ABSTRACT: Whole-breast irradiation (WBI) following breast-conserving surgery (BCS) has been used for several decades as an alternative to mastectomy in the treatment of localized breast cancer, and it has been shown to decrease rates of local-regional recurrence and improve survival rates compared with BCS alone. WBI is delivered using high-energy external beam radiation and typically consists of approximately 5 weeks of daily treatments to the entire breast, with or without inclusion of a “boost” to the primary site. Accelerated partial-breast irradiation (APBI) and accelerated whole-breast irradiation (AWBI) have been developed as alternatives to conventional WBI for selected patients with early-stage breast cancer. Given its large size and long follow-up, the Canadian trial of AWBI has been widely considered as practice-changing, and additional studies of AWBI are maturing or newly-launched. Use of APBI is based on the observation that the majority of local recurrences occur near the primary tumor site. Because a smaller portion of the breast is irradiated, treatment courses can often be abbreviated, and techniques such as conformal external beam, catheter- or balloon-based brachytherapy, and intra-operative radiation have been developed. Data from early APBI randomized trials and retrospective studies report mixed results. However, given the protracted time to local recurrence and complications following breast-conserving therapy, definitive results from contemporary randomized clinical trials comparing conventional WBI against AWBI or APBI are still limited.
Whole-Breast Irradiation (WBI)
Today, many women with early-stage invasive breast cancer are candidates for breast-conserving therapy (BCT), which consists of breast-conserving surgery (BCS) followed by radiation to all or a portion of the treated breast. The goal of BCT is to provide oncologic outcomes equivalent to those of mastectomy while preserving a cosmetically acceptable breast. Mature data from several large prospective randomized trials have shown that overall survival is equivalent with BCT or mastectomy.[1-3]
Results from randomized trials comparing BCS with or without WBI have been analyzed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Whereas the individual trials did not have the statistical power to detect improved survival with the addition of radiation, the EBCTCG meta-analysis demonstrated that the improvement in local control provided by radiation translated into an overall survival benefit.[4,5] The original analysis showed that radiation provided similar proportional reductions in local recurrence in all subgroups of patients, and that prevention of local recurrence at 5 years translated into improved survival at 15 years, at an approximate 4:1 ratio.
In the most recent EBCTCG update, 7 additional trials in low-risk patients were added, follow-up was obtained in the initial 10 trials and, importantly, local and distant recurrences were analyzed together to determine the effect of radiation on 10-year “first recurrence” and 15-year breast cancer death rates. (Technically, the probabilities of local and distant recurrence are not statistically independent, and therefore valid estimates of the separate effects of radiation on local and distant recurrence cannot be obtained.) Overall, WBI reduced the 10-year risk of any first recurrence with a rate ratio (RR) of about half (RR = 0.52), from 35.0% to 19.3% (2P < .00001), and it reduced the 15-year risk of breast cancer death by about one-sixth (RR = 0.82), from 25.2% to 21.4% (2P = .00005). The risk of death from any cause was similarly lower in the radiation arm (34.6% vs 37.6%; 2P = .03), indicating that WBI does not significantly increase non–breast cancer deaths.
The EBCTCG analysis shows the benefit of radiation in preventing recurrence is largest in the first year, but remains substantial throughout the first decade, whereas the benefit in breast cancer deaths becomes apparent only after several years and continues well into the second decade. (Interestingly, 5 years of tamoxifen(Drug information on tamoxifen) therapy also reduced the annual rate of any recurrence over the first 10 years by about one-half [RR = 0.53], but reduced the annual rate of breast cancer death by about one-third [RR = 0.68].) The risk reduction in recurrence and death with radiation was present for women with both negative and positive lymph nodes. Benefit was seen in patients of all ages, and with various tumor grades and sizes, although the absolute magnitude of the benefit varied. Based on the data from this update, the new “4:1 ratio” is between the reduction in first recurrence at 10 years (as opposed to the reduction in local recurrence at 5 years) and the reduction in mortality at 15 years.
The rates of ipsilateral breast tumor recurrence (IBTR) with BCS and WBI have been reduced considerably over time, and the 5-year rate is now about 2%. The reasons for this improvement are several-fold and include better imaging with mammography, more thorough pathologic evaluation of the resected specimens (especially margin status), and improvements in systemic therapy that, when combined with radiation, substantially reduce IBTR.
WBI is well tolerated. Long-term cosmetic outcomes following WBI are quite good, and significant treatment-associated morbidity is rare. In a series of more than 400 patients with stage I/II breast cancer treated with WBI, the rate of unacceptable cosmetic results was 6.7% at 11 years, and was primarily limited to patients who received doses higher than 60 Gy. Rates of other complications—including rib fracture, pericarditis, and tissue necrosis—have also been shown to be quite low, and these risks are likely further decreased with the use of current techniques.The time courses for both local recurrence and treatment complications are long, so long-term follow-up is needed to assess efficacy and safety. There is now extensive long-term experience worldwide using WBI.
