Volume 76, Issue 4 , Pages 963-972, 15 March 2010
American Society for Therapeutic Radiology and Oncology (ASTRO) Emerging Technology Committee Report on Electronic Brachytherapy
Article Outline
- Abstract
- Problem Definition
- Description of the Technology
- Potential Future Development
- Description of Impact
- Evaluation/Summary of Results of Existing Studies
- Identification, Analysis, and Evaluation of Consequences of Non-Use
- Possible Impact
- Disclaimers and Notifications
- Acknowledgment
- Supplementary Data
- References
- Copyright
The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site.
Electronic Brachytherapy, Radiotherapy, interoperative, device terminology, Radiation
Problem Definition
The use of intraoperative radiotherapy (IORT) has a long history in radiation oncology, primarily to deliver single large fractions or a “boost” dose directly in situ, allowing for increased dose delivery and decreased normal tissue exposure (1). Preclinical studies in animals, combined with experience in humans, have provided guidance for safe and effective use of this approach in general.
Intraoperative radiotherapy using electrons has been the favored approach over orthovoltage beams because of better dose homogeneity, decreased treatment time, and less bone absorption attributed to the photoelectric effect. However, orthovoltage IORT has advantages in certain clinical settings and is generally more cost-effective. Recently, electronic brachytherapy (EBT) devices have become commercially available. These devices use EBT sources instead of radioactive isotopes and produce low-energy radiation at a high dose rate (HDR). The potential major advantages of EBT are disposability of the source after use and a lesser requirement for protective shielding during the procedure.
These devices are currently subject only to regulatory clearance by the U.S. Food and Drug Administration (FDA) and do not fall under the purview of the U.S. Nuclear Regulatory Commission (NRC). Regulatory requirements in individual states may vary widely. Reports from the American Association of Physicists in Medicine (AAPM) address calibration and safety measures for radioactive isotopes but do not cover electronic sources. Therefore there is interest in developing standardized dosimetric and regulatory guidelines for these new devices. In this report we describe two of these new technologies, their current status, and their potential applications, as well as the importance of developing guidelines for future clinical use.
Description of the Technology
There are currently two systems that fit the category of EBT. The first is the Axxent Electronic Brachytherapy System (Xoft Inc., Fremont, CA), a system of devices used for delivery of low-energy radiation at an HDR. The second, the Zeiss Intrabeam (Carl Zeiss Surgical, Oberkochen, Germany), is a mobile photon radiosurgery system (PRS) that procures a miniature electron beam–driven X-ray source.
Xoft, Inc., device
SpecificationsThe primary components of the Xoft device include an electronic controller, a miniature electronic X-ray source contained within a flexible probe, and a balloon applicator to apply radiation directly to a tumor bed. The Xoft controller, shown in Fig. 1, delivers power to the EBT source and controls the source movement. The source is a disposable miniaturized X-ray tube that measures approximately 2.2 mm in diameter and has an operating potential of up to 50 kV. It is integrated into a water-cooled, flexible probe assembly (Fig. E1A), measuring 250 mm in length and 5.4 mm in diameter. Details of the X-ray tube located at the tip of the source assembly are shown in Figs. E1B and E1C. The source assembly is connected to a high-voltage cable that is directed into the lumen of the applicator and enables the controller to step the source to preprogrammed dwell positions within the applicator. Power to the source reaches a maximum of 15 W. When the source is active, the radiation output is 0.6 Gy/min at 3 cm from the source axis, as measured in water. During 50 kilovolts peak (kVp) operation, the average of the bremsstrahlung photon spectrum ranges from 26.7 to 34.5 keV as the beam passes through 0 to 4 cm of water, respectively, with a maximum photon energy of 50 keV in each case. These energies are similar to those of iodine 125 (27.2–35.5 keV; mean, 28.4 keV). The controller can be set to operate at 50, 45, or 40 kV and has a maximum beam current of 300 μA.
Fig. 1
Axxent controller showing source assembly and well chamber used for source calibration.
