Boost radiotherapy (RT) improves outcomes for patients with invasive breast cancer, but whether this is applicable to patients with pure ductal carcinoma in situ (DCIS) is unclear. This study examined outcomes from whole breast RT, with or without a boost, and the impact of different dose-fractionation schedules in a population-based cohort of women with pure DCIS treated with breast-conserving surgery (BCS).
Data was analyzed for 957 subjects diagnosed between 1985 and 1999. RT use was analyzed over time. Ten-year Kaplan-Meier local control (LC), breast cancer specific survival (BCSS), and overall survival (OS) were compared using the log-rank test. Cox regression modeling of LC was performed.
Median follow-up was 9.3 years. Of the patient cohort 475 (50%) had no RT (NoRT) after BCS, 338 (35%) had RT without a partial breast boost (RTNoB), and 144 (15%) had RT with boost (RT + B). Subjects with risk factors of local recurrence were more likely to receive RT. Subjects receiving adjuvant RT had a trend toward improved LC (15-year LC: NoRT 87%; RTNoB 94%; RT + B 91%; P = .065). Multivariable analysis showed that RT with or without a boost was significantly associated with improved LC (HR, 0.29 and 0.38, respectively, compared with NoRT, P = .025), with no difference associated with a boost or different dose-fractionation schedules.
Mammographic screening has led to a significant increase in the detection of ductal carcinoma in situ (DCIS).1 DCIS now comprises approximately 20%-30% of mammographically detected breast cancer cases.2, 3 Although DCIS has a high cure rate,3-10 insufficient local therapy may result in invasive recurrence and death from breast cancer.4, 11, 12
Breast-conserving surgery (BCS) followed by radiotherapy (RT) is an accepted management strategy for patients with DCIS.13, 14 RT has been shown by randomized controlled trials to decrease the risk of both invasive and in situ local recurrence by at least half,6, 10, 15, 16 but controversy over which, if any, patients can avoid RT after BCS remains.17, 18
With respect to optimal, whole breast RT dose and fractionation, all of the randomized trials showing benefit of RT in DCIS used RT prescriptions of 50 Gray (Gy) in 25 fractions.6, 10, 15, 16 Randomized trials involving patients with invasive breast cancer have shown that hypofractionated RT is equivalent to RT using standard fractionation, with respect to tumor control and cosmesis.19-21 Recent randomized trials have also shown that boost RT improves local control in younger patients with invasive breast cancer after BCS.22 The applicability of these RT fractionation and boost efficacy data in the setting of pure DCIS is unknown.
To address these controversies, the Trans Tasman Radiation Oncology Group (TROG) recently launched an international clinical trial randomizing patients to hypofractionated versus standard fractionated whole breast RT, plus or minus a partial breast boost in patients with pure DCIS. The results of this study will not be available for many years.
This is a report of a population-based study describing the use of and outcomes from whole breast RT, generally using hypofractionation, with or without a boost, in women with pure DCIS treated with BCS.
MATERIALS AND METHODS
The British Columbia Cancer Agency (BCCA) Breast Cancer Outcomes Unit database was used to identify all women diagnosed between January 1, 1985 and December 31, 1999 in British Columbia with pure DCIS treated with BCS. The BCCA is a provincial organization with 4 regional cancer centers (during the study era), which provides all RT and manages the budget for all antineoplastic systemic therapy for cancer patients diagnosed in British Columbia. The Breast Cancer Outcomes Unit prospectively collects demographic, prognostic, treatment, and outcomes information for all women diagnosed with breast cancer referred to the BCCA for consultation. Electronic data from the prospectively collected BCCA Breast Cancer Outcomes Unit database were supplemented by BCCA chart review.
Between January 1, 1985 and December, 31, 1999, 1642 women were diagnosed with pure DCIS after BCS (without a concomitant or previous invasive cancer of any site or contralateral DCIS) and referred to the British Columbia Cancer Agency (BCCA). Exclusion criteria were initial mastectomy (n = 542), RT given with a boost to supplement the whole breast dose of 45 Gy in 25 fractions (n = 15), and start of RT more than 20 weeks after BCS (n = 27). Patients referred to the BCCA after initial management, either at the time of recurrence or for follow-up, were also excluded (n = 101). The remaining 957 patients formed the cohort for this study.
