Accelerated partial breast irradiation: History, rationale, and controversies

Results from two decades of study have conclusively shown that radiation therapy has an important role in ensuring local control for patients with early-stage breast cancer who are treated with breast-conserving surgery. When breast-conservation therapy was first explored as an alternative to mastectomy, many trials investigated whether surgical resection of the tumor-bearing region of the breast was sufficient, or whether adjuvant irradiation of the entire breast would be required to improve patient outcome. These trials showed that whole-breast irradiation significantly reduced the risk of ipsilateral tumor recurrence after resection of the tumor and the tissue immediately surrounding the tumor (Fisher et al. 2002a; Veronesi et al. 2001; Vinh-Hung and Verschraegen 2004). On the basis of the results of these phase III trials, whole-breast irradiation became a standard component of breast-conservation therapy. Subsequently, two randomized trials investigated whether the addition of a tumor-bed boost following whole-breast irradiation offered further benefit (Bartelink et al. 2002; Romestaing et al. 1997). Both of these studies demonstrated a small but statistically significant reduction in ipsilateral breast tumor recurrence. Correspondingly, the available medical evidence to date suggests that the optimal radiation treatment schedule should include 5 weeks of daily therapy directed to the ipsilateral breast followed by 1 to 1.5 weeks of additional daily therapy directed to the tumor-bed region. A single randomized study has suggested that a 16-fraction course of whole-breast irradiation might also be considered for selected elderly patients with stage I disease (Whelan et al. 2002). The studies investigating radiation and breast-conservation therapy proved to be one of the more significant advances in the local-regional management of breast cancer. It is now accepted that whole-breast irradiation after breast-conserving surgery decreases the risk of local recurrence to very low levels that are comparable to those achieved with mastectomy. Correspondingly, there is consensus that nearly all patients with early-stage breast cancer should be offered the option of being treated with a breast-conserving approach. An equally positive finding of these studies is that the radiation component of breast-conservation therapy is associated with a very low rate of toxicity to normal tissue and that modern local-regional treatment has little impact on the long-term quality of life for breast cancer survivors. Finally, with optimal surgical and radiation treatment the long-term aesthetic outcomes associated with this approach are excellent (Taylor et al. 1995; Wazer et al. 1992). However, despite its many positive benefits, radiation therapy is also associated with some disadvantages, the foremost of which is perhaps the fact that it is a relatively complex and expensive treatment. Radiation treatments require physical resources, such as linear accelerators, simulators, and treatment planning systems, in addition to significant personnel resources, such as specialty-trained physicians, physicists, dosimetrists, and therapists. This level of expertise is not available in every city and the level varies from country to country. A second major downside of radiation therapy is that the treatments are inconvenient. As mentioned, standard whole-breast irradiation in the United States is typically administered over 6-7 weeks and treatments are preceded by 2 or 3 days of treatment planning. The 5-day-a-week treatment schedule may require patients to miss work and can lead to other significant life-style disruptions. These factors are particularly relevant for patients who do not live in close proximity to a radiation treatment facility. Standard whole-breast treatment may require such individuals to temporarily relocate, which might cause financial burdens such as temporary lodging expenses and the costs of missing work. Furthermore, such relocation may mean separating patients from their family, friends, and other supporters. These downsides of radiation have been proven to have consequences. First, some women elect to forgo breast-conservation therapy and to be treated with mastectomy in order to avoid the need for radiation treatments. In fact, a number of studies have found an inverse relationship between the use of breast-conservation therapy and the distance from a patient's home to the nearest radiation facility (Athas et al. 2000). Furthermore, the regions of the country with the lowest density of radiation treatment facilities have the lowest rates of breast-conserving treatments (Farrow et al. 1992). An even more serious consequence that can result from the inconvenience of the radiation treatment schedule is that some patients treated with breast-conservation therapy elect to forgo the radiation component of their treatment. Recent pattern-of-care studies have indicated that approximately 20% of patients with early-stage invasive breast cancer treated in the United States do not receive radiation as a component of breast-conservation therapy (Nattinger et al. 2000). This option has been proven to place these patients at higher risk of tumor recurrence and possibly a higher risk of death. The magnitude of the problem posed by the time required to administer radiation treatments is much greater outside the United States. The shortage of radiation treatment facilities in many countries makes the traditional scheduling of breast treatments impractical. In these countries, there can be extended delays in starting radiation therapy due to patient backlogs, and in other countries, the scheduling of radiation and the shortage of facilities have hindered the use of breast-conservation therapy. One strategy to overcome some of these issues is to accelerate the course of radiation treatments. Although this may seem an intuitive solution, there are biological reasons why the 5- to 6-week treatment course for whole-breast radiation was originally developed. In brief, this schedule was thought to optimize the therapeutic ratio (defined as the probability of achieving tumor control versus the probability of causing normal-tissue injury). Decreasing the radiation treatment schedule to less than 5 weeks would require increasing the daily dose per fraction, and this increase, unfortunately, has a greater effect on the probability of normal-tissue injury than tumor control. A second important determinant of normal-tissue injury in addition to fraction size is the volume of normal tissue that is irradiated. Therefore, it was rational to hypothesize that an optimal therapeutic ratio could be maintained with an accelerated radiation schedule if the volume of normal tissue included in the irradiated volume was minimized. This rationale, along with the clinical desire to shorten the radiation course, led to the investigation of accelerated partial breast irradiation (APBI). In this strategy, radiation is delivered only to the tumor bed region of the breast plus an arbitrarily defined margin. To date, APBI has been delivered with a variety of techniques, including single-fraction intraoperative electron or orthovoltage treatment, low-dose-rate interstitial brachytherapy (temporary implantation of radioactive sources), high-dose-rate interstitial brachytherapy, high-dose-rate brachytherapy delivered with a balloon catheter system (MammoSite; Proxima Therapeutics, Alpharetta, GA), and three-dimensional conformal external beam radiation treatment. Although these strategies differ with respect to many key variables, such as the dose of radiation delivered and the volume of breast tissue treated, they all share the common characteristic of attempting to shorten the treatment schedule from 6 to 7 weeks to a course that lasts 1 week or less.