The combination of radiographic imaging and radiation treatment planning continue to advance the specialty of radiation oncology, providing the ability to create highly conformal dosimetric plans. To maximize the effectiveness of this process, the treatment target must be well imaged and clearly defined. In breast-conservation therapy, the convention is to treat the whole breast. However, whether measured by physical exam or CT evaluation, the extent of breast tissue is difficult to delineate. With con- continued study, it has become obvious that the whole-breast target volume is frequently not completely encompassed within the bounds of standard tangential fields. Despite this, local control rates approach 95% in contemporary studies. On the other hand, knowing that not all patients with early-stage breast cancer benefit from postlumpectomy radiotherapy (approximately 60%), many studies have searched for a reliably identifiable subgroup of breast cancer patients who might be safely excused from postlumpectomy radiation.[ 9,10] This subgroup has not yet been identified, and therefore, it is recommended that all patients should complete radiation therapy following breast-conserving therapy. This logic leads us to the conclusion that the size of the target requiring treatment following lumpectomy is greater than the lumpectomy cavity itself but less than the whole breast. Development of Partial-Breast Irradiation
In the early 1990s, the problem of physician and patient compliance with recommended postlumpectomy radiotherapy was confronted with a proposal suggesting that if the target to be treated following lumpectomy is not the whole breast, but rather, a reduced volume of breast tissue delineated by a margin of tissue around the lumpectomy cavity, then the treatment time could possibly be reduced to 5 days, ie, accelerated partial-breast irradiation. Clinical data have documented that the overwhelming majority of in-breast failures following breast-conservation therapy are in the immediate vicinity of the lumpectomy cavity (referred to as true recurrences). Although the frequency of these true recurrences is greatly reduced with postlumpectomy radiotherapy, the location of the majority of in-breast failures remains at the site of lumpectomy.[2,11,12] Interestingly, the pattern of "elsewhere failures" (in-breast failures remote from the site of lumpectomy) remains infrequent (< 5%) and unaltered with the addition of externalbeam radiotherapy. These data support the concept that the impact of whole wholebreast radiotherapy is exclusively at the site of the original primary lesion and that it does not have the ability to prevent new primary disease from arising elsewhere in the breast at a later date. The clinical failure pattern data suggest that accelerated partial-breast irradiation should be successful and equivalent to standard whole-breast radiotherapy. However, delineation of the target requiring treatment is not yet clearly defined. Shortcomings of Pathologic Studies
There has been considerable speculation on how far microscopic disease might extend from the cavity edge. The most logical place to look for guidance in defining the target would be the pathologic literature, but little contemporary guidance is available. The classic pathologic studies examining mastectomy specimens are now over 20 years old. It would be inappropriate to extrapolate the findings from these studies to patients treated in the modern era, where advanced mammographic technology allows earlier detection, and modern surgical and pathologic techniques enable the removal of malignant lesions with microscopically negative margins. Unfortunately, there is a paucity of contemporary pathologic studies that address this question. To date, three published studies have focused on the distance of microscopic disease extension from the primary lesion.[14-16] These studies suggest that the microscopic extension of disease beyond the primary lesion is no greater than 1 cm in a population of patients more than 45 to 50 years old. The maximal disease extension in younger patients was documented to be beyond 1 cm. Limitations of these studies include low patient numbers, measurement of the extension of ductal carcinoma in situ only, and difficulty in extrapolating the measured distance from the edge of the primary lesion to a case where the surgeon obtained a negative microscopic margin. Although these pathologic studies can be criticized as to their relevance, they support the concept of limitedfield radiotherapy following lumpec- tomy for early-stage breast cancer. Relevant pathologic studies refuting the concept of accelerated partialbreast irradiation and supporting the need for whole-breast radiotherapy have not been identified. Accelerated Partial-Breast Irradiation For accelerated partial-breast irradiation to be accepted into the common practice of radiation oncology, treatment techniques that are safe and reproducible need to be available, and data demonstrating equivalence to standard breast-conservation therapy must be reported. Presently, reports in the literature begin to support both of these requirements. Brachytherapy, three-dimensional (3D) externalbeam, and intraoperative radiotherapy have been the three accelerated partial- breast irradiation treatment approaches investigated. Brachytherapy
In the United States, a fractionated course of high-dose-rate brachytherapy has been the primary focus of treatment delivery. Multicatheter brachytherapy was the initial treatment technique used at the onset of accelerated partial-breast irradiation and is the technique used in the experiences reported with the longest follow-up. Guidelines for implant construction were based on the experience generated from the era prior to the widespread use of electrons, when multicatheter brachytherapy was used to deliver a boost dose to the surgical bed in addition to whole-breast radiotherapy. Building on this experience, coupled with the brachytherapy-only guidelines for sarcoma treatment from Memorial Sloan-Kettering, a dose of 45 Gy low-dose-rate brachytherapy was delivered to the surgical bed plus a 1-to 2-cm margin. Over time, this was converted to high-dose-rate brachytherapy for added control over planning and dose delivery, and for the benefit of outpatient treatment and increased safety for the faculty and staff. Although criticized for its operator dependency and associated learn- learning curve when first starting, the incorporation of radiologic imaging in the guidance of catheter placement in concert with 3D treatment planning has greatly reduced these challenges.[ 18,19] Regardless, there will always be some degree of a learning curve when starting, and there is no possible way to remove the distressing appearance of the breast when multiple catheters are in place.