Central pathology review at the BCCA was available by request of the treating oncologist. If not requested, pathology was reported by community pathologists or by pathologists at academic centers in Vancouver.
During the study era, the use of adjuvant RT, RT dose-fractionation, and a partial breast boost were at the discretion of the treating oncologist, although provincial guidelines were available and regularly updated by the province-wide Breast Tumor Group—all radiation oncologists, medical oncologists, and surgeons treating patients with breast cancer at the BCCA.23-26 At the start of the study era, RT was not routinely recommended for patients with DCIS. The NSABP B24 study opened in British Columbia in 1988, and women were recruited to that study. In the initial part of the study era, BCS was only advised if the disease was unifocal, without comedo-type DCIS, and the patient was suitable for follow-up (clinical exam and mammogram “easy to interpret”). Otherwise, patients were recommended to have mastectomy.
After the publication of the NSABP B17 study in 1993, adjuvant breast RT was recommended for patients with DCIS with tumors >1 cm in diameter, comedocarcinoma, or margins <5 mm who underwent BCS. Women with well-differentiated DCIS, <1 cm diameter and with margins >5 mm were generally managed by wide excision alone. Women with diffuse areas of DCIS (>5 cm or greater than or equal to one-fourth of the breast on mammogram) were recommended to have mastectomy. Tamoxifen was not recommended during the study era outside of available clinical trials. Toward the end of the study era, partial breast boost was generally recommended for women with close or positive margins.23-27
All patients who underwent adjuvant whole breast RT were treated via tangential fields using Co60 or 4-18 MV photon beams at a total dose 40-50 Gy in 15-25 daily fractions, with or without a boost to the surgical bed. Short fractionation was considered standard practice in British Columbia during the study era, with extended fractionation if the patient had noticeable postoperative edema, hematoma, infection, or larger breast size. Choice of fractionation was at the discretion and preference of the treating oncologist. For those receiving the hypofractionated regimen, the dose to the whole breast was usually prescribed as a modal dose: 44 Gy in 16 fractions to the whole breast (equivalent to a prescription of 42.5 Gy to a point at midseparation), two-thirds the distance between the skin and base of the tangent fields when using cobalt in a breast with 20 cm separation.28 Lung correction was usually used. Boost RT was delivered by direct en-face electron beam, using 9-16 MeV electron beams prescribed to dmax, all planned using a clinical mark-up.
Use and Outcomes Analysis
The proportion of patients receiving whole breast RT (with or without a boost) between January 1, 1985 and December 31, 1999 was determined for annual cohorts from date of diagnosis. The proportion undergoing axillary dissection and proportion with positive or close margins were also plotted over time. Radiotherapy doses to the whole breast and boost volume were summarized.
The cohort was analyzed according to 3 treatment groups: BCS alone without RT (NoRT) (n = 475), BCS plus adjuvant whole breast RT within 20 weeks of BCS without a boost (RTNoB) (n = 338), and BCS plus whole breast RT with a partial breast external-beam RT boost (RT + B) (n = 144). The cutoff of 20 weeks was used because of evidence from prior BCOU analyses, which showed that radiotherapy started more than 20 weeks after BCS was less effective among women with invasive breast cancer.29
The treatment groups were compared using Pearson chi-square and Fisher exact tests of homogeneity with respect to patient age at diagnosis (<50 years, 50-69, and >69); nuclear grade (1,2,3, unknown); tumor size (<1.5 cm, 1.5 -4.0 cm, >4.0 cm); the presence of comedocarcinoma (yes, no, unknown); surgical margin status (positive, close [<2mm], negative, unknown); use of re-excision (yes, no); axillary lymph node dissection (yes, no, unknown); use of tamoxifen (yes, no); and the total dose of RT (none, 1-45 Gy, >45 Gy). Total dose was used as a surrogate for the different fractionation schedules after initial analyses showed that almost all subjects treated using hypofractionated (>2 Gy/fraction) schedules received ≤45Gy, whereas all subjects who were treated with standard fractionation (1.8-2 Gy/fraction) received >45 Gy.
