Breast Cancer: New Radiation Treatment Options

Dr. Arthur and colleagues have presented a comprehensive overview of two of the most noteworthy radiotherapy (RT) advances in the contemporary management of breast cancer, ie, short-course hypofractionated RT and intensity-modulated radiotherapy (IMRT). Although both challenge the conventional RT approach to early-stage disease, they differ considerably in that hypofractionated RT refers to treatment of either the entire breast or a part of the breast in a shorter time course than with standard fractionation, whereas IMRT refers to an alteration in the method of treatment delivery. I will discuss each in turn. Hypofractionated Radiotherapy
As Dr. Arthur correctly points out, the current results achieved with breast-conserving surgery and wholebreast RT are excellent, with high rates of tumor control in the breast and minimal complications. With the lessons learned through the years of appropriate mammographic, surgical, and radiotherapeutic techniques, and detailed pathologic specimen assessment, it will be difficult to significantly improve upon the current high rates of tumor control. Therefore, end points such as improvement in patient convenience and possibly further reduction of complications by limiting the extent of RT have been targeted as desired goals. As noted by the authors, it has been clearly shown that mastectomy continues to be performed in patients who are candidates for breast-conserving surgery and RT, and that some patients are receiving substandard care with breast-conserving surgery in the absence of RT. What is not clear is how much of this can be explained by the time and travel commitment necessary to undergo a standard RT treatment course. Undoubtedly this is an issue for some, and if therapeutic options were known to be equal, a shorter course would probably be preferable to most. That said, it is interesting to note that, of the two approaches that deliver short-course RT-hypofractionated whole-breast RT and accelerated partial-breast irradiation-the former has generally not been accepted in this country, despite a randomized trial that has shown equivalence between the short and standard RT course.[1] No randomized trial re- sults to date have demonstrated the same for accelerated partial-breast irradiation. Therefore, something more than convenience alone must be driving the enthusiasm for partial-breast irradiation. Accelerated Partial-Breast Irradiation
Accelerated partial-breast irradiation represents a true paradigm shift. Instead of delivering treatment to the entire breast, the tumor bed with a margin only becomes the target. In justification of this approach, as discussed by Dr. Arthur, patterns of failure historically show that recurrences are predominantly in the region of the tumor bed. But whether it can then be said that the "impact of whole-breast radiotherapy is exclusively at the site of the original primary" may overstate the significance of this pattern of failure. Subclinical tumor deposits away from the tumor bed have clearly been documented in mastectomy series,[ 2] although admittedly, their extent may be more limited in mammographically detected disease. The potential significance of these untreated deposits is relevant, however, when one examines the results of the Milan III trial, in which patients with lesions less than 2.5 cm in size were randomized between quadran tectomy alone vs quadrantectomy and whole-breast RT.[3] With 9-year median follow-up, a significantly higher failure rate was observed in the quadrantectomy-alone arm for lesions of all sizes. Conceptually, accelerated partial-breast irradiation is analogous to a "radiation quadrantectomy" even though, in some cases, the volume of treated tissue is less than a formal quadrantectomy. With follow-up of the Milan III trial now exceeding any published accelerated partial-breast irradiation series, rates of in-breast recurrence are significantly increased in the absence of whole-breast RT. And by virtue of the fact that a quadrantectomy was performed, these failures had to be outside of the index quadrant. We clearly need longer follow-up of the current single-institution accelerated partial-breast irradiation studies before the clinical significance of untreated tumor deposits in the breast can be known. Treatment Variations and Limitations
Accelerated partial-breast irradiation has received considerable attention in the press, and patients are increasingly seeking this as a therapeutic option, but it is important that the current state of knowledge is accurately presented. First, there is considerable variability in the approaches to delivering accelerated partial-breast irradiation. Most relevant studies published to date have used interstitial brachytherapy, yet the majority of these reports have originated from only a few institutions. The use of breast brachytherapy in this country has decreased through the years, as electrons became the preferred method of delivering boost radiotherapy. Therefore, it is unclear how many practicing radiation oncologists are current on breast brachytherapy techniques. Of note, only 12 institutions participated in the Radiation Therapy On- cology Group (RTOG) 95-17 phase II study of low-and high-dose-rate brachytherapy for partial-breast irradiation, which suggests limited enthusiasm for this approach.