- MammoSite-The MammoSite Radiation Therapy System was developed to address the difficulties involved in multicatheter brachytherapy with the goal of simplifying the procedure, improving the reproducibility of dose delivery, and therefore, increasing the availability of accelerated partial-breast irradiation. The research and development of this device has focused on the ability to reproduce the target coverage and dosimetry achieved with published multicatheter brachytherapy techniques. The MammoSite Radiation Therapy System is composed of a 15-cm catheter that is 6 mm in diameter (Figure 1). At the distal end of the catheter is a balloon that can be symmetrically inflated to a sphere with a 4- to 5-cm diameter, or a larger size is available that inflates to 5 to 6 cm. The balloon is placed and inflated in the lumpectomy cavity with the catheter exiting either through the lumpectomy incision or a separate exit wound. Placement is easily accomplished at the time of lumpectomy or postlumpectomy and placed by the involved surgeon or radiation oncologist. When properly placed, treatment is delivered to a uniform 1-cm depth from the balloon surface.[20,21] Since the time of US Food and Drug Administration approval in May 2002, use of the system has been adopted in many locations across the country. It is estimated that more than 4,000 balloons have been used for treatment since that time.
The latest partial-breast technique to be investigated is 3D conformal external-beam radiotherapy. The ability to deliver a similarly conformal dose to the target with a noninvasive approach is attractive to both patients and physicians. Pilot studies have been completed, and a national phase I/II trial has recently been completed.[ 22,23] Unique to this treatment approach is the challenge of adjusting for patient setup error and breathing motion, and assuring that the homogeneous dose delivered is radiobiologically equivalent to the relatively inhomogeneous dose delivered with brachytherapy. The William Beaumont Hospital recently published an update of their pilot experience with 3D conformal partial-breast irradiation. A total of 31 patients have been treated with a median follow-up of 10 months, and 15 patients have been followed for at least 1 year. The described approach includes strict normal tissue dose restrictions, defining the clinical target volume (CTV) as the lumpectomy cavity plus 1 to 1.5 cm, and the planning target volume (PTV) as the 1-cm expansion of the CTV. This additional PTV margin was applied to address the potential for setup error and breathing motion. A treatment scheme of 34 Gy in 10 fractions was initially used for six patients and then altered to 38.5 Gy in 10 fractions. The reported acute toxicity was minimal with no grade 3 toxicities, 3 grade 2, 19 grade 1, and 9 patients with no acute toxicities. Additional follow-up is needed, although it should be noted that the dose scheme used and volumes treated with this technique parallel the brachytherapy partial-breast experience, for which acceptable late toxicity has been reported with 5-year follow-up. Intraoperative Radiotherapy
Beyond the United States, treatment approaches have predominantly been intraoperative, delivering a large single-dose fraction to the target at the time of lumpectomy. Concerns have been voiced regarding the ability to properly select patients and delineate and cover the target, and the risk of fibrosis resulting from the dose delivered as a large single fraction. Despite these concerns, it is hard to argue the attractiveness of a treatment approach that completes all local therapy in one trip to the operating room. To date, the early reports from these investigations have not described excessive failures or soft-tissue toxicity.[25,26] At the University College of London, this treatment is completed with the placement of a soft x-ray device into the lumpectomy cavity to deliver 21 Gy to a 2-mm depth. Intraoperative electrons are used at the European Institute of Oncology, where 21 Gy is delivered to the postlumpectomy breast tissue judged to be at risk for failure. The target is surgically manipulated so that it is easily encompassed within the electron field while temporarily pulling the skin out of the field and placing deep shielding to protect the underlying chest wall and lung. Patient Selection Criteria and Quality Assurance
