Intensity modulated electronic brachytherapy will soon become the brachytherapy treatment of choice for irregularly shaped tumor cavities or those closely bounded by critical structures (2009)

Arguing against the Proposition is Dorin A. Todor, Ph.D. Dr. Todor obtained his Ph.D. in Physics from Old Dominion University, Norfolk, VA, and subsequently completed a medical physics research fellowship at Memorial Sloan-Kettering Cancer Center, New York. He is currently Assistant Professor at the Medical College of Virginia, Virginia Commonwealth University, Richmond, VA. His major research interests include development of real-time imaging of catheters during placement for HDR partial breast irradiation, clinical validation of intraoperative planning, delivery and dosimetric assessment of LDR prostate brachytherapy, and modeling radiobiological effects in prostate and breast brachytherapy. A proposition recently debated in a Medical Physics Point/Counterpoint article deals with the possible ultimate replacement of conventional Ir-192 HDR brachytherapy by miniature x-ray tubes.1 The technological alternative referenced, in which a x-ray source is employed to deliver the radiation, has been termed electronic brachytherapy (EB).2,3 Available miniature x-ray sources are small enough to be introduced into a body cavity through a catheter and provide dose rates comparable to those from radionuclide brachytherapy sources. Initial EB clinical studies have been reported for the treatment of breast and endometrial cancers4,5 with a number of other tumors under consideration. EB has several immediately identifiable advantages: (1) because of the relatively low energy of the x rays, treatments can be delivered in an unshielded room in contrast to the significant protective shielding required for Ir-192 brachytherapy; (2) the low exposure rate allows staff to remain near the treatment couch during dose delivery where they can provide comfort and encouragement to the patient; and (3) since x rays are produced electronically, safety and security concerns associated with the transport and storage of radioactive material are unnecessary and Nuclear Regulatory Commission oversight is not mandated. There are additional advantageous dosimetric properties to consider. Low-energy miniature x-ray source characteristics can be uniquely exploited with an approach called Depth Dose Modulation (DDM).6 This procedure combines source collimation and microindexing to selectively modify the depth-dose characteristics of the source and create customized dose distributions for a variety of brachytherapy applications. A close fitting, two-section adjustable collimator, consisting of a cylindrical band around the lower portion of the source and a cap over its tip, provides predefined aperture settings that can generate controllable beam hardening and attenuation. Microindexing the source using variable step sizes, when combined with modification of the collimator gap width, facilitates the selection of optimal depth-dose characteristics for a given clinical situation. For example, the depth dose can be made to fall off rapidly near critical structures or, conversely, it can be adjusted to fall off less rapidly in the absence of these structures, thereby achieving a more homogeneous dose distribution. Furthermore, the selectable shielding capability that is readily achievable only with a low energy x-ray source provides a powerful tool for developing Intensity Modulated Electronic Brachytherapy (IMEB)7 plans. This capability should make possible the production of more conformal brachytherapy dose distributions in irregularly shaped tumor cavities or those closely bounded by critical structures. This property will potentially permit dose escalation to achieve increased cure rates while reducing normal tissue toxicity. The proposition is provocative, but there is limited evidence to support it. A proof of principle has been offered that electronic brachytherapy (EB) could be “modulated” by collimating and stepping the source.7 The immediate effect of collimation would be the significant prolongation of the treatment time. It is not obvious how a collimated but still cylindrically symmetrical source would improve conformance for irregular targets using a single lumen, when the irregularity would be—as often it is—in the radial direction. Given the large source size ( assembly diameter compared with for Ir192 VariSource), any multi-lumen applicator would be prohibitively large and the inability to travel through curved applicators will severely limit possible applications. There are other more general and important considerations worth mentioning. The proposition mentions “tumor cavities,” implying that the breast is a major site of application. In an evidence-based paradigm, one must remember that virtually all of the long-term accelerated partial breast irradiation (APBI) experience has been acquired in an Ir-192 based delivery setting. The question is: can this experience be used to validate and justify EB, given the significantly different depth dose distribution? A review of clinical data reveals that in 90% of patients with initial negative margins, residual disease was confined to from the edge of the cavity wall.8,9 Most clinical trials, however, require only ,10 making “coverage” with the prescription dose significantly smaller than . However, because the observed elsewhere recurrence rate is less than 1%,11 the radiation effect likely extends beyond the of the assumed target. Simply placing a prescription constraint at