The applicator, shown schematically in Fig. 2, is a balloon with a radiolucent wall that can be visualized on plain films and computed tomography (CT). At present, spherical applicators with diameters ranging from 3 to 6 cm and a 5 to 6 by 7–cm elliptical applicator are available. The shaft of the applicator contains 3 separate lumens. Two ports are designated for inflation of the balloon and insertion of the radiation probe along the treatment pathway. The third port is connected to several drainage holes at the apex and base of the balloon, which feed to extrusion lumens that provide clearance from the wound cavity in the event of seroma development. Figure E2 shows the range of clinical applicators currently available.
Fig. 2
Schema of balloon applicator. Three lumens are used: one each for balloon inflation and insertion of the source assembly and a third for drainage of seroma through two holes on either end of the balloon.
To deliver treatment, a trocar is used to create a pathway for the applicator via a centimeter-sized lateral skin incision. The procedure can be performed at the time of surgery or under local anesthesia in an outpatient suite postoperatively. A rigid metal obturator is placed into the balloon applicator to help guide it into the cavity. The applicator is then positioned within the breast cavity and inflated with sterile saline solution. Ultrasound, plain film, or CT is used to verify the position of the applicator and ensure that the cavity is filled and the surgical margin conforms to the applicator. The applicator shaft is taped to the external skin of the breast for repeated access to the cavity.
Treatment planning is performed in conjunction with CT images by use of a conventional brachytherapy treatment planning system, which incorporates parameters describing the electronic source data. Both the BrachyVision (Varian Medical Systems, Palo Alto, CA) and Plato (Nucletron, Veenendaal, The Netherlands) treatment planning systems have been validated. Plan details, in the form of source dwell positions and dwell times, are downloaded directly to the controller. On the basis of the preset treatment plan, the controller manages source movement through the programmed dwell positions by stepping the source back along the shaft in millimeter increments accordingly. The cable can negotiate up to a 15° curve but requires a fairly straight pathway within the treatment region (2).
Before each treatment, the probe containing the electronically activated source is advanced into the central lumen of the applicator shaft. On the basis of current FDA approval, each source can be used only for a limited beam-on time. This limits the maximum number of treatment fractions that can be delivered by each source, after which the source must be discarded. Once treatment is initiated, the controller moves the source to the furthest distal point inside the shaft of the saline solution–filled balloon and stops it when the source comes in contact with the back wall of the lumen. A typical treatment plan requires the source to then be stepped through 5 to 10 dwell positions. The source is encased in the cooling sheath through which water is pumped continuously during treatment to provide cooling. Any malfunction in either the high-voltage circuit (including the X-ray tube) or the cooling system results in immediate treatment termination, and parameters of the treatment delivered at that time are recorded.
The treatment time for each fraction is usually less than 10 minutes. The controller contains a display showing the elapsed time, total planned time, time remaining at the current dwell position, and a visual display of the source position.
ShieldingThe Xoft device is used in much the same way that current HDR brachytherapy afterloading systems are used in the treatment of early-stage breast cancer. One major difference is that the procedure may be done in a minimally shielded room because of the low-energy nature of the X-ray source. A 15-inch flexible drape of 0.4-mm lead equivalent placed over the breast allows other personnel to be in the room with the patient with minimal exposure (Fig. E3).
Measurements have shown that during treatment, the radiation exposure is on the order of 15 mR/h at a typical operator's location (3). When a flexible drape is placed over the patient in the treatment area, the exposure rate drops to much less than 1 mR/h at this location. As an additional safety feature, the device also has the ability to pause or stop treatment at any time because power to the source can be halted via the controller, thus instantly interrupting X-ray production.
Source calibrationThere is currently no standard from the National Institute of Standards and Technology for the electronic source. The Radiation Calibration Laboratory at the University of Wisconsin has developed a secondary standard based on measurements from exposure of the source to a free-air ionization chamber, and it provides calibration certificates for re-entrant well chambers that can be used for field measurements of source air-kerma strength. A calibrated well chamber (HDR-1000; Standard Imaging, Middleton, WI) coupled with a calibrated electrometer (MAX 4000; Standard Imaging) is provided with the system and used to calibrate each source before clinical use.