Local control (LC) was defined as the absence of recurrent disease in the ipsilateral breast. Patients were censored for the risk of local recurrence upon confirmation of a distant recurrence or death; however, subjects with a concurrent local recurrence and distant recurrence (ie, within 1 month) were counted as having had a local recurrence.
Kaplan-Meier (KM) LC, BCSS, and OS curves for the 3 treatment groups were compared using the log-rank test. Multivariable analysis of LC was performed using Cox proportional hazards regression modeling. Year of diagnosis (arranged to ensure adequate numbers in each group) was included in the model to address changes in the provincial management of DCIS patients during the era of this study. Wald test contrasts of the Cox model coefficients were computed to compare LC for subgroups: with versus without RT, RT with versus without partial breast boost, and with total whole breast RT dose (<45 Gy >45 Gy)vs. SPSS version 17.1 and R 2.8.1 were used for the calculations.
The study was approved by the University of British Columbia Research Ethics Board.
Of the 957 eligible subjects with pure DCIS referred to the BCCA at diagnosis, 50% received RT within 20 weeks of BCS. Among subjects receiving whole breast RT, 30% also received a boost.
Adjuvant RT use increased over time during the study period (Fig. 1). In 1985, none of the subjects received adjuvant RT; in 1999, approximately half of the women (52%) received adjuvant RT. Use of boost RT also increased over the study period. By 1999, 17% of the cohort receiving breast RT also received boost RT. The proportion of cases with positive or close surgical margins decreased significantly during the study period (Fig. 2). The use of axillary lymph node dissection decreased during the study period, from 50% at the start of the era to 9% at the end.
The use of hypofractionated RT was common. Most (77%) of the women who received adjuvant RT received 44 Gy in 16 fractions. The second most commonly used dose-fractionation scheme (17%) was 50 Gy in 25 fractions. Of those who received 45 Gy or less to the whole breast, 32% received boost RT. Of those who received more than 45 Gy to the whole breast, 16% received boost RT. Of the 144 women receiving boost RT, most (64%) received an additional 7.5 Gy given in 3 fractions.
Median follow-up for the entire cohort was 9.3 years. Table 1 compares patient, tumor, and treatment characteristics in the 3 defined treatment groups. Subjects receiving adjuvant radiotherapy (RTNoB and RT + B groups) had higher risk disease, including a larger proportion with grade 3 nuclei, larger tumor size, the presence of comedo histology, and close or involved surgical margins compared with subjects who did not receive RT (Table 1). Thirty-eight percent of the women in the RTNoB and 41% of the women in the RT + B group had Grade 3 tumors compared with 12% in the NoRT group (Pearson chi-square: P < .001). In the NoRT group, 72% of women had tumors less than 1.5 cm in size compared with approximately 50% in the RTNoB and RT + B groups. Comedocarcinoma was present in 25% of the NoRT group compared with 55% and 46% of the tumors in the RTNoB and RT + B groups, respectively. The majority of women (>60%) in all 3 groups had negative surgical margins. However, 29% of the RT + B group had positive surgical margins compared with 12% in the RTNoB group and 9% in the NoRT group (Pearson chi-square: P = .0001).
Table 1. Comparison of Patient, Tumor, and Treatment Characteristics
NoRT indicates breast-conserving surgery alone; RT No Boost, breast-conserving surgery plus whole breast radiotherapy; RT+Boost, breast-conserving surgery plus whole breast radiotherapy plus boost; RT, radiotherapy.
Pearson chi-square P values.
Age, y, median
1.5 cm-4 cm
Axillary node dissection
Total radiotherapy dose
There was a trend toward improved LC with RT compared with the NoRT group (10-yr LC; NoRT: 87%, RTNoB: 94%, and RT + B: 91%, log-rank: P = .065) (Table 2). BCSS did not differ statistically between the 3 groups. There were no breast cancer deaths in the RT + B group, 2 breast cancer deaths in the RTNoB group (0.6%), and 10 breast cancer deaths (2%) in the NoRT group. OS in the groups treated with RT was better than that compared with the NoRT group (log-rank: P = .013) (Table 2).