an arbitrary distance of 1, 1.5, or from the surface of a device or from the lumpectomy cavity wall does not stop the dose distribution at that distance. A more or less arbitrary dose of /fraction at , results in about at or at . We simply do not know what exact dose or margin is appropriate for various sites but we do know that in tandem the values used today are clinically meaningful. Mimicking only the prescription point behavior, which is how EB has been used so far,12 completely ignores the paradigm under which most clinical data have been acquired. The issue of prescription becomes even more complicated when the RBE of low energy x rays, compared to that of the Ir-192 radiation,13 is taken into account. It has been shown4 that V200 and V150, as well as the dose homogeneity index (DHI), correlate with side effects observed in interstitial multi-catheter APBI. In the balloon-based treatment, for example, 200% is likely the highest dose present in the “target,” whereas EB would create a large V300 or higher! It is difficult to understand how such hot spots, previously nonexistent, would be an improvement over the current paradigm. The technical ability to simply produce vastly different dose distributions (the means are irrelevant) is of little use unless, through carefully scrutinized clinical trials, one proves that the new modalities have equivalent or better clinical outcomes. Since most of the side effects associated with high dose regions need many years to be fully realized (also true for treatment “failure”), the word “soon” used in the title is rather misleading. To conclude: It is not clear how the “modulated” version of EB works in real life, or how it would be applied and with what clinical consequences. To extend this to “soon to become the treatment of choice” would be, in the words of A. Greenspan, “Irrational exuberance.” In the words of Albert Einstein, “Knowledge of what is does not open the door directly to what should be.” As is typical of most major technological advances in radiation oncology, the current early stage development of IMEB does not negate its genuine potential for widespread utilization in the near future. When external beam IMRT first moved from theory to clinical practice in the 1990s, it was readily acknowledged that the IMRT treatment planning and delivery systems available early on would profit significantly from continued development to improve their operational functionality. This progress was soon realized. Within a remarkably short time following its introduction, IMRT became widely adopted and is today regarded as an indispensable treatment modality. We can anticipate that IMEB, now in its formative period, will evolve similarly over the next few years into a robust alternative for diverse brachytherapy scenarios. With substantial improvements in EB x-ray source technology currently underway, these miniature devices are becoming smaller and more adaptable to support a wider array of treatment options beyond those restricted to just breast and endometrial sites. The ability to selectively and controllably alter depth-dose profiles by variable collimation and microindexing will overcome the most significant dosimetric disadvantages of EB and open the field to a broad range of applications. Although actual beam-on time might increase somewhat using IMEB because of the source output modulation, just as it does with most IMRT treatments, this temporal increment represents only a fraction of the total time associated with a course of brachytherapy, whether it is intensity modulated or delivered in a more traditional manner. With either approach, there is often much greater time allocated to setup and applicator placement in a patient than that required for the radiation delivery itself. Intensity modulated electronic brachytherapy challenges traditional conventions, mindsets, and prejudices. But the IMEB methodology, which enables the conformality of high dose to a specified tumor volume while maintaining low doses to neighboring sensitive tissues, promises to become a valuable and preferred tool in the radiation oncologist's brachytherapy armamentarium. Electronic brachytherapy is without doubt a novel technique in search of interesting applications. The idea of DDM, presented only as an abstract,7 is intriguing. A compelling and detailed explanation of how DDM would actually be applied to increase the homogeneity of dose distribution in irregularly shaped structures while sparing others is now due. There are foreseeable technical difficulties: the lack of control/feedback over the actual dose rate during delivery and the control of microindexing and of the collimator gap. There is currently significant resistance to the idea of optimization in brachytherapy, in part due to subpar planning software and in part due to the belief of some physicians and physicists that planning “by hand” is better. Optimizing a plan using DDM would be significantly more difficult; nonoptimizing would render it useless! But while the technical problems can probably be solved with expenditure of sufficient resources, only time and carefully controlled clinical trials will validate this new technology. The enthusiasm for the development of a novel source has to be balanced by a healthy skepticism regarding its clinical application. The lack of shielding and regulations for EB has the potential to make brachytherapy more available. A generous goal indeed, but we should remember that so was the government's vow a few years ago to spread the dream of homeownership.