Safety and regulatory considerationsThe low-energy radiation aspect of these devices reduces the need for special room shielding, and personnel can wear lead aprons and/or patients can be draped with lead sheets, allowing much less radiation exposure to staff and family than with conventional isotope-based brachytherapy. However, the device, which does produce radiation, is not currently subject to regulation by the NRC or state departments of public health (or similarly charged agencies). The Conference of Radiation Control Program Directors is currently considering development of a set of template regulations for consideration by its constituent members for individual state presentation and possible adoption. Because the device contains no radioactive source, a radioactive materials license is not required. Concepts from AAPM reports have been proposed to guide usage and quality assurance, but there are currently no reports specifically addressing EBT.
In states where human studies are under consideration, Xoft is currently working with regulators to determine reporting requirements (4). Each preclinical testing site will most likely need to provide radiation exposure data to relevant state agencies as part of the license application.
Dosimetric guidelines and quality assuranceThe relevant AAPM brachytherapy reports covering operational use of the system include the following:
According to TG-56, an HDR remote afterloading system should be subjected to quality-assurance measures including mechanical and radiologic safety, positional accuracy to within 2 mm, temporal accuracy and timer linearity, and accuracy of dose delivery within a margin of less than 2%.
TG-56 also specifies quality-assurance measures for the source calibration and dose distribution. It is recommended that the frequency be based on the radioisotope's half-life, but this provision is not applicable to electronic sources. The margin of error for source calibration should be less than 3%. The dose distribution may be characterized for a single source in water.
TG-59 outlines the training and responsibilities of the staff, as well as the responsibility for documenting written procedures for applicator preparation, insertion, and localization; treatment plan documentation and approval; and quality-assurance procedures and checklists as well as emergency procedures.
TG-152 is charged with evaluating EBT sources. A report has not yet been published, but it is expected that it will address many issues related to quality assurance and clinical application of EBT.
Xoft has developed a proposed quality-assurance checklist that incorporates some provisions of the TG-56 and TG-59 reports. The Conference of Radiation Control Program Directors has formed a task force, and a report is being drafted for review.
Zeiss device
SpecificationsThe Zeiss Intrabeam system is a mobile PRS that produces a miniature electron beam–driven X-ray source (Fig. 3). The electrons are generated and accelerated in the main unit (Fig. E4) and travel via the electron beam drift tube, which is surrounded by the conical applicator sheath such that its tip lies at the epicenter of the applicator sphere (Fig. E5). It provides a point source of low-energy X-rays (50-kV maximum) at the tip of a 3.2-mm-diameter drift tube with a target at the tip emitting a nearly isotropic field of low-energy photons (Fig. E6).
Fig. 3
Miniature X-ray generator (Intrabeam).
The available applicators consist of a cylindrical shank attached to an applicator ball at the distal end that ranges in size from 1.5 to 5 cm in diameter and is open at the proximal end (Fig. E5). The applicators are made of polyetherimide (C37H24O6N2), which has a glass transition temperature of 216 °C and a density of 1.27 g/cm3. They are reusable, biocompatible, and radiation resistant. The applicators are cleaned and sterilized before each use with a pre-vacuum steam sterilization process at 132 °C to 135 °C for 3 to 4 minutes. The applicator transfer function (ATF) takes into account the attenuation and scatter resulting from a given applicator size. The ATF values have been characterized and tabulated as a function of depth.
Once the applicator size has been selected, the X-ray device is mounted on its stand and the applicator is attached to the X-ray unit. An optical interlock system detects the applicator and indicates its proper positioning. Before use, the stand and the X-ray device are wrapped in a sterile clear plastic cover via routine sterile surgical techniques, leaving only the already sterile applicator exposed.
The applicator is inserted into the surgical cavity, and the tumor bed is conformed around the applicator sphere. An intraoperative ultrasound is performed to determine the distance of the applicator surface to the skin, to avoid significant skin doses that occur with distances of less than 1 cm. The applicator is secured in place by the surgeon using subcutaneous sutures around the neck of the sphere. To measure skin dose, a strip of dosimetric film (Gafchromic; International Specialty Products, Wayne, NJ) placed in sterile plastic is taped onto the skin where the device is most superficial.
ShieldingAs the device emits X-rays quasi-isotropically, any person present in the room when the X-rays are switched on should be behind a shielded screen. However, the quick attenuation-of-exposure rate allows treatment to be carried out in a standard operating room (OR).