Table 2. Kaplan-Meier Local Control, Breast Cancer Specific Survival, and Overall Survival Rates for Treated Patients at 5 and 10 Years
LC indicates local control; BCSS, breast cancer specific survival; OS, overall survival; No RT, breast-conserving surgery alone; RT No Boost, breast-conserving surgery plus whole breast radiotherapy; RT + Boost, breast-conserving surgery plus whole breast radiotherapy plus boost.
The patterns of recurrence differed between the 3 groups. Of those with recurrences, one-half had invasive disease and one-half had recurrent DCIS in the NoRT and RTNoB groups compared with only one-quarter with invasive disease in the RT + B group.
Multivariable analysis showed that RT, with or without a boost, was independently associated with better LC (Table 3). Nevertheless, there was no significant difference in LC with different fractionation schemes, or use of the boost. Unknown, intermediate or high grade nuclei, comedo histology, re-excision, and close, positive, or unknown surgical margins were associated with an increased risk of local recurrence (Table 3). Age at diagnosis, use of tamoxifen, and tumor size were not significantly associated with risk of local recurrence. Despite the changes in provincial guidelines during the study era for managing patients with DCIS, year of diagnosis was also not significantly associated with the risk of local recurrence.
Table 3. Cox Regression Multivariate Analyses of Local Recurrence
Hazard ratio (HR) greater than 1 indicates a higher risk of local recurrence compared with control group; BCS only, breast-conserving surgery alone; RT no Boost, breast-conserving surgery plus whole breast radiotherapy; RT with boost, breast-conserving surgery plus whole breast radiotherapy plus boost.
RT ≤45 Gy, no Boost
RT >45 Gy, no Boost
RT ≤45 Gy, with Boost
RT >45 Gy with Boost
Wald tests for contrasts between coefficients confirmed that subjects treated with RT had significantly better LC (P = .0018). There was no significant difference in LC between those treated with RT with or without a boost (P = .30) and no difference between those treated with total whole breast RT dose <45 Gy versus >45 Gy (P = .98).
This study showed that adjuvant RT, with or without a boost, significantly improved LC among subjects with pure DCIS in a population-based cohort, with a similar degree of benefit as the randomized controlled trials.5, 6, 9, 30, 31 In this study, like others in the literature, there were very few subjects who died of breast cancer, regardless of treatment after BCS.5, 6, 9, 32, 33 The absolute difference in LC between subjects receiving RT or no RT was 6% (10-year KM LC was 93% with RT, 87% without RT; log-rank: P = .065); this was associated with a 1.7% absolute difference in 10-year BCSS (log-rank: P = .16). The ratio of local recurrence to deaths from breast cancer (1:3.5) is similar to the ratio of local recurrence to breast cancer deaths reported from randomized trials of patients with invasive breast cancer.34
This study showed that LC was similar whether boost RT was used and with both hypofractionated and standard dose-fractionation schedules. To date, only preliminary results from 1 small randomized trial (that examined the value of boost radiotherapy in patients with DCIS) have been published35; the abstract did not include results on the potential benefit of boost RT. An international, multi-institutional 4-arm randomized study originating from the TROG, in association with the Breast International Group and National Cancer Institute of Canada Clinical Trials Group, has recently opened, randomizing patients with pure DCIS to whole breast RT prescribed 50 Gy in 25 fractions or 42.5 Gy in 16 fractions, with or without a partial breast boost. Another trial randomizing patients with DCIS to 50 Gy to the whole breast RT, with or without a 16 Gy boost, has also been started in France.36 Results from these trials will not be available for several years.
Three randomized studies in patients with invasive breast cancer have shown a significant improvement in LC with boost radiotherapy after BCS, with the largest absolute impacts among patients of younger age22, 37, 38; it is not clear if these results are applicable to patients with DCIS. However,toxicity results from these trials, which would also apply to women with preinvasive cancer, have shown that boost radiotherapy was associated with higher rates of fibrosis, telangiectasia, and worse cosmetic outcome.