Contemporary WBI begins with CT-based planning. Patients are typically treated supine with arms above the head. Other positions, such as prone or lateral decubitus, can be useful for patients with large or pendulous breasts. Left-sided tumors can be treated using a heart block or breath-holding techniques to avoid direct heart irradiation, but significant patient cooperation and special in-room patient-position monitoring are required for the breath-hold technique.
WBI is usually delivered via tangent fields using high-energy x-rays. Forward planning techniques allow addition of sub-fields to optimize dose homogeneity; intensity-modulated radiotherapy (IMRT) is typically not required. Standard tangent fields cover a substantial percentage of level I and II axillary nodes. “High tangent” techniques can be used to treat a greater percentage of the axilla. Treatments are delivered daily to the entire breast in 1.8- to 2-Gy fractions, with total whole-breast doses of 45 to 50 Gy. Two large randomized trials have investigated the impact of a 10 or 16 Gy boost dose to the primary site following BCS and WBI, and both showed that addition of a boost significantly decreased local recurrence rates (from 10.2% to 6.2% at 10 years in the EORTC [European Organisation for Research and Treatment of Cancer] trial and from 4.5% to 3.6% at 5 years in the Lyon trial).[12,13] Provider-assessed rates of fibrosis and telangiectasias were increased with addition of a boost, but patient-reported cosmetic outcomes did not differ.
Accelerated Whole-Breast Irradiation (AWBI)
Conventional WBI is typically delivered over a period of about 5 weeks. Recently, there has been increased interest in accelerated courses of WBI. Accelerated whole breast irradiation (AWBI) shortens the length of the treatment course and has become more feasible due to two major developments: technical improvements in the delivery of breast irradiation that result in a much higher level of dose homogeneity, and a better understanding of the biologic equivalence of accelerated and conventional dose schedules.
Several large randomized trials have investigated AWBI in the treatment of early breast cancer (Table 1).[15-18] In each of these trials, hypofractionated schedules were compared against conventional WBI of 50 Gy in 2-Gy daily fractions. Doses in the experimental arms varied from 39 Gy in 13 fractions in the UK Royal Marsden Hospital/Gloucestershire Oncology Centre (RMH/GOC) and UK Standardisation of Breast Radiotherapy (START) Trial A trials, to 42.5 Gy in 16 fractions in the Canadian trial. No significant differences in overall local control rates between conventional and hypofractionated arms were noted in any trial. Given its large size and long follow-up, the Canadian trial in particular has been widely considered to be practice-changing. In an exploratory subset analysis, women with grade 3 tumors had a 15.6% rate of IBTR in the hypofractionated arm of the Canadian trial vs 4.7% in the conventional fractionation arm (P = .01). This difference was not seen in a large retrospective patient population. Additional data and longer follow-up will be needed to determine whether any patient or tumor factors are associated with increased risk of IBTR following AWBI compared with conventional WBI.
The cosmetic implications of AWBI were also assessed in these trials and were quite favorable. Late breast changes were not significantly different between conventional and hypofractionated arms. Provider- and patient-assessed adverse cosmetic outcomes were significantly higher with 50 Gy than 39 Gy (P = .01) in START A, and significantly higher with 50 Gy than 40 Gy (P = .02) in START B. In a separate analysis, rates of other radiation-related adverse effects were lower for the 39-Gy regimen in START A and 40-Gy regimen in START B compared with the 50-Gy control arms. Continued follow-up will be needed to determine how long-term cosmetic effects and toxicity of AWBI compare with those of conventional WBI.
Based on the available data, a task force of the American Society for Radiation Oncology (ASTRO) has developed guidelines for the use of AWBI. The task force favored a dose schedule of 42.5 Gy in 16 fractions (“Canadian”) and its use in patients aged 50 years or older with pT1–2N0 cancer treated with BCS and not treated with adjuvant chemotherapy, where the dose homogeneity is within +/− 7% and the heart can be excluded from direct irradiation. There was no agreement on the use of a boost.
Additional follow-up data are being obtained on the first-generation AWBI trials, and multiple second-generation AWBI trials have already been launched. Trial designs vary, and various schedules of AWBI (with or without a sequential or concurrent boost) are being compared against conventional WBI or accelerated partial-breast irradiation (APBI). For example, the Radiation Therapy Oncology Group (RTOG) 10-05 trial is currently enrolling early-stage patients and randomizing them to conventional (or “Canadian” hypofractionation) WBI with a sequential boost or to AWBI with a concurrent boost. It is likely that the results of these trials will expand the accepted indications and dose schedules for AWBI.