Measurements performed to complete the commissioning process at the University of California, San Francisco have shown that during treatment, the radiation exposure was on the order of 12 to 15 mR/h at about 2 m from the source (5). A mobile-shielded panel and/or a leaded apron is sufficient to bring the exposure to background level. This allows personnel to stay in the room during the entire procedure. As an additional safety feature, the device also has the ability to pause or stop treatment at any time because power to the source can be halted via the controller, thus instantly interrupting X-ray production.
Source calibrationThe performance of the X-ray source must be verified within 24 h of anticipated use according to the manufacturer's recommendations. The same calibration can be used if more than one treatment is scheduled on the same day. A medical physicist typically spends 2 h in the procedure room, and the pretreatment verification requires 1 h, which amounts to a total of 3 physics-hours per procedure.
The main items that require quality assurance are the X-ray source itself, two ion chamber measuring devices, and an X-ray needle alignment tool. The precise dose rate depends on the diameter of the applicator chosen. The applicators are sterilized and maintained in the OR by appropriate OR staff. The proper balancing of the stand should be verified before each procedure, and rebalancing may be required if any resistance is felt while holding the device with the break released.
The calibration procedures are described in the PRS400 Radiosurgery Treatment System Operator's Manual (PN 99200001 Rev: B).
The calibration procedures include the following steps:
In the event that the needle is bumped, all steps described previously must be performed again. Therefore all equipment required for those steps must be available in the OR.
The values of the IRM count rate, ion chamber current, and secondary ion chamber dose rate should be printed out and included in the patient dose plan. These values will be required for dose-planning purposes.
Dose distribution characteristicsThe dose is generated by a single source position, and therefore the dose distribution is generally spherical. The radiation produced has the typical inverse square law behavior (1/r2). Attenuation in tissue introduces an additional attenuation factor governed by an approximate inverse linear law (1/r). Therefore the radial dose attenuation decreases as the inverse cubic law (1/r3). Dosimetry studies indicate the reproducibility of dose delivery.
The dose rate in water (Do), in grays per minute, is calculated by correcting the reference dose rate (provided by the company) by use of the ion chamber ratio (ICratio) obtained during the calibration process. The radial dose rate distribution in tissue is calculated from the dose rate distribution obtained in a water phantom without the applicator by multiplication with the so-called ATFs, defined as the ratio between the dose rates in the presence and in the absence of the applicator as a function of the radius, r (distance from the target). For a given prescribed dose (Dpx) in grays, the run time (in minutes) is obtained with the following equation:
Typical run times are about 16 and 33 minutes for 2.5- and 5-cm applicators, respectively. The same dose of 5 Gy at a 1-cm depth is prescribed for each patient undergoing Intrabeam treatment for breast cancer.
Technical characteristicsThe system generates a maximum current of 40 μA to produce 50-kV peak X-rays that are emitted from a gold target. The probe is 3.2 mm in diameter and 10 cm in length. The dose rate is fixed and is monitored online with an IRM (i.e., the actual dose delivered is always available in case of problems such as a power failure). Calibration of the device is required before use on any given day. When the patient is ready for treatment, the sterile applicator is secured onto the probe. The prescribed dose is delivered in a single fraction from a single source position. Anisotropy of the quasi-isotropic dose distribution is higher in the proximal direction because of increased filtration. Dose falloff is more pronounced than any radioactive source currently used clinically. Treatment planning does not require imaging, although some centers use intraoperative ultrasound to document distance from the skin surface.
Safety and regulatory considerationsSimilar to the Axxent device, the Zeiss product is not regulated by the NRC or, as yet, by state departments of public health. For IORT devices, the AAPM has proposed guidelines in the TG-72 report, which appear to be relevant: “Intraoperative radiation therapy using mobile electron linear accelerators: Report of AAPM Radiation Therapy Committee Task Group No. 72” (Appendix E1).
The TG-72 report comprehensively describes and recommends the basic components and expertise necessary for the implementation of an IORT program within the OR environment. It provides guidelines on radiation protection issues, machine commissioning of items that are specific to mobile electron linear accelerators, and designs and recommendations regarding an efficient quality-assurance program for mobile systems.
