Prior to the 1970s, the treatment of breast cancer was dominated by radical mastectomy or modified radical mastectomy of the affected breast . This consists of an en bloc removal of the breast, muscles of the chest wall, and contents of the axilla and was advocated as the most appropriate local therapy for women with early-stage breast cancers. However, the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial and other studies, found equivalent survival and local control rates among women treated with breast-conservation therapy (BCT)either mastectomy or lumpectomy followed by whole-breast irradiation (WBI).[3,4] The NSABP B-06 trial, which compared mastectomy to lumpectomy with and without radiotherapy in women with invasive carcinoma, found a 39% local recurrence rate at 20 years with lumpectomy alone, which was decreased to 14% with the addition of radiotherapy. Several other randomized studies demonstrated equivalent long-term survival and disease-free survival rates in patients treated by BCT compared to mastectomy.[2-5]
Additional randomized studies comparing lumpectomy alone to lumpectomy and radiation clearly demonstrate a threefold reduction in local relapse with the use of radiation following breast-conserving surgery.[6-10] More recent meta-analysis of trials comparing lumpectomy alone to lumpectomy and radiation demonstrated not only a threefold higher local relapse rate with the omission of radiation following lumpectomy, but also a small yet statistically significant compromise in overall survival.[11,12] For patients with ductal carcinoma in situ (DCIS), randomized studies comparing lumpectomy alone to lumpectomy plus radiation, conducted by the NSABP and European Organisation for Research and Treatment of Cancer (EORTC), found a 55% and 43% reduction in ipsilateral breast cancer events, respectively, with the addition of radiotherapy.[13,14]
As a result of these data, breast-conservation surgery followed by whole-breast irradiation (BCS+RT) became the standard of care for women with stage 0, I, and II breast cancer. BCS+RT involves the surgical removal of the primary tumor, evaluation of the axillary nodes, followed by whole-breast irradiation. This treatment is extremely well tolerated with minimal long-term complications and favorable cosmetic outcomes.[15,16] Despite the obvious cosmetic and potential psychosocial advantages of BCS+RT, 15% to 30% of patients who undergo lumpectomy do not receive postoperative radiotherapy.[17-20] Many patients may choose mastectomy or lumpectomy alone over BCS+RT due to the protracted course of daily treatment involved with WBI, which consists of daily radiotherapy to the whole breast for 25 treatments usually followed by a boost to the tumor bed, delivered over the course of 6 to 6.5 weeks.[21,22] Other reasons that may steer women away from BCS+RT have been identified as physician bias, patient age, fear of radiation treatments, distance from a radiation treatment facility, and socioeconomic factors.[20,23,24]
Search for an Alternative to WBI
Based on the numerous randomized studies noted above, it is standard of care for all women, regardless of age or tumor size, to receive radiotherapy in the setting of BCT to reduce local recurrence. However, in recent years, investigators have tried to identify subsets of women who may not benefit from the addition of radiotherapy to lumpectomy for early-stage breast cancer.
A prospective study from the Cancer and Leukemia Group B (CALGB) randomized women 70 years of age or older with tumors that were estrogen-receptor-positive and less than 2 cm in diameter to tamoxifen(Drug information on tamoxifen) with or without radiotherapy. In this randomized trial, even though radiotherapy significantly reduced the rate of local recurrence (from 4% to 1%), there was no difference in overall survival, and the investigators concluded that "tamoxifen alone is a reasonable choice for adjuvant treatment in such women." Published simultaneously, a Canadian trial in women over age 50 with early-stage breast cancer demonstrated a local relapse rate of 7.7% with lumpectomy and tamoxifen compared to 0.6% with lumpectomy, tamoxifen, and radiation. Although there was no compromise in survival with the omission of radiation in either trial, these studies were not powered sufficiently to detect small benefits in survival.
Smith et al, using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, identified 8,724 women over age 70 years who met the eligibility criteria for CALGB 9343. They compared those women over age 70 treated with radiotherapy following lumpectomy to those treated by lumpectomy alone. In this nonrandomized study, they found that radiotherapy not only reduced local recurrence but also reduced the rate of any second breast cancer event and subsequent mastectomy. They further identified subgroups, such as women between 70 and 79 years with low comorbidities and those with lobular histology, who derived the greatest benefit from radiotherapy. Of note, in the SEER-Medicare database of women age 70 or greater, only 59% of patients treated with breast-conserving surgery received radiation.
Collectively, these data suggest that for older women, although radiation may be safely avoided, it is rational for elderly women with long life expectancies and low comorbidities to receive radiotherapy after lumpectomy, given its benefit. However, many fail to do so in light of the prolonged course of therapy, resources involved in travel, and distance to a radiotherapy center.