[4] To simplify the brachytherapy option, MammoSite is now available, but there are limitations with this technique, including whether the balloon can conform to the specific surgical cavity and deliver adequate dose to the desired tissue depth, the potential for fibrosis and tissue necrosis related to placement of the balloon (and source) too close to the skin, rupture of the balloon by surgical clips, and the absence of published clinical data suggesting efficacy beyond 2 years. Similarly, there are very limited outcome data using external-beam accelerated partial-breast irradiation, and the intraoperative techniques currently being tested in trials in Europe await outcome results. However, given the limited depth dose of these treatments-particularly low-energy (soft) x-rays with which the prescribed dose reaches only 2 mm- concerns have already been raised. Other factors that are not fully clarified include optimal patient selection (patient age, tumor size, nodal status, tumor histology) and optimal total dose and fraction size. Whether these factors will result in increased rates of in-breast tumor recurrence remains to be seen. All of the previous concerns have focused upon a possible increase in local recurrence following accelerated partial-breast irradiation. If local recurrences increase over time, could survival be adversely affected? A recent meta-analysis of published trials of lumpectomy with and without RT demonstrated a modest but significantly increased risk of death in patients undergoing lumpectomy only.[5] While accelerated partialbreast irradiation includes RT, it is not whole-breast RT, and the question is, Will partial-breast irradiation adversely affect survival? It is the author's opinion that the survival impact will be minimal, but this can only be verified by conducting a randomized trial. Therefore, for many reasons, accelerated partial- breast irradiation should be tested within the confines of an institutional review board-approved trial or, at the very least, be used only following thorough informed consent. Patients have a right to know not only the potential advantages of the technique, but also the limitations of our current knowledge. Intensity-Modulated Radiotherapy
IMRT removes the usual reliance upon flat radiation fields of uniform intensity and instead uses a variable intensity pattern (nonuniform beam intensities within a field) to provide more degrees of freedom for doseshaping and more conformal dose distributions. Thus, IMRT represents an advance in how treatment is delivered rather than an advance in the therapy itself. There is considerable variability in how one defines IMRT. Dose can be delivered using dynamic fields, multiple static fields with static multileaf collimation, tomotherapy, etc, and plans can be either forward planned or, more commonly with IMRT, inversely planned, where the parameters for an acceptable dose distribution are established first and then the isodose distributions and resultant beam arrangements are generated. IMRT has been used as a means to dose-escalate in the treatment of certain tumors. Since dose escalation has generally not been a goal in the management of breast cancer, as the authors have stated, the goals have included improved dose homogeneity and target coverage, and potentially decreased toxicity. Many of these goals can be accomplished, however, using optimized computed tomography- based forward planning, and it is unclear whether IMRT represents a clinical advantage for most women treated to the breast only. Perhaps patients of large body habitus may derive an incremental benefit from further dose homogeneity achieved with IMRT, but outcome studies are needed to compare the best standard treatment to IMRT, to determine whether a clinical benefit exists. I agree with Dr. Arthur et al that if IMRT does provide a clinical benefit over the best current techniques, it may be in the complex cases of locoregional RT requiring field matching where the most benefit could be realized. And it is for that reason that most of the ongoing research at the University of Michigan on IMRT for breast cancer has focused on locoregional RT including treatment of the internal mammary nodes.[6] But even in these cases, clinical studies rather than just dosimetry studies are needed to show a benefit. Outcome studies are in progress. Given that IMRT can yield more homogeneous dose distributions that could possibly lead to better clinical outcomes in some women, why not use it routinely in the treatment of breast cancer? From a practical sense, time is one factor. With the variation in the definition of IMRT, there is a considerable range in the time needed to prepare an IMRT plan. Some centers are able to generate breast plans using IMRT in the same amount of time as standard plans, whereas more complicated plans require significantly more time and effort on the part of the physician, dosimetry and physics staff, and therapists. Adjustments for motion and daily setup variation necessary to minimize rapid dose falloff due to sharp dose gradients are needed for IMRT, and strategies must be incorporated into the treatment plan to account/correct for these. The cost of software and the infrastructure needed to deliver IMRT is another practical consideration. Furthermore, quality assurance standards are needed to monitor the accuracy and safety of computer-controlled IMRT delivery systems.[7] From a theoretical standpoint, some forms of IMRT could result in an increased risk of radiation-induced second cancers.[ 8] IMRT generally involves more fields and the potential for a larger volume of tissue to be exposed to low doses, and can increase total body exposure secondary to leakage irradiation. These factors have been theoretically estimated to increase the risk of second cancers, although the actual risk is unknown. Therefore, the true benefits of IMRT in appropriate patient populations need to be established to balance against these potentially adverse theoretical concerns. Conclusions
With all new advances in care come cautionary concerns that can only be addressed in well-designed clinical studies. Partial-breast irradiation and IMRT should not be exceptions to this approach. As the authors conclude, increasing public awareness of these techniques mandates that we know how best to use them and for whom they represent optimal care. Only through the implementation of clinical trials will these potential advances be optimally integrated into clinical care.