The concepts put forth by TG-72 specifically refer to the Mobetron (Intraop Medical, Sunnyvale, CA) and Novac7 linear accelerator units (Hitesys SRL, Aprilia, Italy); however, “in general, apply to the installation of new IORT programs using mobile linacs [linear accelerators], regardless of manufacturer.” Most of the recommendations regarding procedures are similar to what was followed in practice for installation and use of the Zeiss Intrabeam system at the University of California, San Francisco (5).
Potential Future Development
Present scope of use for Xoft Axxent
The date of approval for marketing of the device by the FDA was December 22, 2005 (K050843). At this time, the scope of the FDA's approved usage has been restricted to postoperative breast cancer treatment. As stated by the FDA, “The Xoft Axxent Electronic Brachytherapy System is intended to provide brachytherapy when the physician chooses to deliver intracavitary or interstitial radiation to the surgical margins following lumpectomy for breast cancer.”
After FDA approval, Xoft initiated a 40-patient postmarketing study that will likely finish accrual by the end of 2008. A voluntary registry has also been established by Xoft in coordination with the American College of Radiation Oncology and the American Society of Breast Surgery (ASBS). The registry is planned to include 1,300 patients. According to current projections released by Xoft, at least four sites are now treating patients and at least nine sites will have started treatment by the end of 2007. These sites are or will be using the device to deliver breast brachytherapy treatment.
Anticipated clinical implementation
Electronic brachytherapy can be delivered in one or multiple fractions. Currently, the fractionation schedule being used in practice resembles that developed for other postsurgical breast brachytherapy applicators that use HDR radioactive isotopes as sources. The fractionation schedule, modeled after that of the B-39/Radiation Therapy Oncology Group (RTOG)–0143 trial of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and RTOG, is comprised of 10 fractions of 340 cGy, delivered twice daily. Confirmatory radiographic imaging is performed at the time of each fraction.
Future potential clinical applications
Other indications for the system are currently being investigated. Xoft is currently developing vaginal applicators for use with the electronic controller and source.
Of note, several variables may be manually controlled including the operating voltage of the anode (penetration depth), beam current (dose rate), dwell positions within the applicator, and time at each dwell point. Therefore the electronic source can be intensity modulated to mimic the penetration and dose rate characteristics of several isotopes, including iodine 125, iridium 192, and palladium 103. However, the limited penetration of the beam may contribute to greater dose conformity and higher dose inhomogeneity between surface and depth.
Present scope of use for Zeiss Intrabeam
The Intrabeam system was first approved for use by the FDA for intracranial tumors in 1999 and was subsequently approved for whole-body use in 2005. The Intrabeam spherical applicators are indicated for use with the Intrabeam system to deliver a prescribed dose of radiation to the tumor bed during intracavitary or IORT treatments.
At the time of this writing, the cumulative reported experience worldwide with the Intrabeam system includes 1,100 patients with brain tumors (primary and metastatic), 1,200 patients with primary breast cancer, and more than 100 cases of varying indications including colorectal cancer, soft tissue sarcomas, head-and-neck tumors, and liver tumors (numbers provided by Zeiss). The routine application of IORT with Intrabeam has included the following:
Future plans by Zeiss are reported to expand the clinical applications for this device to include liver lesions, spine tumors, and vaginal and skin cancers.
Description of Impact
Present status of product marketing
The Breast Center at the WellStar Kennestone Hospital in Marietta, Georgia, was the first to use the Xoft Axxent brachytherapy system to treat patients. Other physicians have adopted the technology and are serving in educational roles with the company. Physicians at Dallas Breast Center, Dallas, Texas, led an industry-sponsored symposium entitled “The Role of the Surgeon in Electronic Brachytherapy of the Breast” at the annual ASBS meeting in Phoenix, Arizona, in May 2007 to discuss best practices for implementation. There are plans for development of a patient registry, which will be administered by ASBS to track patient data and outcomes. In addition, in October 2007 there was a satellite symposium at the annual American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in Los Angeles, California, entitled “Electronic Brachytherapy: Putting the Accent on Access.”
Competing commercially available products
The Xoft system has multiple components. Similar products can therefore be grouped into 3 main categories:
Similar products and price comparisons (Zeiss)
Other IORT devices that have some similar features to the Zeiss Intrabeam are compared in Appendix E1.