Introduction of APBI
In response, accelerated partial-breast irradiation (APBI) has been studied increasingly over the past 15 years as a viable alternative to WBI. In general, APBI involves treating the surgical cavity with a 1- to 2-cm margin, thus reducing the volume of irradiated breast tissue by up to 50% using various radiotherapeutic methods. Technical approaches of partial-breast irradiation include multicatheter interstitial brachytherapy, balloon catheter brachytherapy, three-dimensional conformal external-beam radiotherapy (3D-CRT) and intraoperative radiotherapy (IORT). Treatment is typically delivered postoperatively, over a short period of time, using large fraction sizes.
Advocates of APBI state that it is a safe, well tolerated therapy that allows for equivalent cosmetic outcomes while significantly increasing quality of life and allowing for an effective treatment of the patient's breast cancer. To date, pilot studies of various APBI techniques have been studied, and large, multicenter, randomized controlled studies are underway comparing APBI to WBI.
In standard BCS+RT, radiotherapy is delivered to the whole breast to eliminate areas of occult multicentric in situ or invasive carcinoma. Additional radiotherapy may be delivered to the tumor bed using a boost to eliminate the higher burden of microscopic disease that may have been left in close proximity to the tumor bed after lumpectomy.
Following BCS and whole-breast irradiation, the majority of local relapses occur in close proximity to the tumor bed. When discussing a tumor recurrence in the ipsilateral breast, it is important to note the difference between a true recurrence and the development of a second primary in the irradiated breast. A study from Yale described the development of a new primary when the recurrence was distinctly different from the primary tumor with respect to the histologic subtype, location, or ploidy. In their studies of patients treated with BCT with 15 year data,[27,28] patients developed both true recurrences and new primaries at similar rates until approximately 8 years, when true recurrence rates stabilized but new primary rates continued to rise.
Recht et al also found that the majority of true recurrences occurred in the first 5 to 10 years, but with increasing follow-up, they saw a higher incidence of second primary tumors that developed in other quadrants of the breast. The 20-year update from Veronesi et al comparing mastectomy to BCT showed a nonsignificant difference between the development of new primaries in the ipsilateral breast (0.42 per 100 woman-years of observation) treated with BCT compared with the contralateral breast (0.63 per 100 woman-years of observation).
Several retrospective as well as prospective studies evaluating patterns of local relapse following BCS with or without radiation have shown that the majority of tumor recurrences occurred at or near the original tumor bed.[30,31] Veronesi et al found that failures beyond the lumpectomy cavity occurred in 2.9% of patients, consistent with previously published data of 1.5% and 3.5%,[11,32,33] These data suggest that the true benefit to radiotherapy may be to decrease the recurrence of tumor at or near the tumor bed, but may not prevent the development of new, second primary breast cancers that may occur elsewhere in the irradiated breast.
Anatomic data on the distribution of tumor cells in relation to the primary lesion have been published in surgical series. Holland et al reviewed 217 mastectomy specimens from patients in the Netherlands with tumors less than 4 cm. They reported that the presence of an extensive intraductal component (EIC) was associated with a substantial likelihood of having residual disease located beyond a 2-cm margin from the primary tumor, whereas in patients without an EIC, it was rare for cancer foci to be found more than 2 cm from the primary tumor.
In a recent abstract presented at the European Society for Therapeutic Radiation Oncology (ESTRO) meeting in 2006, Holland studied pathologic and mammographic criteria to identify breast carcinomas of limited extent, defined as an absence of microcalcifications or tumor density beyond the edge of the primary lesion based on mammography and a 1-cm tumor-free margin out of a 2-cm gross surgical margin based on pathology. The group found that 89% of patients who met these criteria were correctly identified as having a true breast carcinoma of limited extent. The authors concluded that by carefully examining radiographic and pathologic data, one may be able to correctly identify patients who may be candidates for "surgical excision of the tumor followed by partial-breast irradiation."
The fact that a majority of true local relapses occur in close proximity to the tumor bed, along with available pathologic data demonstrating minimal microscopic tumor burden more than 1 to 2 cm beyond the primary tumor, provides a rationale for more localized treatment in selected patients. With APBI, a conformal dose of radiation is delivered to a limited volume of breast in a short period of time. Unfortunately, the majority of data regarding APBI involves single-institution, nonrandomized studies with small patient populations. While these data are promising, it is clear that to firmly establish APBI as an acceptable alternative to WBI, prospective randomized studies are necessary. Recently, an intergroup trial (NSABP/Radiation Therapy Oncology Group [RTOG]) launched a large randomized study comparing WBI to APBI for women with early-stage invasive and noninvasive breast cancer. Accrual has been brisk and is expected to close earlier than expected.