Several retrospective analyses have examined the effect of total radiotherapy dose or use of boost doses in patients with DCIS, using multivariable analyses.8, 39-42 These studies found no difference in local recurrence with total RT doses above or below 60Gy,42 or between doses <60 Gy, 60-66 Gy, or >66 Gy.11, 39, 40 Some of the patients in the series reported by Solin et al form part of the cohort for the current study. Vargas et al also found no benefit to a boost dose of 16 Gy, but did show that use of electron beam energy less than 9 MeV for the boost was associated with higher risk of local recurrence.8 Omlin et al used the Rare Cancer Network to specifically examine the benefit of boost RT in women with DCIS, aged 45 years or younger, and found RT significantly improved 10-year LC rates over BCS alone. Boost RT further improved 10-year LC rates over whole breast RT after BCS, with no difference in overall survival.41
In the current analysis, there was no significant improvement in LC or BCSS with the use of a boost after whole breast RT. This finding is in keeping with the other series (except for that reported by Omlin et al), but may pertain to the low event rates and small sample size of the group who received boost radiotherapy. As a partial breast boost was used primarily for subjects with positive or close margins, the finding that those in the RT + B arm had achieved a level of LC similar to the rest of the study cohort is reassuring. Additional boost radiotherapy may have compensated for the higher proportion of positive or close margins in that subgroup. There still may be benefit to a boost in patients with DCIS, as in invasive breast cancer, particularly in the subgroups with young age or close or positive margins.
The current study showed that there was no difference in outcomes for those treated with hypofractionated breast RT compared with those treated with RT using standard fractionation. While all randomized trials in subjects with DCIS have used whole breast doses of 50 Gy using 2 Gy fractions, randomized trials of subjects with invasive breast cancer found no difference in either cosmetic or cancer control outcomes for subjects treated with 50 Gy given in 25 fractions compared with 40 Gy in 15 fractions, 41.3 Gy in 13 fractions, or 42.5 Gy in 16 fractions.19-21 Radiobiologically, preliminary data suggest that the α/β ratio for invasive breast cancer for ipsilateral local tumor control is 4.1 Gy (95% CI, 1.0-9.7),43 which is similar to that for late normal tissue changes in the breast (3.6 Gy [95% CI, 1.8-5.4]).21, 43, 44 This would suggest a potential benefit to hypofractionation for breast cancer, as improvement in the therapeutic ratio would be expected to be small (comparing standard 2 Gy fraction with larger fraction sizes). The current study is the first to specifically report the effect of alternative fractionation in subjects with DCIS, and supports the belief that the patients with pure DCIS can be treated effectively with hypofractionated regimens. This hypothesis will be tested in the ongoing TROG randomized trial described earlier, but results will not be available for several years.
In keeping with multivariate analyses of factors affecting LC from randomized and retrospective series, this study confirmed that the presence of comedo histology, high nuclear grade, and close, positive, or unknown surgical margin status were associated with an increased risk of local recurrence.5, 10, 31 In contrast, this study found that neither overall tumor size nor young age was associated with increased risk of local recurrence. Re-excision was associated with a lower rate of LC, which likely represented the finding that those with higher risk tumors were more likely to proceed to re-excision.
A limitation of this study was that information on the mode of DCIS detection was not available. While results in the literature have differed,30, 41, 45-49 some have shown that mammographically detected DCIS carries better prognosis than DCIS diagnosed on the basis of a palpable mass, independent of other prognostic factors.5, 7, 50 As the study era progressed, mammographic detection became an increasingly common means of diagnosis, as the Screening Mammography Program of British Columbia was established and expanded.2
Another study limitation regarding boost efficacy is that the dose used (most commonly 7.5Gy in 3 fractions) was relatively low. Romestaing et al, however, showed that a dose of 10 Gy in 5 fractions significantly improved LC in subjects with invasive breast cancer in a randomized trial.38 Unlike patients with invasive disease, there remains little evidence that boost radiotherapy improves outcomes for patients with DCIS.
This large, population-based series of patients with DCIS treated in British Columbia with long-term follow-up has confirmed that adjuvant RT after BCS improves local control, with little change in survival. This study suggests that hypofractionation for DCIS is as effective as fractionation schedules using 2 Gy per fraction. Boost radiotherapy was associated with similar LC as whole breast RT alone, despite being used more frequently with higher risk disease.
CONFLICT OF INTEREST DISCLOSURES
This work was funded in part by operating grants from the Canadian Breast Cancer Foundation, BC/Yukon Chapter, and the Canadian Breast Cancer Research Alliance, DEX grant (No. 015701).