Evaluation/Summary of Results of Existing Studies
Mature clinical data specifically using the Xoft device have not been published. However, a number of small-scale industry-sponsored studies have addressed the characteristics of the produced radiation, safety considerations related to the device, and feasibility of the device for clinical use. More specifically, several issues were addressed including relative biological effectiveness (RBE) of radiation of an HDR and low energy, dose distributions obtained with a variable energy source, application of TG-43 formalism, in vivo animal feasibility studies, stability of X-ray exposure, manufacturing standards for commercial source production, and design deficiencies. For a comprehensive review of these studies, primarily in abstract form only, please refer to Appendix E2.
Radiobiological considerations for IORT
There is a significant body of literature that addresses the clinical efficacy of single large-fraction radiotherapy delivered via IORT for various organ sites (6). The central radiobiological considerations of IORT have been (1) single fraction vs. multiple fractionation schedules and early- and late-reacting tissues; (2) dose rate effects; and (3) organ tolerance. This literature is beyond the scope of this report; however, it provides basic clinical guidelines in terms of organs and tolerance doses for the safe application of IORT in general.
With respect to the Zeiss Intrabeam system, there have been 2 published studies by Herskind et. al. 7, 8 that address specific aspects of the radiobiology of the device. The first provides a model of the distribution of RBE around the spherical applicators for single-dose treatment (7). It addresses specific features associated with using PRS that influence radiobiological considerations including (1) the radiation quality of a 50-kV source (RBE increases with decreasing photon energy), (2) the steep dose gradient around the source, and (3) prolonged radiation delivery associated with the PRS system (20–35 minutes). The authors used a modification of the linear–quadratic formalism used to calculate RBE as a function of dose for different low-energy X-ray spectra (9) to calculate RBE values as a function of dose and treatment time. Their main findings were that radial depth–dose curves became shallower with increasing applicator size and that the RBE varied between the surface and 20-mm depth according to applicator size and treatment time. Assuming a half-life of 15 minutes for recovery from sublethal damage, the RBE ranged from 1.28 to 2.21 for the 3-cm applicator and from 1.20 to 1.98 for the 5.0-cm applicator.
In a subsequent study the effect of simultaneous induction and repair of sublethal damage associated with prolonged treatment time was evaluated (8). The authors used the linear–quadratic model, which accounted for treatment time by multiplying the quadratic coefficient with the Lea-Catcheside time factor. On the basis of these models and clonogenic assay experiments in hamster fibroblast cell line v79, they concluded that simultaneous radiation damage and repair occurred with protracted treatment time for radiation qualities with RBEs greater than 1 and that half-time of repair was approximately 15 minutes.
Clinical toxicity studies using Zeiss Intrabeam
To date, only acute toxicity and efficacy data associated with Intrabeam as a boost treatment for breast cancer have been published. One report describes acute toxicity in 84 patients at a single institution who received lumpectomy and immediate 20-Gy IORT prescribed at the applicator surface (10). Toxicities were prospectively documented by use of European Organisation for Research and Treatment of Cancer criteria. In general, treatment was well tolerated without any Grade 3 to 4 toxicity. Acute effects 1 week after IORT included wound healing problems (2%), Grade 1 to 2 erythema (3%), palpable seroma (6%), and mastitis (2–4%). At 4 weeks after IORT, there was Grade 1 erythema (6%), induration at the tumor bed (5%), mastitis (4%), and hematoseroma (14%). Another published report summarized local recurrence data from 5 institutions comprising 321 patients who received IORT as a boost using Intrabeam followed by whole-breast irradiation (11). The patients had mostly T1 to T2 tumors, and 29% had axillary node–positive disease. After primary surgery, IORT was delivered to 5 to 7 Gy at a 1-cm depth, followed by whole-breast external beam radiotherapy. One hundred sixty-four patients had a minimum of 2 years of follow-up (range, 3–80 months). The estimated 5-year Kaplan-Meier actuarial local recurrence rate was 2.6%.