When reviewing the literature, specific attention should be directed to the details regarding patient selection criteria and quality assurance guidelines involved in the treatment experience. In studies for which both of these entities are clearly included, the outcome data are consistent and comparable to the conventional whole-breast external-beam experience (Table 1).[20,22-36] Conservative patient selection criteria have been outlined by both the American Brachytherapy Society (ABS) and the American Society of Breast Surgeons (ASBS).[37,38] Both groups agree that patients should be older than 45 to 50 years and all cases should first be acceptable for conventional breast-conservation therapy. Additional selection criteria include primary lesions that are unifocal, small (ABS suggests < 3 cm, ASBS recommends < 2 cm), resected with negative microscopic margins, and with axillary lymph nodes evaluated and negative. The ABS advises restricting accelerated partial-breast irradiation to patients with infiltrating ductal carcinoma histology only, based on the fact that little data exist to suggest that additional histologies should be included. The ASBS is in concordance with this, but with the addition of ductal carcinoma in situ, extrapolating from data suggesting that wide excision alone may be sufficient treatment.[ 39] The guidelines for quality assurance should include a target definition of at least the lumpectomy cavity plus a 1- to 2-cm margin, and the methodology of treatment delivery describing verification of the prescribed dose to the target volume. All three of these partial-breast treatment approaches allow for thorough evaluation for proper patient selection and subsequent target delineation and assurance of target coverage prior to treatment delivery. Additionally, these approaches allow for dose delivery that is fractionated, reducing the risk of late toxicity, ie, fibrosis or fat necrosis. Future Directions
Although accelerated partial-breast irradiation is being offered in an increasing number of facilities across the United States, this treatment approach has not yet been accepted as an alternative method of local management for early-stage breast cancer by the entire breast oncology community. Some physicians believe additional data supporting the concept of accelerated partial-breast irradiation are needed prior to generalized acceptance; however, it should be noted that patients are now seeking out locations that offer accelerated partial- breast irradiation, and an increasing number of physicians are offering this treatment based on current data. Despite the availability of 5-year data and the acceptance of this treatment approach, additional investigation is necessary. Future studies should appropriately focus on the development of well-conducted protocols that will further define the appropriate patient selection criteria and continue the development of treatment techniques. Several phase I/II trials are now being conducted, and many more are in development. Additionally, a national phase III trial which will be jointly managed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG), has been developed and will be open for accrual later this year. Hypofractionated Whole-Breast Irradiation Reduction of treatment time to improve patient access and maximize availability of treatment resources has also been the focus of study in Cana da. In a prospective randomized trial, investigators have demonstrated the equivalency of two radiation treatment schemes, thus reducing the treatment time from 5 to 3 weeks while maintaining the conventional whole-breast treatment target. In this trial, 1,234 patients were randomized between a short course of radiotherapy, 42.5 Gy in 16 fractions, and a standard course of radiotherapy, 50 Gy in 25 fractions. All patients were diagnosed with T1/T2 infiltrating breast carcinoma and resected with microscopically negative margins. All patients were axillary node-negative. With a median follow-up of 69 months, they reported the observed local recurrence rate, disease-free survival, overall survival, and cosmetic outcome to be equivalent. Local re- currence rates at the time of the report were 3.2% vs 2.8% for the standard and short treatment courses, respectively. Cosmetic outcome was reported as good/excellent in approximately 75% in both treatment arms. These results have mostly been ignored in the United States, as there continues to be a reluctance to adopt this hypofractionated treatment course. Although there has been some level of academic discussion regarding the possible limitations of these data, it would appear that the motivation to change from a 6-week course that includes a boost to a 3-week course without a boost is lacking. The actual reasoning behind this lack of motivation is uncertain but may be due to the overshadowing anticipation of accelerated partial-breast irradiation, which will reduce the overall treatment time to 5 days. Nevertheless, it should be noted that the NSABP has recently extended their adjuvant external-beam radiotherapy guidelines for all existing protocols to include the Canadian hypofractionated treatment scheme.