can not be simply assumed that they help patients live longer or better. In fact, due to the reasons outlined above, we cannot even assume that the outcomes are as good as what is seen with “conventional” techniques in many cases! The possibilities of geographic miss, underdosage, or overdosage are real, even before taking into account the uncertainties in target delineation, deformation, motion, and heterogeneities.[ 3-8] Researchers should take into account the differential costs of replanning to account for tumor regression during treatment when calculating quality-adjusted life-years and cost-effectiveness.

Furthermore, two recent articles offer poignant reminders of how often the perception of academic clinicians that a new, experimental cancer treatment shall produce an outcome better than the standard treatment is proven wrong by prospective randomized trials.[10,11]

In part 2 of this article, which will appear in the next issue of ONCOLOGY, the authors describe the state of the science for various disease sites, with considerations of tumor control and toxicity rates after traditional conformal radiation therapy, and whether phase III trials support an additional benefit from the advanced technologies.

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