Two studies describing experience treating patients with brain tumors by use of the Intrabeam have been published. Takakura and Kubo (12) treated 76 brain tumors with the Intrabeam device after biopsy or excision. They report 2-year survival rates of 89% among 18 patients with anaplastic astrocytoma and 42% among 19 cases of GBM, which compared favorably with the results reported by the Japanese Brain Tumor Registry (77% and 21%, respectively). Another group from Massachusetts General Hospital (13) described its experience after treating 72 metastatic brain tumors in 60 patients. They report local control of 81% of lesions at a median of 6 months' follow-up, which was comparable to results achieved with resection and stereotactic radiosurgery.
Finally, Algur et al. (14) provided a preliminary report (abstract only) from experience in 24 patients with locally advanced or recurrent colorectal cancer treated with the Intrabeam at the Cleveland Clinic. Eleven patients had adherent tumor. They concluded that the use of Intrabeam IORT was relatively safe and did not increase the length of hospital stay in these difficult cases.
There are two ongoing clinical trials using the Intrabeam system. One is a randomized international multicenter trial, TARGIT, designed to determine whether a single dose of IORT delivered by Intrabeam is equivalent to conventional fractionated whole-breast irradiation for highly selected patients with relatively low-risk early-stage invasive breast cancer. Currently, 17 sites have enrolled more than 1,250 patients with an accrual goal of 2,200 patients. The second is a dose-escalation study of pediatric gliomas that is ongoing at the Chicago Children's Hospital.
Identification, Analysis, and Evaluation of Consequences of Non-Use
Advantages of EBT over existing technologies are as yet unproven in terms of efficacy or patient outcomes. Viable and tested treatment methods are available for the intraoperative environment and include electron beam IORT and HDR. In addition, treatment for accelerated partial-breast irradiation (APBI) is also currently available in the form of external beam radiotherapy and via various HDR brachytherapy techniques. The aforementioned modalities require licensed, qualified, authorized individuals to oversee the process and deliver the treatments. Moreover, use of these modalities requires a properly shielded facility.
Possible Impact
The impact of clinical use of EBT could be far-reaching and, if used properly, has potential to benefit patients. However, if applied improperly in an unregulated environment, use could potentially cause harm. As was noted in the technical sections of this report, EBT is currently an unregulated treatment delivery modality for cancer therapy, with minimal clinical data available from small single-institution studies, none with significant follow-up. The EBT devices currently commercially available propose usages analogous to the still investigational HDR APBI technique. Electronic brachytherapy is currently subject only to medical device review by the FDA, which considers safety and effectiveness of the device based on a standard that does not assess efficacy, outcomes, or potential clinical applications. Because the devices do not contain any radioactive source, they are not subject to regulation by, or user standards for, radioactive devices, as overseen by the NRC. Neither are the devices currently regulated by state public health departments. Inappropriate use of these devices by a medical practitioner or, potentially, a nonmedical individual who is not properly trained in their use or who uses them in inappropriate circumstances may lead to patient harm.
The doses for various EBT applications used are typically hypofractionated (single large fraction or several large dose fractions), as extrapolated from other radioactive source applications, which may or may not be appropriate. Although the source is low energy, the radiation dose per fraction is very high, and with a corresponding HDR, there is potential for patient injury similar to the types of injury that can occur with HDR radioisotope brachytherapy. There is also the potential for electrical or heat injury to patients that is not inherent in HDR therapy. As with HDR isotopic brachytherapy, the application of EBT leaves little room for error because only one or very few fractions are delivered, so precision and accuracy are critical.
There are currently no accepted calibration standards for EBT. Therefore there can be large uncertainties associated with absorbed dose measurement at low energies. This means that, depending on where ionization chamber calibrations are done, different centers could potentially deliver different doses of radiation, even if the prescriptions are the same. Moreover, the impact of tissue composition heterogeneities on absorbed dose can easily add 20% to 30% uncertainties to absorbed dose estimates. In addition, the dose rates can vary between and during applications. Accepted quality-assurance standards do not yet exist, so individual centers could inadvertently admit systematic errors into the calibration or treatment delivery processes. Although the AAPM has published Task Group reports on the recommended procedures for brachytherapy dosimetry, HDR treatment delivery and calibration, and use of intraoperative devices, there is no state or federal requirement that these guidelines be adhered to when using EBT devices. In the few theoretic studies evaluating RBE for these devices, described earlier in this report, the RBE varied widely between 1.20 and 2.21 depending on applicator size and other factors. Dose fractionation schemes have varied widely. The clinical impact of the rapid dose falloff is unknown. Finally, the effects of EBT on tumor and normal tissues are not yet well understood, given the paucity of clinical studies.
At the time of completion of this review, the Xoft device was solely approved for partial-breast brachytherapy, which is analogous to Ir-192 HDR brachytherapy techniques that have been available only since 2002. Accelerated partial-breast irradiation with HDR brachytherapy itself is considered an experimental modality that is currently the subject of ongoing randomized trials, such as the RTOG 0413/National Surgical Adjuvant Breast and Bowel Project B-39 trial and the TARGIT trial, comparing its efficacy with conventional whole-breast irradiation (15). It will be several years before any results of these Phase III studies are published.
Because APBI is itself considered an investigational technique, using EBT to deliver APBI could also be considered investigational. The RBE calculations for these devices suggest the RBE may be only 1.3, and dose comparisons to HDR sources are not as yet validated. Such calculations are theoretic and must be validated by clinical studies. Because the kVp must be specified, unlike a fixed energy for any given day of treatment with HDR sources, the energy spectrum and, ultimately, the dose calculation may be altered by small changes in kVp, increasing the complexity of brachytherapy treatment with EBT relative to HDR.
The Zeiss Intrabeam device is currently used for IORT applications for low-energy treatment, primarily for intracranial tumors and after lumpectomy for breast cancer, but also a variety of other body applications. In small published reports, intraoperative doses have varied widely, between 5 and 20 Gy per single fraction at different depths. In some jurisdictions no user regulations are in place, so there is no requirement for a radiation oncologist to be involved in the procedure, although a physicist is typically required to perform pretreatment calibrations and intraoperative monitoring. Therefore intraoperative EBT could potentially be performed by a surgeon or other personnel who have limited or no expertise in radiation treatment of cancer, brachytherapy principles, dose delivery principles, radiation safety and biology, or normal tissue tolerances. The complexities of dose gradient, RBE, and fractionation principles may be unfamiliar to professionals outside of the field of radiation oncology. This situation could lead to inappropriate patient selection, inaccurate or technically inadequate treatment delivery, and poor patient outcomes, in terms of both added toxicity and poorer cancer control.
The manufacturers of these devices have plans to expand the sites for treatment. Intrabeam already has approval for all body applications and is developing applicators for liver, spine, skin, and gynecologic cancers. Xoft currently has approval for breast applications only and is developing applicators for gynecologic cancers. Many of these new sites require special expertise in brachytherapy techniques, especially gynecologic cancers. Hypofractionated treatment of many sites, but in particular the brain and spine, require detailed knowledge of normal tissue toxicity to avoid potentially debilitating or life-threatening treatment-related toxicity.
There are potential therapeutic advantages inherent in the low-energy EBT device compared with HDR sources. The primary advantage is that the low energy obviates the need for special room shielding and personnel can wear lead aprons or patients can be draped with lead sheets, allowing much less exposure to staff and visitors and less expense to the facility for special shielding in the clinic. There is greater potential for dose modulation because of the ability to specify kVp. The dose intensity may be modulated to mimic a variety of HDR sources, although the beam has more limited penetration characteristics. Electronic brachytherapy may provide less anisotropy than single-dwell HDR devices. However, properly trained professionals are best able to take advantage of any potential treatment planning advantages and to ensure appropriate administration in a safe manner.
Disclaimers and Notifications
Emerging Technology Committee note
Assignment of this project to the Task Group was made on March 27, 2007, and data collection for preparation of the full report available on the ASTRO Web site and this condensed version was closed on January 1, 2008. Clinical, physics, or biology data and regulatory revisions available after that date are not included in this review.
This document was prepared by the Emerging Technology Committee (ETC) of the American Society for Radiation Oncology.
Acknowledgment
The Task Group and Emerging Technology Committee wish to acknowledge the assistance of Subir Nag, M.D., in preparation of portions of this document.
Supplementary Data
References
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Conflict of interest: none.
PII: S0360-3016(09)03553-6
doi:10.1016/j.ijrobp.2009.10.068
© 2010 Published by Elsevier Inc.
Volume 76, Issue 4 , Pages 963-972, 15 March 2010
